DOI: 10.1111/jdv.16273 JEADV REVIEW ARTICLE The role of the interleukin-23/Th17 pathway in cardiometabolic comorbidity associated with psoriasis A. Egeberg,1,* P. Gisondi,2 J.M. Carrascosa,3 R.B. Warren,4 U. Mrowietz5 1 Department of Dermatology and Allergy, Gentofte Hospital, Hellerup, Denmark 2 Section of Dermatology and Venereology, University of Verona, Verona, Italy 3 Department of Dermatology, University Hospital Germans Trias i Pujol, Autonomous University of Barcelona (UAB), Badalona, Spain 4 Dermatology Centre, Salford Royal NHS Foundation Trust, Manchester NIHR Biomedical Research Centre, The University of Manchester, Manchester, UK 5 Psoriasis-Center at the Department of Dermatology, University Medical Center Schleswig-Holstein, Kiel, Germany *Correspondence: A. Egeberg. E-mail: alexander.egeberg@gmail.com Abstract Alterations in the innate and adaptive immunity underpin psoriasis pathophysiology, with the Th17 cells subset now recognized as the fundamental cells in the key controlling pathway involved in its pathogenesis. Since psoriasis is a systemic disease with important comorbidity, further knowledge on the interleukin (IL)-23/Th17 axis led to the hypothesis that there may be shared pathogenic pathways between primary skin disease and comorbidity. Psoriasis has been iden- tified as a risk factor for cardiovascular and metabolic disease, and increasing evidence gives support to this epidemio- logical observation from the clinical-pathologically field. As an example, increased levels of IL-23 and IL-23R have been found in human atherosclerotic plaque, and levels correlated with symptom duration and mortality. Also, upregulation of IL-23/IL-17 seems to play an important role in both myocardial damage and stroke, with interesting reports on deleteri- ous effect neutralization after administration of related anti-bodies in both associated conditions. In diabetic patients, increased levels of IL-23/IL-17 have also been observed and available data support a synergistic role of IL-23/IL-17 in b-cells damage. In obesity, signs of an expansion of Th17 subset in adipose tissue have been reported, as well as elevated concentrations of IL-23 in obese patients. In non-alcoholic fatty liver disease, closely related to metabolic syndrome, but also in other mentioned cardiometabolic disorders, a predominance of IL-23 and other related pro- inflammatory factors has been identified as participating in their pathogenesis. Thus, the involvement of the IL-23/Th17 axis in these shared psoriasis-cardiometabolic pathogenic mechanisms is reviewed and discussed in the light of the existing preclinical and clinical evidence, including that from comorbid psoriasis patients. Received: 8 October 2019; Accepted: 21 January 2020 Conflict of interest Dr. Carrascosa has received honoraria as consultant and/or speaker and/or consultant and/or participated as PI/SI from Pfizer, Eli Lilly, AbbVie, Almirall, Leo Pharma, Samsung Bioepis, Novartis, Celgene and Janssen Pharmaceuticals. Dr. Egeberg has received research funding from Pfizer, Eli Lilly, the Danish National Psoriasis Foundation, and the Kgl Hof- bundtmager Aage Bang Foundation, and honoraria as consultant and/or speaker from AbbVie, Almirall, Leo Pharma, Samsung Bioepis, Pfizer, Eli Lilly, Novartis, Galderma, Dermavant, UCB, Bristol-Myers Squibb, and Janssen Pharmaceu- ticals. Dr. Gisondi has received honoraria as consultant and/or speaker and/or consultant and/or participated as PI/SI from Pfizer, Eli Lilly, AbbVie, Almirall, Leo Pharma, Novartis, Celgene, UCB and Janssen Pharmaceuticals. Dr. Mrowietz has received honoraria, unrestricted educational grants, and has participated as investigator in clinical trials of products of the sponsor of this publication. Dr. Warren: Research Grants: AbbVie, Almirall, Amgen, Celgene, Janssen Pharmaceu- ticals, Eli Lilly, Leo Pharma, Novartis, Pfizer and UCB. Consulting Fees: AbbVie, Almirall, Amgen, Boehringer Ingelheim, Celgene, Janssen Pharmaceuticals, Leo Pharma, Eli Lilly, Novartis, Pfizer, Sanofi, Xenoport and UCB. Funding sources This publication was funded by Almirall R&D, Barcelona, Spain. JEADV 2020, 34, 1695–1706 © 2020 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. 1696 Egeberg et al. Introduction neutrophils, innate lymphoid cells (ILCs) and cd-T cells also Plaque psoriasis is a prevalent chronic, immune-mediated secrete IL-17A. IL-17A belongs to the IL-17 cytokine family inflammatory disease classically characterized by typical skin comprising five more isoforms (A–F), indeed IL-17A and IL-17F lesions. Comorbidity is commonly present in psoriasis patients, share similar functions.9,16,17 IL-17A is positioned as a link consistent with the systemic nature of the disease. Car- between innate and adaptive immunity; it acts as an early media- diometabolic disease accounts for a substantial proportion of tor of the immune response at mucosal surfaces, by inducing the this comorbidity to the point of psoriasis being considered an production of a variety of pro-inflammatory molecules from tis- independent risk factor for cardiovascular disease (CVD).1 Cur- sues and activated cells, which result in recruiting neutrophils to rent evidence points to the role of Th17 cells and interleukin-23 tissues.9,16 Interestingly, neutrophils can secrete IL-17 them- (IL-23) on this condition.1,2 Growing knowledge of its car- selves, acting as an amplifier and inducing the recruitment and diometabolic comorbidity suggests this pathway may be a link activation of additional neutrophils. Thus, neutrophils seem to between cutaneous and beyond-the-skin manifestations of have a role not only in acute but also in chronic inflammation.12 psoriasis. Unlike other subsets, Th17 cells do not depend on its effector Cytokines are core mediators enabling communication, regu- CK IL-17 for differentiation. Rather, combinations of IL-23 plus lation and coordination between immune cells. Cytokines, along IL-6, IL-1b and TGF-b are required for an efficient differentia- with antigens and antigen-presenting cells (APCs) existing in the tion of Th17 subset (Fig. 1).9 environment, are determinant for na€ıve CD4+ cells to differenti- Due to plasticity observed in CD4+ T cells, differentiation of ate in any of the known effector, memory or regulator subsets; Th17 in the presence of IL-23 leads to tissue inflammation in turn, the dominant cytokine profile secreted by each subset is because of IL-23-induced downregulation of IL-10 (involved in responsible for their functional role.3,4 Treg cells function). Conversely, differentiation and function of The Th17 subset was the third effector subset discovered as a Treg is mediated by TGF-b, but, in the presence of IL-6, Treg lineage of CD4+ T cells, along with the previously known Th1 differentiation is inhibited in favour of Th17 (Fig. 2).9 and Th2 subsets.5–7 In humans, Th17 cells play a role in the defence against extracellular bacteria and fungi8,9 and have a rec- The IL-23/Th17 axis in psoriasis ognized role in development and maintenance of autoimmune Prevalence of psoriasis is estimated between 1.5% and 5% in and chronic inflammatory diseases.5,10 Throughout the Th17 most developed countries; it affects approximately 125 million biologic cycle and function, a complex net of transcription people worldwide,1,18 plaque psoriasis being the most frequent factors and mediators are involved,8–10 among which IL-23 and form of the disease.19 Despite the primary cause of psoriasis IL-17A emerge as critical upstream and downstream CKs, being unknown, some genetic factors are acknowledged risk fac- respectively.8 tors for its development.20,21 Further, a dysregulated immune Interleukin-23 belongs to the IL-12 cytokine family, along response involving keratinocytes, vascular endothelial cells, with IL-12 and IL-27 (involved in Th1 differentiation), and Th17, Th1, Treg, cd-T cells, DCs, macrophages, neutrophils, IL-35 (involved in Treg differentiation and function). Dendritic mast cells and NK cells underlies the pathogenesis of cells (DCs), monocytes and macrophages (i.e. APCs) from acti- psoriasis.19,22,23 vated skin and mucosae are the main IL-23-secreting cells.11 The primary consideration of