Induction of Systemic Autoimmunity by a Xenobiotic Requires Endosomal TLR Trafficking and Signaling from the Late Endosome and Endolysosome but Not Type I IFN

Funding Agencies|National Institutes of Health [ES007511, ES021464, ES022625, HL114408]
Type I IFN and nucleic acid-sensing TLRs are both strongly implicated in the pathogenesis of lupus, with most patients expressing IFN-induced genes in peripheral blood cells and with TLRs promoting type I IFNs and autoreactive B cells. About a third of systemic lupus erythematosus patients, however, lack the IFN signature, suggesting the possibility of type I IFN-independent mechanisms. In this study, we examined the role of type I IFN and TLR trafficking and signaling in xenobiotic systemic mercury-induced autoimmunity (HgIA). Strikingly, autoantibody production in HgIA was not dependent on the type I IFN receptor even in NZB mice that require type I IFN signaling for spontaneous disease, but was dependent on the endosomal TLR transporter UNC93B1 and the endosomal proton transporter, solute carrier family 15, member 4. HgIA also required the adaptor protein-3 complex, which transports TLRs from the early endosome to the late endolysosomal compartments. Examination of TLR signaling pathways implicated the canonical NF-kappa B pathway and the proinflammatory cytokine IL-6 in autoantibody production, but not IFN regulatory factor 7. These findings identify HgIA as a novel type I IFN-independent model of systemic autoimmunity and implicate TLR-mediated NF-kappa B proinflammatory signaling from the late endocytic pathway compartments in autoantibody generation.

Escalante, Gabriela M.Scripps Research Institute, CA 92037 USA (author)
Huang, HuaScripps Research Institute, CA 92037 USA (author)
Haraldsson, Katarina M.Scripps Research Institute, CA 92037 USA (author)
Hultman, PerLinköpings universitet,Avdelningen för neuro- och inflammationsvetenskap,Medicinska fakulteten,Region Östergötland, Klinisk patologi(Swepub:liu)perhu66 (author)
Christy, Joseph M.Scripps Research Institute, CA 92037 USA (author)
Pawar, Rahul D.Scripps Research Institute, CA 92037 USA (author)
Mayeux, Jessica M.Scripps Research Institute, CA 92037 USA (author)
Gonzalez-Quintial, RosanaScripps Research Institute, CA 92037 USA (author)
Baccala, RobertoScripps Research Institute, CA 92037 USA (author)
Beutler, BruceUniversity of Texas Southwestern Medical Centre Dallas, USA (author)
Theofilopoulos, Argyrios N.Scripps Research Institute, CA 92037 USA (author)
Kono, Dwight H.Scripps Research Institute, CA 92037 USA (author)
Scripps Research Institute, CA 92037 USAAvdelningen för neuro- och inflammationsvetenskap (creator_code:org_t)

In:Journal of Immunology: AMER ASSOC IMMUNOLOGISTS199:11, s. 3739-37470022-17671550-6606

By the author/editor: Pollard, K. Mich ...; Escalante, Gabri ...; Huang, Hua; Haraldsson, Kata ...; Hultman, Per; Christy, Joseph ...; show more...; Pawar, Rahul D.; Mayeux, Jessica ...; Gonzalez-Quintia ...; Baccala, Roberto; Beutler, Bruce; Theofilopoulos, ...; Kono, Dwight H.; show less...

About the subject

NATURAL SCIENCES: NATURAL SCIENCES; and Biological Scien ...; and Immunology

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