Thalidomide Exerts Anti-Inflammatory Effects in Cutaneous Lupus by Inhibiting the IRF4/NF-ҡB and AMPK1/mTOR Pathways
Domingo Bover, Sandra (Vall d'Hebron Institut de Recerca (VHIR))
Solé Marcé, Cristina (Vall d'Hebron Institut de Recerca (VHIR))
Moliné, Teresa (Hospital Universitari Vall d'Hebron)
Ferrer, Berta (Hospital Universitari Vall d'Hebron)
Cortés Hernández, Josefina (Vall d'Hebron Institut de Recerca (VHIR))
Universitat Autònoma de Barcelona

Data:	2021
Resum:	Thalidomide is effective in patients with refractory cutaneous lupus erythematosus (CLE). However, the mechanism of action is not completely understood, and its use is limited by its potential, severe side-effects. Immune cell subset analysis in thalidomide's CLE responder patients showed a reduction of circulating and tissue cytotoxic T-cells with an increase of iNKT cells and a shift towards a Th2 response. We conducted an RNA-sequencing study using CLE skin biopsies performing a Therapeutic Performance Mapping System (TMPS) analysis in order to generate a predictive model of its mechanism of action and to identify new potential therapeutic targets. Integrating RNA-seq data, public databases, and literature, TMPS analysis generated mathematical models which predicted that thalidomide acts via two CRBN-CRL4A- (CRL4 CRBN) dependent pathways: IRF4/NF-ҡB and AMPK1/mTOR. Skin biopsies showed a significant reduction of IRF4 and mTOR in post-treatment samples by immunofluorescence. In vitro experiments confirmed the effect of thalidomide downregulating IRF4 in PBMCs and mTOR in keratinocytes, which converged in an NF-ҡB reduction that led to a resolution of the inflammatory lesion. These results emphasize the anti-inflammatory role of thalidomide in CLE treatment, providing novel molecular targets for the development of new therapies that could avoid thalidomide's side effects while maintaining its efficacy.
Ajuts:	Ministerio de Economía y Competitividad PI15/02145
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Cutaneous lupus ; Mechanism of action ; New therapy ; Thalidomide
Publicat a:	Biomedicines, Vol. 9 (december 2021) , ISSN 2227-9059

DOI: 10.3390/biomedicines9121857
PMID: 34944673

18 p, 4.2 MB

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