psoriasis as a Th1/Tc1-mediated Structurally, IL-23 is a heterodimer composed of a unique p19 disease19,24 was supported by efficacy of monoclonal antibodies subunit (IL-23p19) and a p40 subunit, common to IL-23 and targeting p40 subunit of IL-12, the cytokine considered crucial IL-12.12 IL-23 is essential in the enhancement of memory T cells, in the Th1 differentiation.25 However, IL-23 identification regulation of antibody production, induction of IFN-c and pro- almost two decades ago,12 together with the fact that IL-23 liferation of Th17 cells secreting IL-17 and IL-22, contributing shared with IL-12 the same p40 subunit, and the knowledge to immune response against infection, but also attributed a acquired on the pathway IL-23/Th17 have actually changed the pathogenic role in autoimmune diseases and cancer.8,11,13 IL-23 paradigm.2,19,22,26 is essential in Th17 differentiation because this CK is a strong When any factor acts as a trigger on genetically predisposed inducer of STAT3, which mediates signalling along with retinoic skin, the inflammatory cascade and a dysregulated interaction acid orphan receptor C2 [RORC2 (RORct in mice)].2,11 Mem- between innate and adaptive immune components and cells of ory T cells upon activation by TGF-b and IL-6, but not na€ıve T the skin are initiated. Stressed keratinocytes start an innate cells, express the IL-23 receptor, suggesting that IL-23 plays a immune response by producing antimicrobial peptides (AMPs), crucial role in Th17 expansion, survival and pathogenicity.5,7,14 ß-defensins, cytokines and chemokines. These molecules attract Interleukin-17A, along with IL-17F and IL-22 are the effector neutrophils to and activate resident mast cells in the skin, and it interleukins of Th17 cells.15 Although IL-17A is preferentially is predominantly these two types of cells that contain IL-17 in produced by Th17 cells, they are not its exclusive source; other psoriasis. Also, keratinocytes release self-DNA that forms com- cells, like monocytes, DCs, natural killer (NK) T cells, plexes with cytokines and AMPs, inducing activation of DCs JEADV 2020, 34, 1695–1706 © 2020 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology IL-23/Th17 and psoriasis comorbidities 1697 Th17 cell differentiation Th17 cell stabilization and amplification and maintenance Naïve APC T-cell DC IL-6 IL-1β IL-23p19 IL-23 IL-23p40 TGF-β IL-12Rβ1 IL-23 Receptor P P P P P P Tyk2 Jak2 P P IL-23 STAT3 STAT3 P P P STAT3 RORγT P IL-21 Nucleus Nucleus Differentiated Th17 cell STAT3 Th17 cell STAT3 P P P RORγT P STAT3 TNFγ IL-22 IL-17A-F IL-21 IL-12Rβ1 IL-23R Angiogenesis IL-23 Receptor Inflammation Immune cell recruitment Tissue damage Tissue remodeling Figure 1 Schematic representation of Th17 cells developmental mechanism, regulators involved and effector functions. which migrate into the lymph nodes.15,27 There, derived inflam- cells may lead them to switch to a non-classical phenotype matory milieu results in na€ıve T cells being exposed to specific (ex-Th17) producing IFN-c but having lost its IL-17 expression. patterns of cytokines inducing subset differentiation,28,29 thus These cells exhibit increased survival, and more active cytokine adding adaptive responses. Differentiated Th17 cells leave the production are resistant to suppressive action of Treg cells and nodes through the skin, where they produce IL-17.22,30 Some can elude treatments targeting IL-17.32 Thus, Th17 lineage cells subsets of these activated Th17 cells, as well as other types of T or key upstream mediators of their differentiation would need to cells, are programed to remain in the skin, so that populations be targeted instead. of autoreactive tissue-resident cells will persist and contribute to Activated Th17 cells induce the production of the pro- psoriasis pathology.31 inflammatory cytokines IL-17A-F, IL-22, IL-21 and TNF-a.2 The presence of TGF-b IL-6 and IL-1b induces initial differ- Effects of IL-17A are stimulation of neutrophils recruitment and entiation to Th17 cells and leads to upregulation of IL-23R activation, enhancement of angiogenesis, mediation of tissue expression (required for IL-23 signalling).7,8,29 Then, IL-23 remodelling, direct activation of keratinocytes and, synergisti- released by DCs and APCs can link its receptor, activating Th17 cally with TNF-a, enhancement of inflammation.22 IL-22 cells and contributing to their phenotype maintenance.2,22 induces keratinocyte hyperproliferation and AMPs secretion by Therefore, IL-23 plays a crucial role for expansion and survival keratinocytes, is involved in tissue remodelling and its levels of the Th17 subset.7 Its role might be even more critical in have been showed to correlate with psoriasis severity.33–35 IL-21 autoimmune inflammation considering that plasticity of Th17 participates in expression of IL-23R and RORct.36 TNF-a can JEADV 2020, 34, 1695–1706 © 2020 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology 1698 Egeberg et al. Treg Th17 Suppression on Host defense, T effector cells inflammation TGF-β TGF-β IL-6 IL-23 IL-10 IL-6 IL-17 TGF-β IL-21 IL-22 Retinoid acid IL-23R GM-CSF IL-2 Chemokines IL-25 IFNγ IL-4 IL-27 Treg Th17 IL-10 Treg Th17 Figure 2 Schematic representation of Treg and Th17 cells regulation, stimulator and inhibitor molecules involved in development and ultimate effector action of each pathway. increase IL-23 synthesis, which in turn enhances synthesis of classically believed and independent of IFN-c, and (ii) IL-17 as well as of IFN-c by memory T cells, eventually con- strengthen the predominant role of the IL-23/Th17 axis in the tributing to perpetuation of skin inflammatory process.7,13,22 current pathogenic model of psoriasis. Animal studies have demonstrated that IL-23, but not IL-12, intradermal injections induce a psoriasis-like disease in mice Psoriasis and cardiovascular diseases: what is the with elevated transcription of IL-23/Th17-related genes.37,38 Fur- place for the IL-23/Th17 axis? ther, a number of studies in psoriasis patients and healthy con- trols have shown increased levels of p40 and p19 subunits, but Overview not p35 subunit (the unique IL-12 subunit), and IFN-c in psori- Psoriasis is a disorder affecting, but not limited to, the skin. atic lesions, compared with adjacent non-lesioned or healthy Thus, cardiac, metabolic, gastrointestinal, pulmonary and kidney skin.39–41 These findings may suggest that most of the pro- disease, as well as malignancies, infections, or psychiatric disor- inflammatory role attributed to IL-12 would really arise from ders are associated conditions with variable incidence in psoria- IL-23. Histochemical studies also suggest that psoriatic ker- sis, which increase the disease burden and the mortality risk, atinocytes could contribute to skin inflammation by secreting particularly in severe psoriasis.1 sufficient IL-23 to amplify memory T-cell-produced IFN-c.39 Cardiovascular disease deserves special mention in psoriasis, Additionally, genetic studies have demonstrated associations as per results reported in large-scale epidemiological studies. between genes IL23A (encoding the IL-23p19 subunit), IL23B CVD constitutes the first or second cause of mortality (after (encoding the IL-12/23p40 subunit), and IL23R (encoding the malignancies) among psoriasis patients,44–46 and the risk is IL-23R subunit), but not IL12A (encoding the IL12p35 subunit), higher among severe patients.44,45 Duration has also been associ- and the presence of psoriasis.42 ated with CVD risk.1,47 In terms of excess mortality, CVD was Not only cytokines and related molecules increased in psori- attributed globally an excess rate of 1.44 (95% CI: 1.43–1.45) per atic lesions but the result of lacking them, have been investi- 1000 person-years;46 in absolute terms CVD is the main driver gated. Deficiency in p40 results in a great decrease in plaque of excess mortality in psoriasis.45 Consistent with these findings, formation and markers of inflammation, according to results psoriasis patients are at higher risk of cardiovascular events, in from animal studies. When the effect of lacking p35 or p19 sub- particular those with severe disease (RR to general population units was studied