Impact of SLC15A4, TASL and TASL2(Gm6377) deficiency on endolysosomal TLR7 and TLR9 responses
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PROVIDER: PRJNA1112874 | ENA |
REPOSITORIES: ENA
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Project description:Nucleic acid sensing by endolysosomal TLR7-9 results in the induction of antiviral and proinflammatory transcriptional responses. We recently identified TASL as the innate immune adaptor mediating TLR7-9-induced IRF5 activation via the interaction with SLC15A4, but its relevance in primary murine cells remained unexplored. Here we assessed the impact of deficiency in TASL and/or its previously uncharacterized paralogue Gm6377, named here TASL2, on endolysosomal TLR responses in primary bone-marrow-derived pDCs and splenic B cells. Double knockout TASLxTASL2 (TASLDKO) phenocopied the strong impairement observed in cells from SLC15A4-deficient feeble mice, while single TASL or TASL2 deficiency showed partial effect. Altogether, this study demonstrates that the SLC15A4-TASL/TASL2 complex play a critical role for TLR7-9-driven inflammatory responses.
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Project description:Endosomal Toll-like receptors (TLRs) play an important role in the etiology of systemic autoimmune diseases such as SLE, where DNA- and RNA-associated autoantigens activate autoreactive B cells through TLR9- and TLR7-dependent pathways, respectively. Nevertheless, TLR9-deficient autoimmune prone mice develop more severe clinical disease, while TLR7-deficient and TLR7/9-double deficient autoimmune-prone mice develop less severe disease. To determine whether the regulatory activity of TLR9 is B cell intrinsic, we have now directly compared the functional properties of autoantigen activated WT, TLR9-deficient and TLR7-deficient B cells, in an experimental system where proliferation depends on BCR/TLR co-engagement. In vitro, TLR9-deficient cells are less dependent on survival factors for a sustained proliferative response than either WT or TLR7-deficient cells. The TLR9-deficient cells also preferentially differentiate toward the plasma cell lineage, as indicated by expression of CD138, sustained expression of IRF4, and other molecular markers of plasma cells. In vivo, autoantigen-activated TLR9-deficient cells give rise to greater numbers of autoantibody producing cells. Our results identify distinct roles for TLR7 and TLR9 in the differentiation of autoreactive B cells that explain the capacity of TLR9 to limit, and TLR7 to promote, the clinical features of SLE.
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Project description:TLR3, TLR7, and TLR9 stimulation induces many mouse inflammatory and autoimmune cytokines or immune receptors DRGN were cultures 5 days prior to a 16 hour stimulation - Three separate studies were analyzed for inflammatory response
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