Epithelial TLR4 Signaling Activates DUOX2 to Induce Microbiota-Driven Tumorigenesis
Burgueño, Juan F. (University of Miami-Miller School of Medicine. Department of Medicine)
Fritsch, Julia (University of Miami-Miller School of Medicine. Department of Medicine)
González, Eddy E. (Universidad de Concepción Department of Pathophysiology. School of Biological Science)
Landau, Kevin S. (University of Miami-Miller School of Medicine. Department of Medicine)
Santander, Ana M. (University of Miami-Miller School of Medicine. Department of Medicine)
Fernández, Irina (University of Miami-Miller School of Medicine. Department of Medicine)
Hazime, Hajar (University of Miami-Miller School of Medicine. Department of Medicine)
Davies, Julie M. (University of Miami-Miller School of Medicine. Department of Medicine)
Santaolalla, Rebeca (University of Miami-Miller School of Medicine. Department of Medicine)
Phillips, Matthew C. (University of Miami-Miller School of Medicine. Department of Medicine)
Diaz, Sophia (University of Miami-Miller School of Medicine. Department of Medicine)
Dheer, Rishu (University of Miami-Miller School of Medicine. Department of Medicine)
Brito, Nivis (University of Miami-Miller School of Medicine. Department of Medicine)
Pignac-Kobinger, Judith (Department of Medicine. Division of Gastroenterology. University of Miami-Miller School of Medicine)
Fernandez, Ester (Universitat Autònoma de Barcelona. Departament de Biologia Cel·lular, de Fisiologia i d'Immunologia)
Conner, Gregory E. (University of Miami-Miller School of Medicine. Department of Cell Biology)
Abreu, Maria T. (Department of Microbiology and Immunology. University of Miami-Miller School of Medicine)

Data:	2021
Resum:	Background & Aims: Chronic colonic inflammation leads to dysplasia and cancer in patients with inflammatory bowel disease. We have described the critical role of innate immune signaling via Toll-like receptor 4 (TLR4) in the pathogenesis of dysplasia and cancer. In the current study, we interrogate the intersection of TLR4 signaling, epithelial redox activity, and the microbiota in colitis-associated neoplasia. Methods: Inflammatory bowel disease and colorectal cancer data sets were analyzed for expression of TLR4, dual oxidase 2 (DUOX2), and NADPH oxidase 1 (NOX1). Epithelial production of hydrogen peroxide (HO) was analyzed in murine colonic epithelial cells and colonoid cultures. Colorectal cancer models were carried out in villin-TLR4 mice, carrying a constitutively active form of TLR4, their littermates, and villin-TLR4 mice backcrossed to DUOXA-knockout mice. The role of the TLR4-shaped microbiota in tumor development was tested in wild-type germ-free mice. Results: Activation of epithelial TLR4 was associated with up-regulation of DUOX2 and NOX1 in inflammatory bowel disease and colorectal cancer. DUOX2 was exquisitely dependent on TLR4 signaling and mediated the production of epithelial HO. Epithelial HO was significantly increased in villin-TLR4 mice; TLR4-dependent tumorigenesis required the presence of DUOX2 and a microbiota. Mucosa-associated microbiota transferred from villin-TLR4 mice to wild-type germ-free mice caused increased HO production and tumorigenesis. Conclusions: Increased TLR4 signaling in colitis drives expression of DUOX2 and epithelial production of HO. The local milieu imprints the mucosal microbiota and imbues it with pathogenic properties demonstrated by enhanced epithelial reactive oxygen species and increased development of colitis-associated tumors. The inter-relationship between epithelial reactive oxygen species and tumor-promoting microbiota requires a 2-pronged strategy to reduce the risk of dysplasia in colitis patients.
Nota:	Altres ajuts: National Institute of Diabetes and Digestive and Kidney Diseases (R01DK099076), the Micky & Madeleine Arison Family Foundation Crohn's & Colitis Discovery Laboratory, and Martin Kalser Chair to Maria T. Abreu.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Ulcerative Colitis ; NADPH Oxidases ; Colitis-Associated Cancer ; Microbiome
Publicat a:	Gastroenterology, Vol. 160 Núm. 3 (february 2021) , p. 797-808.e6, ISSN 1528-0012

DOI: 10.1053/j.gastro.2020.10.031
PMID: 33127391

18 p, 4.9 MB

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