separately, results showed the development ranged 1.70–3.04; 1.38–1.59; and 1.37–1.39, for myocardial of more severe or milder inflammation, respectively, than infarction, stroke and CV mortality, respectively).48–50 These controls.43 data support the hypothesis of psoriasis as an independent factor All these findings highlight the divergent roles of IL-12 and for CV events. In this regard, severe psoriasis was found to con- IL-23 in psoriasis and consistently (i) point to the involvement fer an additional 6.2% absolute risk of a 10-year rate of CV of IL-12 in pro-inflammatory effects might be lower than events compared with the general population.51 Indeed, a study JEADV 2020, 34, 1695–1706 © 2020 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology IL-23/Th17 and psoriasis comorbidities 1699 showed that a high percentage of patients at low or intermediate plaque instability by both increasing macrophages and DCs sus- CV risk according to Framingham score must be reclassified as ceptibility to apoptosis and downregulating Bcl-2, which triggers intermediate and high risk, respectively, when psoriasis was Th1 and Th17 responses and releases ROS.63 In patients with added as a scoring factor.52 atherosclerosis, IL-23 and IL23R were increased in atheroscle- These epidemiological data are consistent with findings about rotic plaques, compared with non-affected vessels and higher abnormalities in lipid profiles of psoriasis patients. An abnormal levels of IL-23 that were observed in patients with more recent lipid pattern consisting of higher cholesterol concentrations in symptoms. Moreover, long-term outcomes showed an adjusted the very low-density lipoproteins (LDL) and high-density association between higher IL-23 plasma levels and mortality.64 lipoproteins (HDL) fractions as well as higher levels of Apo A1 Of note, blocking IL-12 by vaccination reduced atherogenesis; have been demonstrated at the onset of disease. This suggests however, involvement of IL-23 in the effect could not be distin- psoriasis predisposition to lipid abnormalities, and hypothesizes guished, because an anti-p40 antibody was used.65 a detrimental role of HDL-c and Apo A1 caused by oxidative The beneficial effect of antibody treatment on both skin and modifications.53 Of note, features of oxidative stress and impair- CV outcomes is a promising line of investigation already yield- ment of the antioxidant system have been evidenced in psoria- ing positive findings. As an example, antibodies targeting IL-12/ sis.54–56 Levels of lipoprotein(a) [Lp(a)] have been reported to 23p40, IL-23p19 and IL-17A/RA were administered to murine be increased in psoriasis and positively correlated with markers models of psoriasis developing CVD in response to systemic of oxidative stress and negatively with markers of antioxidant inflammation in a recent study. Treatment attenuated acanthosis activity.55,57 Significantly lower levels of HDL-c, and higher in correlation with lengthening time to occlusive thrombus for- levels of total cholesterol, LDL cholesterol and/or triglycerides mation (with similar results to those from wild-type controls), (TG) have been reported too.54,57 Both lipid abnormalities and supports a common pathogenic pathway for both conditions.66 oxidative stress have been suggested to act along with inflamma- tion in psoriasis to eventually induce atherosclerosis and increase Coronary artery disease the CVR in these patients.58,59 Coronary artery disease (CAD) has been showed to have higher Despite pathogenic links between psoriasis and CVD warrant- prevalence among psoriasis patients. Myocardial infarction (MI) ing further investigation, growing evidence shows the role of may be the first manifestation of CAD, and its risk may be chronic inflammation and immune dysfunction, so that both increased up to threefold, compared with non-psoriatic con- could share some dysregulated pathways, such as increased trols.67–69 Interestingly, higher prevalence of psoriasis among oxidative stress, monocyte and neutrophil modulation, endothe- CAD patients has also been reported.70 lial dysfunction and IL-23/Th17 signalling (Fig. 3).1 In line with Certain polymorphisms of the human gene IL-23 R have been this, it has been proposed that psoriasis and atherosclerosis associated with the risk and severity of atherosclerosis.71,72 Inves- would share immunological mechanisms involving IL-12/Th1 tigations on myocardial injury, hypertrophy and remodelling and IL-23/Th17 pathways, leading either to the plaque growth mechanisms are providing growing knowledge on the role of the promoted by TNF-a and IFN-c from differentiated Th1, or to Th17 pathway. In murine models of MI, Avalos  et al. found the plaque vulnerability caused by intraplaque angioneogenesis increased post-MI levels of IL-6, IL-23 and TGF-b mRNA in the and haemorrhage, promoted by Th17 effector CKs. Further, Th1 left ventricle. Surprisingly, levels of IL-17A mRNA were not and Th17 proliferation would be favoured by a decrease in Treg increased in the whole LV but only in the infarcted region, sug- number and function, with subsequent lower levels of TGF-b gesting a role in the ventricular remodelling after MI.73 and IL-10, both associated with anti-inflammatory and CV pro- Remodelling, responsible for ventricular dysfunction and tective effects.60 heart failure frequently developed after MI, is characterized by Several animal studies with either psoriasis or atherosclerosis dilation and fibrosis phenomena in the myocardium and related models have found the IL-23/Th17 axis to link psoriasis and vas- to immune response after myocardial damage.74–76 Several stud- cular damage and dysfunction. Studies with mice overexpressing ies addressing the potential role played by IL-23 have showed a IL-17A in keratinocytes and mimicking many hallmark skin fea- deleterious effect on MI models. Yan et al. demonstrated that tures of severe psoriasis in humans, have demonstrated that IL-23 rapidly increases after MI up to 3 days, whilst IL-23R and alterations of IL-17A and related downstream cytokines drove IL-17A upregulate progressively up to 7 days, and IL-17R not only cutaneous but vascular inflammatory changes remains elevated until 14 days. The deficiency of IL-23, IL-17A [increased reactive oxygen species (ROS) formation, oxidative and cdT cells resulted in a protective effect in mice, with higher stress, endothelial dysfunction, arterial hypertension and prema- survival after MI, less enlargement and less severe dysfunction of ture death].61,62 Evidence from upstream cytokines have been the LV, compared with wild-type controls. Thus, IL-23 from reported as well. In models of atherosclerosis, an increase in macrophages and neutrophils would act as an indispensable IL-23 secretion induced by the granulocyte-macrophage colo- upstream regulator of IL-17A, driving its production from cdT ny-stimulating factor (GM-CSF) has been shown to promote cells. Recruitment of cdT cells would also be favoured by IL-23, JEADV 2020, 34, 1695–1706 © 2020 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology 1700 Egeberg et al. Figure 3 Scheme of involvement of Th17/IL-23 axis in psoriasis and cardiometabolic diseases. CAD, coronary artery disease; CV, car- diovascular; CVR, cardiovascular risk; NAFLD, non-alcoholic fatty liver disease; NGF, nerve growth factor; PAD, peripheral artery disease; PAI-1, plasminogen activator inhibitor-1; TIA, transient ischaemic attack; VEGF, vascular endothelial growth factor.. Yellow: CV diseases. Green: Metabolic diseases. whilst IL-17A would promote neutrophil infiltration and fibrosis prospectively assess the potential benefit of biologic therapy in in myocardial tissue. These changes were evident from day 7 psoriasis-CVD patients. Nevertheless, the inflammatory hypoth- after MI, suggesting these mechanisms are crucial in remod- esis has been tested prospectively in two large randomized clini- elling.75 Additional studies with animal models of ischaemia/ cal trials involving around 25 000 CVD patients. The CANTOS reperfusion injury consistently showed increases of IL-23 in the study demonstrated the benefit of targeting IL-1b to reduce CV injured myocardium. IL-23 