FADD prevents RIP3-mediated epithelial cell necrosis and chronic intestinal inflammation

Abstract

Intestinal immune homeostasis depends on a tightly regulated cross talk between commensal bacteria, mucosal immune cells and intestinal epithelial cells (IECs). Epithelial barrier disruption is considered to be a potential cause of inflammatory bowel disease; however, the mechanisms regulating intestinal epithelial integrity are poorly understood. Here we show that mice with IEC-specific knockout of FADD (FADD(IEC-KO)), an adaptor protein required for death-receptor-induced apoptosis, spontaneously developed epithelial cell necrosis, loss of Paneth cells, enteritis and severe erosive colitis. Genetic deficiency in RIP3, a critical regulator of programmed necrosis, prevented the development of spontaneous pathology in both the small intestine and colon of FADD(IEC-KO) mice, demonstrating that intestinal inflammation is triggered by RIP3-dependent death of FADD-deficient IECs. Epithelial-specific inhibition of CYLD, a deubiquitinase that regulates cellular necrosis, prevented colitis development in FADD(IEC-KO) but not in NEMO(IEC-KO) mice, showing that different mechanisms mediated death of colonic epithelial cells in these two models. In FADD(IEC-KO) mice, TNF deficiency ameliorated colon inflammation, whereas MYD88 deficiency and also elimination of the microbiota prevented colon inflammation, indicating that bacteria-mediated Toll-like-receptor signalling drives colitis by inducing the expression of TNF and other cytokines. However, neither CYLD, TNF or MYD88 deficiency nor elimination of the microbiota could prevent Paneth cell loss and enteritis in FADD(IEC-KO) mice, showing that different mechanisms drive RIP3-dependent necrosis of FADD-deficient IECs in the small and large bowel. Therefore, by inhibiting RIP3-mediated IEC necrosis, FADD preserves epithelial barrier integrity and antibacterial defence, maintains homeostasis and prevents chronic intestinal inflammation. Collectively, these results show that mechanisms preventing RIP3-mediated epithelial cell death are critical for the maintenance of intestinal homeostasis and indicate that programmed necrosis of IECs might be implicated in the pathogenesis of inflammatory bowel disease, in which Paneth cell and barrier defects are thought to contribute to intestinal inflammation.

Death receptor-independent FADD signalling triggers hepatitis and hepatocellular carcinoma in mice with liver parenchymal cell-specific NEMO knockout

“…However, the liver of 8-week-old NEMO LPC-KO /FADD LPC-KO mice displayed some focal necrotic lesions that were surrounded by granulocytes (Figure 1b), indicating that FADD ablation protected NEMO-deficient hepatocytes from apoptosis but triggered focal necrotic hepatocyte death resulting in mildly elevated serum ALT levels. Given the important role of FADD in preventing RIPK3-mediated necroptosis, [18][19][20] Figure S2D). In addition, immunostaining for cytokeratin 19 (CK19) revealed that FADD deficiency prevented oval cell expansion in NEMO LPC-KO / FADD LPC-KO mice (Supplementary Figure S2B).…”

TAK1 control of cell death

“…55,93 Similarly, epidermal-and intestinal epithelium-specific deletion of Fadd, which abrogates caspase-8 activation, causes inflammatory skin disease and IBD-like ileitis. 94,95 Although either Tak1 or Fadd/caspase-8 deletion causes cell death, the types of cell death are different. Tak1 deletion is associated with the activation of downstream caspase-3, 55,82 whereas deletion of caspase-8 induces necroptosis in vivo, which is rescued by deletion of Ripk3.…”

“…Tak1 deletion is associated with the activation of downstream caspase-3, 55,82 whereas deletion of caspase-8 induces necroptosis in vivo, which is rescued by deletion of Ripk3. 54,95,96 Why are the timing and features of tissue injury so similar in mice having deletion of Tak1 or …”

Distinct roles of RIP1–RIP3 hetero- and RIP3–RIP3 homo-interaction in mediating necroptosis

“…[5][6][7] Physiological function of necroptosis has been illustrated in host defense, [8][9][10][11] inflammation, [12][13][14][15][16] tissue injury, 10,17,18 and development. [19][20][21] Necroptosis can be induced by a number of different extracellular stimuli such as tumor necrosis factor (TNF).…”