Necroptosis of Intestinal Epithelial Cells Induces Type 3 Innate Lymphoid Cell-Dependent Lethal Ileitis

A short form of cellular FLICE-inhibitory protein encoded by CFLARs promotes necroptosis. While necroptosis is involved in various pathological conditions, the detailed mechanisms are not fully understood. Here we generated transgenic mice where CFLARs was integrated onto the X-chromosome. All male CFLARs Tg mice died perinatally due to severe ileitis. While necroptosis was observed in various tissues of CFLARs Tg mice, large numbers of intestinal epithelial cells (IECs) died by apoptosis. Deletion of Ripk3 or Mlkl, essential genes of necroptosis, prevented both necroptosis and apoptosis, and rescued lethality of CFLARs Tg mice. Type 3 innate lymphoid cell (ILC3)s were activated and recruited to the small intestine along with upregulation of Interleukin 22 (Il22) in CFLARs Tg mice. Deletion of ILC3s or Il22 rescued lethality of CFLARs Tg mice by preventing apoptosis, but not necroptosis of IECs. Together, these results reveal an unexpected role for ILC3s in connecting necroptosis and apoptosis.