upregulation was also associated events,83 whilst the CIRT study did not find this positive with enlargement of infarct size, high levels of typical biomarkers effect.84 of myocardial damage (LDH and CK), pro-inflammatory responses (with increase of IL-17A, IL-6 and TNF-a releasing) Cerebrovascular disease and pro-apoptotic effects (higher apoptotic index and lower Bcl- As mentioned earlier, stroke is a major cardiovascular event with 2/Bax ratio). Through activation of JAK2/STAT3, IL-23 induces a higher incidence among psoriasis population.47–50 secretion of IL-17A, which eventually reinforces the inflamma- It is accepted that inflammation plays a crucial role within tory response and myocardial damage.77,78 Importantly, neutral- the complex pathophysiology of ischaemic stroke, particularly ization of IL-23 by administration of anti-IL-23p19 antibodies in exacerbation of brain damage. When ischaemia occurs, significantly reduced IL-17A levels and ischaemia/reperfusion activation of microglia may result in secretion of both pro- injury.77,79 inflammatory CKs (from M1 phenotype, characterized by The inflammatory hypothesis of atherothrombosis has been high expression of IL-23 and IL-12) and neuroprotective present in the medical and research community for the last mediators (from M2 phenotype, characterized by high expres- decade. In the field of rheumatology disease, this has led to sion of IL-10).85 Other cells, like macrophages, infiltrate the explore a potential cardioprotective effect of biologic treatments brain in the earlier phases of infarction, whilst neutrophils targeting these inflammation pathways in psoriasis patients.80–82 and lymphocytes join in later phases.86 Likewise, activated Despite results from these retrospective studies being consistent microglia is polarized to the M2 phenotype in the acute with the overlapping mechanisms underlying both psoriasis phase, switching to M1 later, mainly in the ischaemic penum- and CVD, no studies to date have been conducted to bra.85,87 IL-23 secreted from macrophages and DCs promotes JEADV 2020, 34, 1695–1706 © 2020 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology IL-23/Th17 and psoriasis comorbidities 1701 expansion of Th17 and cdT cells producing IL-17, contribut- It is accepted that inflammation underlies the pathogenesis of ing to post-stroke brain damage.88,89 hypertension, and activated immune cells are critical factors The importance of this pathway has been observed in sev- within this process.97–99 In particular, an involvement of IL-23/ eral studies, which have shown elevations of the IL-23/IL-17 IL-17 pathway has been evidenced in this field too. axis and IL-23R associated with worsening of neuron damage, T cells and macrophages accumulate in kidneys and perivas- compared with controls in animal stroke models.86,87,90 In cular space. DCs are potent activators of T cells, which are humans, increased levels of IL-23 along with a markedly polarized towards Th17 differentiation due to secretion of IL-6, increased proportion of IL-17A-producing cells and elevation TNF-a and IL-23 secretion and STAT3 phosphorylation and sig- of IL-17A levels, as well as other CKs, have been identified at nalling. IL-17A produced by activated Th17 happened to be crit- several time points after stroke in comparison with con- ical for vascular dysfunction and maintenance of trols.91,92 Moreover, a positive correlation was found between hypertension,99,100 and its production is increased in response to IL-23 levels and lesion volume.92 An increase of pro-inflam- angiotensin-II stimulus.101 It has been observed that increased matory mediators occurred simultaneously with a decrease in stretch of hypertensive arteries activates endothelium, releasing Treg cells and IL-10 levels,91 supporting the hypothesis of a IL-6, IL-23 and ROS whilst reducing nitric oxide (NO), and pro-inflammatory/anti-inflammatory imbalance as a mecha- favouring STAT3 activation.100 Studies have also showed that nism involved in stroke and brain damage. Results from a isoketals (or isolevuglandins, derived from free radical-mediated study in mice are in line with this hypothesis, since lipid peroxidation) accumulate in DCs in hypertension, promot- immunomodulation exerted by bone marrow stem cells ing cytokine production and being able to act as neoantigens reduced IL-23 and IL-17 levels in serum and peri-infarcted when adducted to proteins, activating DCs.98,99 These isoketal- area.86 modified proteins have been found to be elevated in circulating The effect of blocking IL-23/IL-17 has also been studied in monocytes and DCs from hypertensive patients.98 stroke models. Interestingly, IL-23 deficient animals showed sig- Since an imbalance between Th17 and Treg is thought to nificantly lower levels of cdT cells, subsequent lower secretion of underlie, at least in part, the pathophysiology of CV disorders, IL-17 and a decreased infarct size.90 Similar results were Liu et al.102 studied whether the use of common anti- obtained after inhibition of IL-12/IL-23p40 subunit.93 Specific hypertensive and hypolipemiant drugs might have any effect on suppression of IL-23p19 subunit resulted in lower levels of pro- this pathway. Patients treated with a combination of telmisartan inflammatory IL-23 and IL-17 concurrent with upregulation of and rosuvastatin showed synergistic decrease of serum pro- the Treg transcription factor FoxP3. Blocking of p19 subunit inflammatory components, including IL-23, Th17 cells and was, thus, associated with a less pronounced delayed phase of IL-17A, as well as increase of anti-inflammatory components, cerebral ischaemia and reduced infarction and neurological including Treg, FoxP3 and IL-10, and a reduction of carotid dysfunction.88 intima-media thickness by ultrasound.102 Peripheral artery disease Metabolic diseases and psoriasis: what is the Lower limbs peripheral arterial disease (PAD) is a common syn- place for the IL-23/Th17 axis? drome among the adult population, mostly caused by atherosclerosis. In psoriatic patients, a 98% higher risk of PAD Overview has been reported, compared with controls [OR: 1.98 (95% CI: Metabolic disorders are more prevalent among patients with 1.32–2.82)].94 psoriasis. Different meta-analyses found that psoriatic patients Despite the scarce literature addressing the role of inflamma- have 27% higher risk of diabetes (RR: 1.27; 95% CI, 1.16–1.40) tion in PAD, the potential involvement of IL-23 in this disease and more than twofold risk of metabolic syndrome (OR: 2.26; was assessed in a case-control study, which first showed a signifi- 95% CI, 1.70–3.01). Indeed, psoriasis may act a as risk factor cant increase of IL-23 levels in PAD patients compared with for difficult-to-control diabetes. Conversely, metabolic disor- controls.95 ders may act as a risk factor for psoriasis development.1 Also, obesity is more frequent among psoriatic patients (OR: 1.66; Hypertension 95% CI: 1.46–1.89) and may be a negative factor for systemic Data from epidemiological studies show that hypertension is treatment response.1 A relationship between psoriasis severity more prevalent among psoriasis patients [OR: 1.58 (95% CI: and obesity and metabolic syndrome has also been 1.42–1.76)], and prevalence is associated with psoriasis severity.1 observed.103,104 Non-alcoholic fatty liver disease (NAFLD), a Furthermore, psoriasis patients are prone to suffer difficult-to- disorder associated with metabolic syndrome, has also been control hypertension, being 16.5 times and 19.9 times more shown to have a prevalence that is clearly higher among the likely to require three- or four-drug treatment, respectively, than psoriatic population.105 Fig. 3 represents the relationship non-psoriatic hypertensive patients.96 between these diseases and psoriasis. JEADV 2020, 34, 1695–1706 © 2020 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology 1702 Egeberg et al. Obesity as well as increased total and intra-epithelial T-cell density. Obesity is a central feature associated with increased risk of Expression of IL-23, IFN-c, TGF-b and TNF-a were also related metabolic dysfunction, including insulin resistance, dia- increased both in lamina propria and