ICMI 2015

PS.5 Role of RIPK2 in protecting the intestinal epithelium from Caspase-8 mediated apoptosis

Thursday, July 16, 2015: 6:20 PM
Hall Maritim, Ground Floor (Maritim Hotel)
Dominique Bozec , Icahn School of Medicine at Mount Sinai, New York, NY
Stephanie Dahan , Mount Sinai Medical School, New York, NY, United States
Garabet Yeretssian , Icahn School of Medicine at Mount Sinai, New York, NY, United States
NOD1 and NOD2 are cytosolic innate immune sensors of bacteria. Downstream of NODs, RIPK2 is an essential adaptor that triggers NF-κB and MAPK signalling. Accumulating evidence emphasizes that dysregulation of NOD-RIPK2 immune axis in the intestine can lead to inflammatory bowel diseases. While NOD receptors were extensively studied for controlling innate immunity and intestinal homeostasis, the role of RIPK2 in preserving homeostasis and protecting from gut inflammation remains elusive. Here, we show that impairment of intestinal epithelial barrier integrity predisposes RIPK2-deficient mice to acute experimental colitis, resulting in increased intestinal epithelial cell (IEC) death, intestinal inflammation and mortality. Blockade of caspase activation rescued Ripk2-/- mice from colitis by promoting IEC proliferation and tissue repair, whereas RIPK3 ablation did not prevent excessive intestinal inflammation and tissue damage caused by RIPK2 deficiency. Colonocytes depleted of RIPK2 were highly sensitive to TNFα-induced apoptosis through engagement of caspase-dependent processes. Interestingly, RIPK2 negatively regulated apoptosis of colonocytes independently of NOD signalling. Moreover, macrophages from wild-type and Ripk2-/- mice were equally resistant to TNFα- or MDP-mediated cell death. Mechanistically, RIPK2 interacted with caspase-8 to activate NF-κB signalling in a kinase-independent manner, thereby contributing to apoptotic resistance and ensuring IEC survival. Thus, our results define a unique scaffolding property of RIPK2 in protecting IECs from caspase-8-mediated apoptosis and reveal the RIPK2-caspase-8 complex as a critical hub at the crossroad of apoptosis and innate immunity.