The Deubiquitinating Enzyme OTUD5 Sustains Inflammatory Cytokine Response in Inflammatory Bowel Disease

• Published in: Journal of Crohn's and colitis 2022-01, Vol.16 (1), p.122-132
• Main Authors: Dinallo, Vincenzo, Di Fusco, Davide, Di Grazia, Antonio, Laudisi, Federica, Troncone, Edoardo, Di Maggio, Giulia, Franzè, Eleonora, Marafini, Irene, Colantoni, Alfredo, Ortenzi, Angela, Stolfi, Carmine, Di Daniele, Nicola, Monteleone, Ivan, Monteleone, Giovanni
• Format: Article
• Language: English
• Subjects: Animals; Biopsy; Cytokines - immunology; Endopeptidases - immunology; Female; Humans; Inflammatory Bowel Diseases - immunology; Male; Mice; Mice, Inbred BALB C; Ubiquitin-Specific Proteases - immunology
• ISSN: 1873-9946; 1876-4479
• DOI: 10.1093/ecco-jcc/jjab121

Abstract Background and Aims The inflammatory bowel disease [IBD]-associated immune response is marked by excessive production of a variety of inflammatory cytokines, which are supposed to sustain and amplify the pathological process. OTUD5 is a deubiquitinating enzyme, which regulates cytokine production by both innate and adaptive immune cells. Here, we investigated the expression and role of OTUD5 in IBD. Methods OTUD5 expression was evaluated in mucosal samples of patients with Crohn’s disease [CD], patients with ulcerative colitis [UC], and controls, as well as in mice with trinitrobenzene-sulphonic acid [TNBS]-induced colitis by real-time polymerase chain reaction, western blotting, immunohistochemistry, and immunofluorescence. Moreover, OTUD5 was assessed in lamina propria mononuclear cells [LPMC] stimulated with inflammatory cytokines. TNF-α, IL-6, and IL-10 were evaluated in LPMCs of IBD patients and in colitic mice transfected with a specific OTUD5 antisense oligonucleotide [AS]. Results OTUD5 protein, but not RNA, expression was increased in inflamed ileal and colonic mucosal samples of patients with CD and patients with UC as compared with controls. In IBD, OTUD5-expressing cells were abundant in both epithelial and lamina propria compartments, and non-CD3+, HLA-DR+ LPMC were one of the major sources of the protein. OTUD5 expression was enhanced by IFN-γ through a p38/MAPK-dependent mechanism, and the AS-induced knockdown of OTUD5 in LPMCs of IBD patients and colitic mice reduced TNF-α. Conclusions Our data show that OTUD5 is overexpressed in both CD and UC and suggest the involvement of such a protein in the amplification of the aberrant cytokine response in IBD.