epithelium, as were IL-17A betes, dyslipidaemia, hypertension and NAFLD, separately or levels, suggesting Th17 cells are expanded in obesity.111 together comprising metabolic syndrome.106,107 In individuals with body mass index (BMI) above 25 kg/m2, each 5 kg/m2 Non-alcoholic fatty liver disease increase has been associated with 30% increase in overall mortal- Non-alcoholic fatty liver disease develops through a process of ity, 40% increase in CV mortality and 60% increase in diabetic fat deposition on liver cells, in an alcohol consumption non- mortality.107 On the other hand, association between psoriasis dependent way. Mild forms of this disorder include steatosis, and obesity has been largely supported by evidence. Epidemio- whilst severe forms are characterized by cell damage and include logical studies point to the risk of psoriasis being increased in steatohepatitis, potentially progressing to cirrhosis. NAFLD is the obese population; further, the risk increases with increasing the leading cause of altered levels of hepatic enzymes in Western BMI.108,109 Obesity may negatively affect systemic treatment of countries, and considered as the hepatic manifestation of meta- psoriasis, including biologics; in psoriasis patients, a 12% (95% bolic syndrome. Prevalence of NAFLD is higher among patients CI: 1.01–1.24) increased risk of treatment interruption because with metabolic syndrome and those with obesity; a correlation of lack of effectiveness and a 17% (95% CI: 1.02–1.36) increased between obesity severity and prevalence of NAFLD have been risk of adverse event occurrence has been associated with each established.105,115 The indolent development and subsequent 5 kg/m2 increase in BMI.110 Conversely, improved treatment underdiagnosis of NAFLD contrast with the dramatic fact that responses have been observed in patients after weight loss, with its aggressive form is the second most common cause of liver improved outcomes in both clinical (PASI) and quality of life transplantation in the USA.116 (DLQI) variables.108 Non-alcoholic fatty liver disease is associated with psoriasis, It is accepted that a close relationship between obesity and with a higher frequency observed among these patients.105 chronic inflammation exists. Macrophages and T cells with pro- Gisondi et al. found NAFLD was present in 47% of patients with inflammatory effects accumulate in adipose tissue whilst anti- plaque psoriasis, compared with a frequency of 28% in matched inflammatory Treg cells are diminished.111 T cells can interact healthy controls. Some biomarkers (IL-6, adiponectin) and PASI with DCs, regulating inflammatory response; in turn, adipose score were higher in psoriasis patients with NAFLD than in tissue can secrete multiple molecules, including cytokines those without hepatic affectation.115 A later study found a simi- (adipokines) with effects on inflammation signalling and lar prevalence (44% vs. 26%). In this study, both patients and endothelial dysfunction.112,113 Interestingly, dysregulated levels controls presenting NAFLD were scored with the NAFLD fibro- of adipokines in psoriasis patients have been reported, suggest- sis score. Psoriatic patients obtained higher scoring and were at ing these molecules may be a link between inflammation, obe- higher risk of liver fibrosis than controls.117 sity, psoriasis and conditions improving CV risk.113 The IL-23/Th17 pathway and an imbalance between pro- and Due to the current consideration of obesity as a chronic low- anti-inflammatory signalling seem to play a role in NAFLD as inflammation state, a potential involvement of the IL-23 path- well. Imbalanced levels of Th17/Treg has been demonstrated in way in obesity has been investigated. In obese mice, an increased animal models. An increase in proportion of Th17 cells and level of DCs derived from adipose tissue (ATDCs) with an related cytokines IL-6, IL-23 and IL-17, and RORcs expression immature phenotype has been found infiltrating adipose tissue. along with a decrease in Treg cells and FoxP3 expression have These ATDCs secreted higher levels of IL-6, TGF-b and IL-23 been identified in murine models118 but also in humans,119 and than those DCs derived from spleen. Higher levels of IL-23p19 suggest a pro-inflammatory predominance involved in the and IL-12/IL-23p40 mRNA, but not IL-12p35, were also demon- pathogenesis of NAFLD. Likewise, an increase in Th17 cells and strated. These findings suggest ATDCs promote Th17 differenti- related gene expression was observed in specimens of human liv- ation in adipose tissue, mediated by IL-23 and other CKs. This ers affected with steatohepatitis.120 Some investigations using hypothesis was tested by administering anti-IL-6 or anti-IL-23 monoclonal antibodies and other agents with an inhibitory effect antibodies, resulting in a reduction of Th17 cells.112 Consistent on Th17 differentiation have resulted in a decrease of Th17 and results were observed in a study with obese women. Significantly pro-inflammatory molecules as well as reduced liver immune increased serum concentrations of IL-23, IL-17, as well as leptin cell infiltration, steatosis, and hepatic injury.119 and macrophage migration inhibition factor (MIF), were evi- denced, whilst IL-12 and IFN-c levels remained unchanged. No Insulin resistance and diabetes mellitus correlation between IL-17 or IL-23 levels and leptin and MIF Psoriasis patients are at higher risk of diabetes mellitus (DM), were observed, which support an IL-23-dependent increase of independently of other risk factors, and are more likely to IL-17 in obese patients.114 Another study showed that obese require pharmacological treatment for their diabetes mellitus. individuals0 intestine feature an increased jejunal mucosa surface Further, likelihood of insulin resistance and diabetic JEADV 2020, 34, 1695–1706 © 2020 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology IL-23/Th17 and psoriasis comorbidities 1703 complications increase with psoriasis severity.1 Psoriasis patients stage the standard-of-care for psoriasis comorbidity is essential have triple risk [HR: 3.02 (95% CI: 2.42; 3.63)] of dying because too and further evidence is needed to confirm or refute this sup- of endocrine, nutritional and metabolic disorders than controls, position. independently of DM contribution to CV mortality.121 A gen- ome-wide association study showed three different single-nucleo- Acknowledgements tide polymorphism, two of them located in the gene IL12B and 1 The authors would like to thank Esther Prieto, MD and Eva in the gene IL-23R, associated with between 2.7- and 5.9-fold Mateu, PhD of TFS S.L. for editorial assistance and writing sup- higher risk of developing DM2 in patients with psoriasis.122 port. RBW is supported by the Manchester NIHR Biomedical Immune cells, including T cells and DCs, are acknowledged to Research Centre. infiltrate pancreatic islets tissue, activating inflammatory and autoimmune responses in type 1 DM that eventually result in References 1 Takeshita J, Grewal S, Langan SM et al. Psoriasis and comorbid diseases: b-cells destruction.123 Evidence on IL-23 axis involvement has epidemiology. J Am Acad Dermatol 2017; 76: 377–390. been reported. In a preclinical study, it was observed that both 2 Toussirot E. The IL23/Th17 pathway as a therapeutic target in TGF-b + IL-6 and IL-23 + IL-6 can polarize na€ıve T cells to chronic inflammatory diseases. Inflamm Allergy Drug Targets 2012; IL-17-producing Th17. However, Th17 cells polarized in the 11: 159–168. 