Excessive endosomal TLR signaling causes inflammatory disease in mice with defective SMCR8-WDR41-C9ORF72 complex function

Activation of Toll-like receptors by microbes or host-derived molecules triggers signaling that promotes inflammation and may contribute to the development of autoimmunity. Here we show that excessive signaling by the innate immune Toll-like receptors (TLRs) TLR3, TLR7, and TLR9 is causative for inflammatory disease in mice with mutations of Smcr8. The cellular mechanism for their hyperactivation is likely prolonged ligand-receptor contact in lysosomes and phagosomes, the trafficking of which is regulated by the SMCR8-WDR41-C9ORF72 complex in immune cells. We also show that Smcr8 and Wdr41 mutations sensitize mice to chemically induced colitis. Our findings reveal an important negative regulatory mechanism that limits endosomal TLR signaling and shed light on the mechanism by which deficiencies of C9ORF72 or SMCR8 cause inflammation.