title: Negative regulation of TLR signaling in myeloid cells--implications for autoimmune diseases.
abstract: Toll-like receptors (TLR) are transmembrane pattern recognition receptors that recognize microbial ligands and signal for production of inflammatory cytokines and type I interferon in macrophages and dendritic cells (DC). Whereas TLR-induced inflammatory mediators are required for pathogen clearance, many are toxic to the host and can cause pathological inflammation when over-produced. This is demonstrated by the role of TLR-induced cytokines in autoimmune diseases, such as rheumatoid arthritis, inflammatory bowel disease, and systemic lupus erythematosus. Because of the potent effects of TLR-induced cytokines, we have diverse mechanisms to dampen TLR signaling. Here, we highlight three pathways that participate in inhibition of TLR responses in macrophages and DC, and their implications in autoimmunity; A20, encoded by the TNFAIP3 gene, Lyp encoded by the PTPN22 gene, and the BCAP/PI3K pathway. We present new findings that Lyp promotes TLR responses in primary human monocytes and that the autoimmunity risk Lyp620W variant is more effective at promoting TLR-induced interleukin-6 than the non-risk Lyp620R protein. This suggests that Lyp serves to downregulate a TLR inhibitory pathway in monocytes, and we propose that Lyp inhibits the TREM2/DAP12 inhibitory pathway. Overall, these pathways demonstrate distinct mechanisms of negative regulation of TLR responses, and all impact autoimmune disease pathogenesis and treatment.
authors.affiliation: Immunology Program, Benaroya Research Institute at Virginia Mason, Seattle, WA, USA.|Department of Immunology, University of Washington, Seattle, WA, USA.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Hamerman
authors.affiliation: Immunology Program, Benaroya Research Institute at Virginia Mason, Seattle, WA, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Pottle
authors.affiliation: Immunology Program, Benaroya Research Institute at Virginia Mason, Seattle, WA, USA.
authors.forename: Minjian
authors.initials: M
authors.lastname: Ni
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Yantao
authors.initials: Y
authors.lastname: He
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Zhong-Yin
authors.initials: ZY
authors.lastname: Zhang
authors.affiliation: Translational Research Program, Benaroya Research Institute at Virginia Mason, Seattle, WA, USA.
authors.forename: Jane H
authors.initials: JH
authors.lastname: Buckner
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology*; D002352:Carrier Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology*; D006801:Humans; D056747:Immunomodulation; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000276:immunology*; D022423:Myeloid Cells / Q000276:immunology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000378:metabolism*; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; C520779:ODF2L protein, human; D051193:Toll-Like Receptors; C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3
keywords: Toll-like receptors; autoimmune disease; dendritic cells; macrophages; signal transduction