title: Inactivation of DAP12 in PMN inhibits TREM1-mediated activation in rheumatoid arthritis.
abstract: Rheumatoid arthritis (RA) is an autoimmune disease characterized by dysregulated and chronic systemic inflammatory responses that affect the synovium, bone, and cartilage causing damage to extra-articular tissue. Innate immunity is the first line of defense against invading pathogens and assists in the initiation of adaptive immune responses. Polymorphonuclear cells (PMNs), which include neutrophils, are the largest population of white blood cells in peripheral blood and functionally produce their inflammatory effect through phagocytosis, cytokine production and natural killer-like cytotoxic activity. TREM1 (triggering receptor expressed by myeloid cells) is an inflammatory receptor in PMNs that signals through the use of the intracellular activating adaptor DAP12 to induce downstream signaling. After TREM crosslinking, DAP12's tyrosines in its ITAM motif get phosphorylated inducing the recruitment of Syk tyrosine kinases and eventual activation of PI3 kinases and ERK signaling pathways. While both TREM1 and DAP12 have been shown to be important activators of RA pathogenesis, their activity in PMNs or the importance of DAP12 as a possible therapeutic target have not been shown. Here we corroborate, using primary RA specimens, that isolated PMNs have an increased proportion of both TREM1 and DAP12 compared to normal healthy control isolated PMNs both at the protein and gene expression levels. This increased expression is highly functional with increased activation of ERK and MAPKs, secretion of IL-8 and RANTES and cytotoxicity of target cells. Importantly, based on our hypothesis of an imbalance of activating and inhibitory signaling in the pathogenesis of RA we demonstrate that inhibition of the DAP12 signaling pathway inactivates these important inflammatory cells.
authors: Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, Florida, United States of America.
authors: Xianghong
authors: X
authors: Chen
authors: Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, Florida, United States of America.
authors: Erika A
authors: EA
authors: Eksioglu
authors: Department of Internal Medicine, Division of Rheumatology, University of South Florida College of Medicine, Tampa, Florida, United States of America.
authors: John D
authors: JD
authors: Carter
authors: Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, Florida, United States of America.
authors: Nicole
authors: N
authors: Fortenbery
authors: Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, Florida, United States of America.
authors: Sarah S
authors: SS
authors: Donatelli
authors: Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, Florida, United States of America.
authors: Junmin
authors: J
authors: Zhou
authors: Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, Florida, United States of America.
authors: Jinhong
authors: J
authors: Liu
authors: Department of Immunology, Tianjin Medical University Cancer Hospital and Research Institute, Tianjin, China.
authors: Lili
authors: L
authors: Yang
authors: Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, Florida, United States of America.
authors: Danielle
authors: D
authors: Gilvary
authors: Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, Florida, United States of America.
authors: Julie
authors: J
authors: Djeu
authors: Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, Florida, United States of America; Department of Immunology, Tianjin Medical University Cancer Hospital and Research Institute, Tianjin, China.
authors: Sheng
authors: S
authors: Wei
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000378:metabolism*; D016022:Case-Control Studies; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009504:Neutrophils / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D000073871:Triggering Receptor Expressed on Myeloid Cells-1
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D011971:Receptors, Immunologic; C408842:TREM1 protein, human; C110546:TYROBP protein, human; D000073871:Triggering Receptor Expressed on Myeloid Cells-1
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