3 McInnes IB. Role of Cytokines in the Immune System. UpToDate Inc, presence of IL-23 secreted larger amounts of IL-17, IL-22 and Waltham, MA, 2015. URL http://www.uptodate.com (last accessed: 1 expressed more IL-23R on their surface, compared with those June 2018). polarized in the presence of TGF-b. When these cells were 4 Ballas ZK. T Helper Subsets: Differentiation and Role in Disease. UpTo- injected into non-obese diabetic mice, all animals developed dia- Date Inc., Waltham, MA, 2016. URL http://www.uptodate.com (last accessed: 1 June 2018). betes. On the contrary, TGF-b-polarized cells showed a Treg 5 Langrish CL, Chen Y, Blumenschein WM et al. IL-23 drives a patho- phenotype with significantly higher secretion of IL-10; interest- genic T cell population that induces autoimmune inflammation. J Exp ingly, these cells did not induce DM when injected into mice.124 Med 2005; 201: 233–240. This study suggest a diabetogenic potential for the IL-23/Th17 6 Dong C. Diversification of T-helper-cell lineages: finding the family root of IL-17-producing cells. Nat Rev Immunol 2006; 6: 329–333. axis and raises again the hypothesis of a Th17/Treg imbalance 7 McGeachy MJ, Cua DJ. The link between IL-23 and Th17 cell-mediated dependent on a predominant CK milieu. immune pathologies. Semin Immunol 2007; 19: 372–376. Consistent with animal investigations, the involvement of the 8 Wilson NJ, Boniface K, Chan JR et al. Development, cytokine profile and function of human interleukin 17-producing helper T cells. Nat IL-23/Th17 pathway in diabetic humans has also been reported. Immunol 2007; 8: 950–957. Fatima et al.125 found that IL-23 and IL-17A, among other pro- 9 Bettelli E, Korn T, Oukka M, Kuchroo VK. Induction and effector func- inflammatory cytokines were significantly upregulated in type 1 tions of T(H)17 cells. Nature 2008; 453: 1051–1057. diabetic patients, exhibiting a relationship with age and gly- 10 Louten J, Boniface K, de Waal Malefyt R. Development and function of TH17 cells in health and disease. J Allergy Clin Immunol 2009; 123: caemia and suggesting a synergistic interaction of IL-23, IL-17A 1004–1011. and TNF-a in b-cells damage. Similarly, a later study showed an 11 Behzadi P, Behzadi E, Ranjbar R. IL-12 family cytokines: general charac- age-dependent increase of IL-23 mRNA and augmented levels of teristics, pathogenic microorganisms, receptors, and signalling pathways. IL-17A and IL-22, among other CKs, in type 2 diabetic patients, Acta Microbiol Immunol Hung 2016; 63: 1–25. 12 Oppmann B, Lesley R, Blom B et al. Novel p19 protein engages IL- confirming a role in DM onset.126 12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity 2000; 13: 715–725. Conclusions 13 Tang C, Chen S, Qian H, Huang W. Interleukin-23: as a drug tar- The IL-23/Th17 axis has a prominent role in pathophysiology of get for autoimmune inflammatory diseases. Immunology 2012; 135: 112–124. psoriasis, in which the upregulation of this pathway, together 14 Stritesky GL, Yeh N, Kaplan MH. IL-23 promotes maintenance but not with other inflammatory cytokines (e.g. TNF and type I IFN), commitment to the Th17 lineage. J Immunol Baltim Md 1950 2008; 181: contributes to develop a ‘pro-inflammatory state’ in psoriasis 5948–5955. patients. A growing body of recent evidence suggests inflamma- 15 Prinz I, Sandrock I, Mrowietz U. Interleukin-17 cytokines: effectors and targets in psoriasis-A breakthrough in understanding and treatment. tion, through multiple mediators and pathways, is mechanisti- J Exp Med 2020; 217: e20191397. https://doi.org/10.1084/jem.20191397 cally involved in most of cardiac and metabolic chronic diseases, 16 Kolls JK, Linden A. Interleukin-17 family members and inflammation. including obesity and non-alcoholic fat liver, known common Immunity 2004; 21: 467–476. 17 Onishi RM, Gaffen SL. Interleukin-17 and its target genes: mecha- psoriasis associated conditions. Here, we have reviewed the evi- nisms of interleukin-17 function in disease. Immunology 2010; 129: dence on the IL-23/Th17 pathway and suggest its upregulation 311–321. (in addition to detrimental lifestyle) is a potential root of many 18 Parisi R, Symmons DPM, Griffiths CEM, Ashcroft DM. Identification cardiometabolic psoriasis comorbidity. This overlapping has also and Management of Psoriasis and Associated ComorbidiTy (IMPACT) project team. Global epidemiology of psoriasis: a systematic review of led to the hypothesis that highly specific monoclonal antibodies incidence and prevalence. J Invest Dermatol 2013; 133: 377–385. developed for systemic treatment of psoriasis might have an 19 Boehncke W-H. Etiology and pathogenesis of psoriasis. Rheum Dis Clin effect on the progression of its comorbidity, although at this North Am 2015; 41: 665–675. JEADV 2020, 34, 1695–1706 © 2020 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology 1704 Egeberg et al. 20 Prieto-Perez R, Cabaleiro T, Dauden E, Ochoa D, Roman M, Abad-San- 40 Lee E, Trepicchio WL, Oestreicher JL et al. Increased expression of inter- tos F. Genetics of psoriasis and pharmacogenetics of biological drugs. leukin 23 p19 and p40 in lesional skin of patients with psoriasis vulgaris. Autoimmune Dis 2013; 2013: 613086. J Exp Med 2004; 199: 125–130. 21 Ovejero-Benito MC, Mu~ noz-Aceituno E, Reolid A, Saiz-Rodrıguez M, 41 Chen X, Tan Z, Yue Q, Liu H, Liu Z, Li J. The expression of interleukin- Abad-Santos F, Dauden E. Pharmacogenetics and pharmacogenomics in 23 (p19/p40) and interleukin-12 (p35/p40) in psoriasis skin. J Huazhong moderate-to-severe psoriasis. Am J Clin Dermatol 2018; 19: 209–222. Univ Sci Technolog Med Sci 2006; 26: 750–752. 22 Puig L. The role of IL 23 in the treatment of psoriasis. Expert Rev Clin 42 Nair RP, Duffin KC, Helms C et al. Genome-wide scan reveals associa- Immunol 2017; 13: 525–534. tion of psoriasis with IL-23 and NF-kappaB pathways. Nat Genet 2009; 23 Cai Y, Shen X, Ding C et al. Pivotal role of dermal IL-17-producing cd 41: 199–204. T cells in skin inflammation. Immunity 2011; 35: 596–610. 43 Kulig P, Musiol S, Freiberger SN et al. IL-12 protects from psoriasiform 24 Austin LM, Ozawa M, Kikuchi T, Walters IB, Krueger JG. The majority skin inflammation. Nat Commun 2016; 7: 13466. of epidermal T cells in Psoriasis vulgaris lesions can produce type 1 44 Salahadeen E, Torp-Pedersen C, Gislason G, Hansen PR, Ahlehoff O. cytokines, interferon-gamma, interleukin-2, and tumor necrosis factor- Nationwide population-based study of cause-specific death rates in alpha, defining TC1 (cytotoxic T lymphocyte) and TH1 effector popula- patients with psoriasis. J Eur Acad Dermatol Venereol 2015; 29: tions: a type 1 differentiation bias is also measured in circulating blood 1002–1005. T cells in psoriatic patients. J Invest Dermatol 1999; 113: 752–759. 45 Svedbom A, Dalen J, Mamolo C et al. Increased cause-specific mortality 25 Leonardi CL, Kimball AB, Papp KA et al. Efficacy and safety of ustek- in patients with mild and severe psoriasis: a population-based Swedish inumab, a human interleukin-12/23 monoclonal antibody, in patients register study. Acta Derm Venereol 2015; 95: 809–815. with psoriasis: 76-week results from a randomised, double-blind, pla- 46 Lee M-S, Yeh Y-C, Chang Y-T, Lai M-S. All-cause and cause-specific cebo-controlled trial (PHOENIX 1). Lancet Lond Engl 2008; 371: mortality in patients with psoriasis in Taiwan: a Nationwide Population- 1665–1674. based Study. J Invest Dermatol 2017; 137: 1468–1473. 26 Nograles KE, Zaba LC, Guttman-Yassky E et al. Th17 cytokines inter- 47 Egeberg A, Skov L, Joshi AA et al. The relationship between duration of leukin (IL)-17 and IL-22 modulate distinct inflammatory and ker- psoriasis, vascular inflammation, and cardiovascular events. J Am Acad atinocyte-response pathways. Br J Dermatol 2008; 159: 1092–1102. Dermatol 2017; 77: 650–656.e3. 27 Ganguly D, Chamilos G, Lande R et al. Self-RNA-antimicrobial peptide 48 Armstrong EJ, Harskamp CT, Armstrong AW. Psoriasis and major complexes activate human dendritic cells through TLR7 and TLR8. J Exp adverse cardiovascular events: a systematic review and meta-analysis of Med 2009; 206: 1983–1994. observational studies. J Am Heart Assoc 2013; 2: e000062. 28 Aggarwal S, Ghilardi N, Xie M-H, de Sauvage FJ, Gurney AL. Inter- 49 Samarasekera EJ, Neilson JM, Warren RB, Parnham J, Smith CH. Inci- leukin-23 promotes a distinct CD4 T cell activation state characterized dence of cardiovascular disease in individuals with psoriasis: a systematic by the production of interleukin-17. J Biol Chem 2003; 278: 1910–1914. review and meta-analysis. J Invest Dermatol 2013; 133: 2340–2346. 29 Bettelli E, Carrier Y, Gao W et al. Reciprocal developmental pathways 50 Raaby L, Ahlehoff O, de Thurah A. Psoriasis and cardiovascular events: for the generation of pathogenic effector TH17 and regulatory T cells. updating the evidence. Arch Dermatol Res 2017; 309: 225–228. Nature 2006; 441: 235–238. 