Systemic lupus erythematosus (SLE) is an autoimmune syndrome typified by autoantibodies against DNA, chromatin, and RNA-associated proteins. Experimental evidence from our group and others suggests that RNA- and DNA-containing immune complexes isolated from SLE patients activates dendritic cells (DCs) through the nucleic acid sensors TLR7 and TLR9, respectively. Using a highly parallel shRNA pooled screening strategy; we identified several additional genes that positively regulate innate responses to stimulatory RNA and DNA complexes that contribute to SLE pathology. Here we show that triggering receptor expressed on myeloid cells like 4 (Treml4) regulates innate sensing of dsDNA and ssRNA in macrophages and DCs. To validate these findings we generated TREML4-deficient mice. We found that dsDNA or ssRNA stimulation of DCs isolated from TREML4-deficient mice produced significantly less IL-1 beta compared to wild-type DCs. We also observed lower caspase-1 and pro-inflammatory cytokines in Treml4 deficient DCs. In addition, AIM2 expression and function are significantly impaired in TREML4-deficient cells compared to wild-type cells. Our results suggest further study of this new signaling intermediate will give better insight into autoimmune diseases, such as SLE and may serve as a potential therapeutic target.
- Copyright © 2013 by The American Association of Immunologists, Inc.