ABSTRACT
Anti-TNF antibodies are effective for treating patients with inflammatory bowel disease (IBD), but many patients fail to respond to anti-TNF therapy, highlighting the importance of TNF-independent disease. We previously demonstrated that acute deletion of two IBD susceptibility genes, A20 (Tnfaip3) and Abin-1 (Tnip1), in intestinal epithelial cells (IECs) sensitizes mice to both TNF-dependent and TNF-independent death. Here we show that TNF-independent IEC death after A20 and Abin-1 deletion is rescued by germ-free derivation or deletion of MyD88, while deletion of Trif provides only partial protection. Combined deletion of Ripk3 and Casp8, which inhibits both apoptotic and necroptotic death, completely protects against death after acute deletion of A20 and Abin-1 in IECs. A20 and Abin-1-deficient IECs are sensitized to TNF-independent, TNFR-1-mediated death in response to lymphotoxin alpha (LTα) homotrimers. Blockade of LTα in vivo reduces weight loss and improves survival when combined with partial deletion of MyD88. These data show that microbial signals, MyD88, and LTα all contribute to TNF-independent intestinal injury.
SUMMARY Here we show that germ-free derivation, MyD88 deletion, combined Ripk3 and Casp8 deletion, or anti-LTα, all reduce TNF-independent intestinal injury after A20 and Abin-1 deletion.
Competing Interest Statement
A.Marson is a compensated co-founder, member of the boards of directors, and a member of the scientific advisory boards of Spotlight Therapeutics and Arsenal Biosciences. A.Marson was a compensated member of the scientific advisory board at PACT Pharma and was a compensated advisor to Juno Therapeutics and Trizell. A.Marson owns stock in Arsenal Biosciences, Spotlight Therapeutics, and PACT Pharma. A.Marson has received fees from Merck and Vertex and is an investor in and informal advisor to Offline Ventures. The Marson lab has received research support from Juno Therapeutics, Epinomics, Sanofi, GlaxoSmithKline, Gilead, and Anthem. The Kattah lab receives research support from Eli Lilly. The authors have no additional financial interests.
Footnotes
↵* Co-first author