BACKGROUND: Inflammatory bowel disease (IBD) is characterized by a chronic inflammation of the gut, partly driven by defects in the innate immune system. Considering the central role of inflammasome signaling in innate immunity, we studied inflammasome components in IBD mucosa. METHODS: Expression of genes encoding inflammasome sensor subunits was investigated in colonic mucosal biopsies from 2 cohorts of patients with IBD and controls. RESULTS: A significant upregulation (>2-fold change in expression, false discovery rate <0.05) of the PYHIN inflammasomes AIM2 and IFI16 in active IBD versus controls was found. Also IFI16 was significantly increased in inactive IBD versus controls. Moreover, responders to anti-tumor necrosis factor therapy showed decreased expression of these inflammasomes although IFI16 remained significantly increased in responders showing endoscopic healing versus controls. AIM2 was mainly expressed in epithelial cells, whereas IFI16 was expressed in both lymphocytes and epithelial cells. Functional activation of predominant AIM2/IFI16-mediated inflammasomes in active IBD colon was shown by the presence of the downstream effectors CASP1 and HMGB-1 in inflamed mucosa. CONCLUSIONS: Our results highlight the importance of PYHIN inflammasome signaling in IBD and also link anti-tumor necrosis factor responsiveness to inflammasome signaling. Together, this points to the potential value of the inflammasome pathway as a new therapeutic target for IBD treatment.
BACKGROUND:Inflammatory bowel disease (IBD) is characterized by a chronic inflammation of the gut, partly driven by defects in the innate immune system. Considering the central role of inflammasome signaling in innate immunity, we studied inflammasome components in IBD mucosa. METHODS: Expression of genes encoding inflammasome sensor subunits was investigated in colonic mucosal biopsies from 2 cohorts of patients with IBD and controls. RESULTS: A significant upregulation (>2-fold change in expression, false discovery rate <0.05) of the PYHIN inflammasomes AIM2 and IFI16 in active IBD versus controls was found. Also IFI16 was significantly increased in inactive IBD versus controls. Moreover, responders to anti-tumor necrosis factor therapy showed decreased expression of these inflammasomes although IFI16 remained significantly increased in responders showing endoscopic healing versus controls. AIM2 was mainly expressed in epithelial cells, whereas IFI16 was expressed in both lymphocytes and epithelial cells. Functional activation of predominant AIM2/IFI16-mediated inflammasomes in active IBD colon was shown by the presence of the downstream effectors CASP1 and HMGB-1 in inflamed mucosa. CONCLUSIONS: Our results highlight the importance of PYHIN inflammasome signaling in IBD and also link anti-tumor necrosis factor responsiveness to inflammasome signaling. Together, this points to the potential value of the inflammasome pathway as a new therapeutic target for IBD treatment.
Authors: Gerard E Kaiko; Feidi Chen; Chin-Wen Lai; I-Ling Chiang; Jacqueline Perrigoue; Aleksandar Stojmirović; Katherine Li; Brian D Muegge; Umang Jain; Kelli L VanDussen; Bridie J Goggins; Simon Keely; Jessica Weaver; Paul S Foster; Daniel A Lawrence; Ta-Chiang Liu; Thaddeus S Stappenbeck Journal: Sci Transl Med Date: 2019-03-06 Impact factor: 17.956
Authors: Daniel B Graham; Guadalupe J Jasso; Amanda Mok; Gautam Goel; Aylwin C Y Ng; Raivo Kolde; Mukund Varma; John G Doench; David E Root; Clary B Clish; Steven A Carr; Ramnik J Xavier Journal: Cell Rep Date: 2018-07-24 Impact factor: 9.423
Authors: Jay V Patankar; Tanja M Müller; Srinivas Kantham; Miguel Gonzalez Acera; Fabrizio Mascia; Kristina Scheibe; Mousumi Mahapatro; Christina Heichler; Yuqiang Yu; Wei Li; Barbara Ruder; Claudia Günther; Moritz Leppkes; Mano J Mathew; Stefan Wirtz; Clemens Neufert; Anja A Kühl; Jay Paquette; Kevan Jacobson; Raja Atreya; Sebastian Zundler; Markus F Neurath; Robert N Young; Christoph Becker Journal: Nat Cell Biol Date: 2021-07-08 Impact factor: 28.824