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

• Published in: The Journal of immunology (1950) Vol. 199; no. 11; pp. 3739 - 3747
• Main Authors: Pollard, K Michael, Escalante, Gabriela M, Huang, Hua, Haraldsson, Katarina M, Hultman, Per, Christy, Joseph M, Pawar, Rahul D, Mayeux, Jessica M, Gonzalez-Quintial, Rosana, Baccala, Roberto, Beutler, Bruce, Theofilopoulos, Argyrios N, Kono, Dwight H
• Format: Journal Article
• Language: English
• Published: United States American Association of Immunologists 01.12.2017
• Subjects: Animals; Autoantibodies; Autoantibodies - metabolism; Autoimmune diseases; Autoimmune Diseases - chemically induced; Autoimmune Diseases - immunology; Autoimmunity; Blood cells; Cells, Cultured; Compartments; Endosomes - metabolism; Female; Humans; Inflammation; Interferon; Interferon Type I - metabolism; Interleukin 6; Interleukin-6 - genetics; Interleukin-6 - metabolism; Lupus; Lupus Erythematosus, Systemic - immunology; Lymphocytes B; Lysosomes - metabolism; Male; Membrane Transport Proteins - genetics; Membrane Transport Proteins - metabolism; Mercury; Mice; Mice, Inbred C57BL; Mice, Inbred NZB; Mice, Knockout; NF-kappa B - genetics; NF-kappa B - metabolism; NF-κB protein; Nucleic acids; Pathogenesis; Peripheral blood; Protein Transport; Receptor, Interferon alpha-beta - genetics; Rodents; Signal Transduction; Systemic lupus erythematosus; Toll-Like Receptors - genetics; Toll-Like Receptors - metabolism; Xenobiotics
• ISSN: 0022-1767; 1550-6606; 1550-6606
• DOI: 10.4049/jimmunol.1700332

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-κB 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-κB proinflammatory signaling from the late endocytic pathway compartments in autoantibody generation.