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.

Levels of soluble TREM-1 in children with newly diagnosed type 1 diabetes and their siblings without type 1 diabetes: a Danish case-control study

“…We cannot rule out that intra‐islet expression of TREM‐1—on neutrophils and monocytes—fuels the autoimmune response against the β‐cells. In addition, the TREM‐1/DAP12 pathway has also been positively associated with rheumatoid arthritis (RA)—another autoimmune disease—and studies have suggested that sTREM‐1 may in fact function as a decoy receptor in terms of competing with TREM‐1 for ligand‐binding . Contrary to this hypothesis other studies on the role of sTREM‐1 in infections and sepsis indicate that sTREM‐1 increases TREM‐1 mRNA and thereby promotes inflammation .…”

“…In addition, the TREM-1/DAP12 pathway has also been positively associated with rheumatoid arthritis (RA)-another autoimmune disease-and studies have suggested that sTREM-1 may in fact function as a decoy receptor in terms of competing with TREM-1 for ligand-binding. 31,32 Contrary to this hypothesis other studies on the role of sTREM-1 in infections and sepsis indicate that sTREM-1 increases TREM-1 mRNA and thereby promotes inflammation. 14 Both findings could also be supported by our study.…”

Mediators of inflammation and bone remodeling in rheumatic disease

“…TREM1 is similar to TREM2 in that it also signals through DAP12; however, whereas TREM2 regulates osteoclast differentiation, TREM1 controls inflammation and induces secretion of pro-inflammatory cytokines from polymorphonuclear cells (PMNs) [81]. PMNs isolated from RA synovial fluid and blood express increased levels of TREM1 and DAP12 compared to healthy patients [82]. Furthermore, expression is significantly enhanced in healthy donor PMNs after 24-hour stimulation with TNF, IL-6, or IL-17.…”

GPR84 and TREM-1 Signaling Contribute to the Pathogenesis of Reflux Esophagitis

“…Soluble TREM-1 was shown to be elevated in serum and expressed on CD68 + macrophages in the intestinal lamina propria in patients with acute and chronic IBD (25,27). Recently, isolated PBMCs from primary specimens of patients with rheumatoid arthritis showed an increased expression of TREM-1, with a subsequent increased activation of ERK and MAP kinases, secretion of IL-8 and RANTES (28). This result further supports the relevance of our findings, which link TREM-1 to MAP kinase signaling, IL-8 and RANTES in "subchronic" inflammatory conditions.…”