51 Mehta NN, Yu Y, Pinnelas R et al. Attributable risk estimate of severe 30 Keijsers RRMC, Joosten I, van Erp PEJ, Koenen HJPM, van de Kerkhof psoriasis on major cardiovascular events. Am J Med 2011; 124: 775. PCM. Cellular sources of IL-17 in psoriasis: a paradigm shift? Exp Der- e1–6. matol 2014; 23: 799–803. 52 Mehta NN, Krishnamoorthy P, Yu Y et al. The impact of psoriasis on 31 Clark RA. Resident memory T cells in human health and disease. Sci 10-year Framingham risk. J Am Acad Dermatol 2012; 67: 796–798. Transl Med 2015; 7: 269rv1. 53 Mallbris L, Granath F, Hamsten A, St ahle M. Psoriasis is associated with 32 Basdeo SA, Cluxton D, Sulaimani J et al. Ex-Th17 (Nonclassical Th1) lipid abnormalities at the onset of skin disease. J Am Acad Dermatol cells are functionally distinct from classical Th1 and Th17 cells and are 2006; 54: 614–621. not constrained by regulatory T cells. J Immunol Baltim Md 1950 2017; 54 Pietrzak A, Michalak-Stoma A, Chodorowska G, Szepietowski JC. Lipid 198: 2249–2259. disturbances in psoriasis: an update. Mediators Inflamm 2010; 2010: 33 Wolk K, Witte E, Wallace E et al. IL-22 regulates the expression of genes 535612. https://doi.org/10.1155/2010/535612 responsible for antimicrobial defense, cellular differentiation, and mobil- 55 Ferretti G, Bacchetti T, Campanati A, Simonetti O, Liberati G, Offidani ity in keratinocytes: a potential role in psoriasis. Eur J Immunol 2006; 36: A. Correlation between lipoprotein(a) and lipid peroxidation in psoria- 1309–1323. sis: role of the enzyme paraoxonase-1. Br J Dermatol 2012; 166: 204–207. 34 Liang SC, Tan X-Y, Luxenberg DP et al. Interleukin (IL)-22 and IL-17 56 Peluso I, Cavaliere A, Palmery M. Plasma total antioxidant capacity and are coexpressed by Th17 cells and cooperatively enhance expression of peroxidation biomarkers in psoriasis. J Biomed Sci 2016; 23: 52. antimicrobial peptides. J Exp Med 2006; 203: 2271–2279. 57 Pietrzak A, Kadzielewski J, Janowski K et al. Lipoprotein (a) in patients 35 Ekman A-K, Bivik Eding C, Rundquist I, Enerb€ack C. IL-17 and IL-22 with psoriasis: associations with lipid profiles and disease severity. Int J promote keratinocyte stemness in the germinative compartment in pso- Dermatol 2009; 48: 379–387. riasis. J Invest Dermatol 2019; 139: 1564–1573.e8. 58 Zhou Q, Mrowietz U, Rostami-Yazdi M. Oxidative stress in the patho- 36 Zhou L, Ivanov II, Spolski R et al. IL-6 programs T(H)-17 cell differenti- genesis of psoriasis. Free Radic Biol Med 2009; 47: 891–905. ation by promoting sequential engagement of the IL-21 and IL-23 path- 59 Asha K, Singal A, Sharma SB, Arora VK, Aggarwal A. Dyslipidaemia & ways. Nat Immunol 2007; 8: 967–974. oxidative stress in patients of psoriasis: emerging cardiovascular risk fac- 37 Chan JR, Blumenschein W, Murphy E et al. IL-23 stimulates epidermal tors. Indian J Med Res 2017; 146: 708–713. hyperplasia via TNF and IL-20R2-dependent mechanisms with implica- 60 Armstrong AW, Voyles SV, Armstrong EJ, Fuller EN, Rutledge JC. A tale tions for psoriasis pathogenesis. J Exp Med 2006; 203: 2577–2587. of two plaques: convergent mechanisms of T-cell-mediated inflamma- 38 Rizzo HL, Kagami S, Phillips KG, Kurtz SE, Jacques SL, Blauvelt A. IL- tion in psoriasis and atherosclerosis. Exp Dermatol 2011; 20: 544–549. 23-mediated psoriasis-like epidermal hyperplasia is dependent on IL- 61 Karbach S, Croxford AL, Oelze M et al. Interleukin 17 drives vascular 17A. J Immunol Baltim Md 1950 2011; 186: 1495–1502. inflammation, endothelial dysfunction, and arterial hypertension in pso- 39 Piskin G, Sylva-Steenland RMR, Bos JD, Teunissen MBM. In vitro and riasis-like skin disease. Arterioscler Thromb Vasc Biol 2014; 34: 2658– in situ expression of IL-23 by keratinocytes in healthy skin and psoriasis 2668. lesions: enhanced expression in psoriatic skin. J Immunol Baltim Md 62 Sch€ uler R, Brand A, Klebow S et al. Antagonization of IL-17A attenuates 1950 2006; 176: 1908–1915. skin inflammation and vascular dysfunction in mouse models of JEADV 2020, 34, 1695–1706 © 2020 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology IL-23/Th17 and psoriasis comorbidities 1705 psoriasis. J Invest Dermatol 2019; 139: 638–647. https://doi.org/10.1016/ 83 Ridker PM, Everett BM, Thuren T et al. Antiinflammatory therapy with j.jid.2018.09.021 canakinumab for atherosclerotic disease. N Engl J Med 2017; 377: 63 Subramanian M, Thorp E, Tabas I. Identification of a non-growth factor 1119–1131. role for GM-CSF in advanced atherosclerosis: promotion of macrophage 84 Ridker PM, Everett BM, Pradhan A et al. Low-dose methotrexate apoptosis and plaque necrosis through IL-23 signaling. Circ Res 2015; for the prevention of atherosclerotic events. N Engl J Med 2019; 116: e13–e24. 380: 752–762. 64 Abbas A, Gregersen I, Holm S et al. Interleukin 23 levels are increased in 85 Zhao S-C, Ma L-S, Chu Z-H, Xu H, Wu W-Q, Liu F. Regulation of carotid atherosclerosis: possible role for the interleukin 23/interleukin 17 microglial activation in stroke. Acta Pharmacol Sin 2017; 38: 445–458. axis. Stroke 2015; 46: 793–799. 86 Ma S, Zhong D, Chen H et al. The immunomodulatory effect of bone 65 Hauer AD, Uyttenhove C, de Vos P et al. Blockade of interleukin-12 marrow stromal cells (BMSCs) on interleukin (IL)-23/IL-17-mediated function by protein vaccination attenuates atherosclerosis. Circulation ischemic stroke in mice. J Neuroimmunol 2013; 257: 28–35. 2005; 112: 1054–1062. 87 Wang M, Zhong D, Zheng Y et al. Damage effect of interleukin (IL)-23 66 Li Y, Golden JB, Camhi MI et al. Protection from psoriasis-related on oxygen-glucose-deprived cells of the neurovascular unit via IL-23 thrombosis after inhibition of IL-23 or IL-17A. J Invest Dermatol 2018; receptor. Neuroscience 2015; 289: 406–416. 138: 310–315. 88 Zheng Y, Zhong D, Chen H et al. Pivotal role of cerebral interleukin-23 67 Furue M, Tsuji G, Chiba T, Kadono T. Cardiovascular and metabolic during immunologic injury in delayed cerebral ischemia in mice. Neuro- diseases comorbid with psoriasis: beyond the skin. Intern Med Tokyo Jpn science 2015; 290: 321–331. 2017; 56: 1613–1619. 89 Brait VH, Arumugam TV, Drummond GR, Sobey CG. Importance 68 Hjuler KF, B€ ottcher M, Vestergaard C et al. Increased prevalence of of T lymphocytes in brain injury, immunodeficiency, and recovery coronary artery disease in severe psoriasis and severe atopic dermatitis. after cerebral ischemia. J Cereb Blood Flow Metab 2012; 32: Am J Med 2015; 128: 1325–1334.e2. 598–611. 69 Mahiques-Santos L, Soriano-Navarro CJ, Perez-Pastor G, Tomas- 90 Gelderblom M, Gallizioli M, Ludewig P et al. IL-23 (Interleukin-23)- Cabedo G, Pitarch-Bort G, Valcuende-Cavero F. Psoriasis and producing conventional dendritic cells control the detrimental IL-17 (in- ischemic coronary artery disease. Actas Dermosifiliogr 2015; 106: terleukin-17) response in stroke. Stroke 2018; 49: 155–164. 112–116. 91 Hu Y, Zheng Y, Wu Y, Ni B, Shi S. Imbalance between IL-17A-produ- 70 Picard D, Benichou J, Sin C et al. Increased prevalence of psoriasis in cing cells and regulatory T cells during ischemic stroke. Mediators patients with coronary artery disease: results from a case-control study. Inflamm 2014; 2014: 813045. https://doi.org/10.1155/2014/813045 Br J Dermatol 2014; 171: 580–587. 92 Jiang C, Kong W, Wang Y et al. Changes in the cellular immune system 71 Zhang M, Cai Z-R, Zhang B et al. Functional polymorphisms in inter- and circulating inflammatory markers of stroke patients. Oncotarget leukin-23 receptor and susceptibility to coronary artery disease. DNA 2016; 8: 3553–3567. Cell Biol 2014; 33: 891–897. 93 Konoeda F, Shichita T, Yoshida H et al. Therapeutic effect of IL-12/23 72 Kave M, Shadman M, Alizadeh A, Samadi M. Analysis of the association and their signaling pathway blockade on brain ischemia model. Biochem between IL-23R rs11209026 polymorphism and incidence of atheroscle- Biophys Res Commun 2010; 402: 500–506. rosis. Int J Immunogenet 2015; 42: 341–345. 94 Prodanovich S, Kirsner RS, Kravetz JD, Ma F, Martinez L, Federman 73  Avalos AM, Apablaza FA, Quiroz M et al. IL-17A levels increase in the DG. Association of psoriasis with coronary artery, cerebrovascular, and infarcted region of the left ventricle in a rat model of myocardial infarc- peripheral vascular diseases and mortality. Arch Dermatol 2009; 145: tion. Biol Res 2012; 45: 193–200. 