Necroptosis of intestinal epithelial cells induces innate lymphoid cell-dependent lethal ileitis in preterm mice

CFLARs encodes short form of cellular FLICE-inhibitory protein that blocks apoptosis, but promotes necroptosis in vitro. Here, we generate transgenic mice expressing CFLARs on the X-chromosome, designated as XCFY or XCFX mice. All XCFY mice die perinatally due to severe ileitis, whereas XCFX mice appear to be normal and fertile. Intestinal epithelial cell (IEC)s of XCFY mice die by necroptosis that subsequently induces massive apoptosis of IECs. Deletion of Ripk3 or Mlkl that are essential for necroptosis rescues embryonic lethality of XCFY mice by preventing both apoptosis and necroptosis of IECs. Surprisingly, deletion of RORγt+ ILC3s or Il22 rescues embryonic lethality of CFLARs Tg mice by preventing apoptosis, but not necroptosis of IECs. Thus, necroptosis of IECs triggered by cFLIPs activates RORγt+ ILC3s, resulting in induction of lethal ileitis in preterm mice. To identify the gene expression profiles of RNAs from the intestines of WT mice and CFLARs Tg mice, we compared gene expression of the intestines of WT mice and CFLARs Tg mice by microarray.