700–703. 74 Arslan F, de Kleijn DP, Pasterkamp G. Innate immune signaling in car- 95 David A, Saitta S, De Caridi G et al. Interleukin-23 serum levels in diac ischemia. Nat Rev Cardiol 2011; 8: 292–300. patients affected by peripheral arterial disease. Clin Biochem 2012; 45: 75 Yan X, Shichita T, Katsumata Y et al. Deleterious effect of the IL-23/IL- 275–278. 17A axis and cdT cells on left ventricular remodeling after myocardial 96 Armstrong AW, Lin SW, Chambers CJ, Sockolov ME, Chin DL. Psoria- infarction. J Am Heart Assoc 2012; 1: e004408. sis and hypertension severity: results from a case-control study. PLoS 76 Thygesen K, Alpert JS, Jaffe AS et al. Third universal definition of ONE 2011; 6: e18227. myocardial infarction. J Am Coll Cardiol 2012; 60: 1581–1598. 97 Coffman TM. Under pressure: the search for the essential mechanisms 77 Hu X, Ma R, Lu J et al. IL-23 promotes myocardial I/R injury by of hypertension. Nat Med 2011; 17: 1402–1409. increasing the inflammatory responses and oxidative stress reactions. 98 Kirabo A, Fontana V, de Faria APC et al. DC isoketal-modified proteins Cell Physiol Biochem 2016; 38: 2163–2172. activate T cells and promote hypertension. J Clin Invest 2014; 124: 4642– 78 Liao Y, Hu X, Guo X, Zhang B, Xu W, Jiang H. Promoting effects of IL- 4656. 23 on myocardial ischemia and reperfusion are associated with increased 99 Dixon KB, Davies SS, Kirabo A. Dendritic cells and isolevuglandins in expression of IL-17A and upregulation of the JAK2-STAT3 signaling immunity, inflammation, and hypertension. Am J Physiol Heart Circ pathway. Mol Med Rep 2017; 16: 9309–9316. Physiol 2017; 312: H368–H374. 79 Zhu H, Li J, Wang S, Liu K, Wang L, Huang L. Hmgb1-TLR4-IL-23-IL- 100 Loperena R, Van Beusecum JP, Itani HA et al. Hypertension and 17A axis promote ischemia-reperfusion injury in a cardiac transplanta- increased endothelial mechanical stretch promote monocyte differentia- tion model. Transplantation 2013; 95: 1448–1454. tion and activation: roles of STAT3, interleukin 6 and hydrogen perox- 80 Wu JJ, Poon K-YT, Channual JC, Shen AY-J. Association between ide. Cardiovasc Res 2018; 114: 1547–1563. tumor necrosis factor inhibitor therapy and myocardial infarction 101 Madhur MS, Lob HE, McCann LA et al. Interleukin 17 promotes angio- risk in patients with psoriasis. Arch Dermatol 2012; 148: tensin II-induced hypertension and vascular dysfunction. Hypertens Dal- 1244–1250. las Tex 1979 2010; 55: 500–507. 81 Ahlehoff O, Skov L, Gislason G et al. Cardiovascular disease event rates 102 Liu Z, Zhao Y, Wei F et al. Treatment with telmisartan/rosuvastatin in patients with severe psoriasis treated with systemic anti-inflammatory combination has a beneficial synergistic effect on ameliorating Th17/ drugs: a Danish real-world cohort study. J Intern Med 2013; 273: Treg functional imbalance in hypertensive patients with carotid 197–204. atherosclerosis. Atherosclerosis 2014; 233: 291–299. 82 Gulliver WP, Randell S, Gulliver S et al. Do biologics protect patients 103 Langan SM, Seminara NM, Shin DB et al. Prevalence of metabolic syn- with psoriasis from myocardial infarction? a retrospective cohort. drome in patients with psoriasis: a population-based study in the United J Cutan Med Surg 2016; 20: 536–541. Kingdom. J Invest Dermatol 2012; 132: 556–562. JEADV 2020, 34, 1695–1706 © 2020 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology 1706 Egeberg et al. 104 Singh S, Young P, Armstrong AW. Relationship between psoriasis and 116 Wong RJ, Aguilar M, Cheung R et al. Nonalcoholic steatohepatitis is the metabolic syndrome: a systematic review. G Ital Dermatol E Venereol second leading etiology of liver disease among adults awaiting liver 2016; 151: 663–677. transplantation in the United States. Gastroenterology 2015; 148: 547– 105 Carrascosa JM, Bonanad C, Dauden E, Botella R, Olveira-Martın A; en 555. nombre del Grupo de Trabajo en Inflamaci on Sistemica en Psoriasis. 117 Gisondi P, Barba E, Girolomoni G. Non-alcoholic fatty liver disease Psoriasis and nonalcoholic fatty liver disease. Actas Dermosifiliogr 2017; fibrosis score in patients with psoriasis. J Eur Acad Dermatol Venereol 108: 506–514. 2016; 30: 282–287. 106 Jung UJ, Choi M-S. Obesity and its metabolic complications: the role of 118 He B, Wu L, Xie W et al. The imbalance of Th17/Treg cells is involved adipokines and the relationship between obesity, inflammation, insulin in the progression of nonalcoholic fatty liver disease in mice. BMC resistance, dyslipidemia and nonalcoholic fatty liver disease. Int J Mol Sci Immunol 2017; 18: 33. 2014; 15: 6184–6223. 119 Paquissi FC. Immune imbalances in non-alcoholic fatty liver dis- 107 Upadhyay J, Farr O, Perakakis N, Ghaly W, Mantzoros C. Obesity as a ease: from general biomarkers and neutrophils to interleukin-17 disease. Med Clin North Am 2018; 102: 13–33. axis activation and new therapeutic targets. Front Immunol 2016; 108 Gisondi P, Del Giglio M, Girolomoni G. Considerations for systemic treat- 7: 490. ment of psoriasis in obese patients. Am J Clin Dermatol 2016; 17: 609–615. 120 Tang Y, Bian Z, Zhao L et al. Interleukin-17 exacerbates hepatic steatosis 109 Gisondi P, Del Giglio M, Di Francesco V, Zamboni M, Girolomoni G. and inflammation in non-alcoholic fatty liver disease. Clin Exp Immunol Weight loss improves the response of obese patients with moderate-to- 2011; 166: 281–290. severe chronic plaque psoriasis to low-dose cyclosporine therapy: a ran- 121 Skov L, Thomsen SF, Kristensen LE, Dodge R, Hedegaard MS, Kjellberg domized, controlled, investigator-blinded clinical trial. Am J Clin Nutr J. Cause-specific mortality in patients with psoriasis and psoriatic arthri- 2008; 88: 1242–1247. tis. Br J Dermatol 2018; 180: 100–107. 110 Carrascosa JM, Vilavella M, Garcia-Doval I et al. Body mass index in 122 Eirıs N, Gonzalez-Lara L, Santos-Juanes J, Queiro R, Coto E, Coto- patients with moderate-to-severe psoriasis in Spain and its impact as an Segura P. Genetic variation at IL12B, IL23R and IL23A is associated with independent risk factor for therapy withdrawal: results of the Biobada- psoriasis severity, psoriatic arthritis and type 2 diabetes mellitus. J Der- derm Registry. J Eur Acad Dermatol Venereol 2014; 28: 907–914. matol Sci 2014; 75: 167–172. 111 Monteiro-Sepulveda M, Touch S, Mendes-Sa C et al. Jejunal T cell 123 Lehuen A, Diana J, Zaccone P, Cooke A. Immune cell crosstalk in type 1 inflammation in human obesity correlates with decreased enterocyte diabetes. Nat Rev Immunol 2010; 10: 501–513. insulin signaling. Cell Metab 2015; 22: 113–124. 124 Bellemore SM, Nikoopour E, Schwartz JA, Krougly O, Lee-Chan E, 112 Chen Y, Tian J, Tian X et al. Adipose tissue dendritic cells enhances Singh B. Preventative role of interleukin-17 producing regulatory T inflammation by prompting the generation of Th17 cells. PLoS ONE helper type 17 (Treg 17) cells in type 1 diabetes in non-obese diabetic 2014; 9: e92450. mice. Clin Exp Immunol 2015; 182: 261–269. 113 Lynch M, Ahern T, Sweeney CM et al. Adipokines, psoriasis, systemic 125 Fatima N, Faisal SM, Zubair S et al. Role of Pro-inflammatory cytokines inflammation, and endothelial dysfunction. Int J Dermatol 2017; 56: and biochemical markers in the pathogenesis of Type 1 diabetes: correla- 1103–1118. tion with age and glycemic condition in diabetic human subjects. PLoS 114 Sumarac-Dumanovic M, Stevanovic D, Ljubic A et al. Increased activity ONE 2016; 11: e0161548. of interleukin-23/interleukin-17 proinflammatory axis in obese women. 126 Fatima N, Faisal SM, Zubair S, Siddiqui SS, Moin S, Owais M. Int J Obes 2005 2009; 33: 151–156. Emerging role of interleukins IL-23/IL-17 axis and biochemical 115 Gisondi P, Targher G, Zoppini G, Girolomoni G. Non-alcoholic fatty markers in the pathogenesis of Type 2 diabetes: association with age liver disease in patients with chronic plaque psoriasis. J Hepatol 2009; and gender in human subjects. Int J Biol Macromol 2017; 105: 51: 758–764. 1279–1288. JEADV 2020, 34, 1695–1706 © 2020 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology