SIGNR1-mediated phagocytosis, but not SIGNR1-mediated endocytosis or cell adhesion, suppresses LPS-induced secretion of IL-6 from murine macrophages.

C-type lectin receptors (CLRs) serve as phagocytosis receptors for pathogens and also function as adhesion molecules and in the recognition and endocytosis of glycosylated self-antigens. In the present study, we demonstrated that phagocytosis mediated by a mouse mannose-binding CLR, SIGNR1 significantly suppressed the LPS-induced secretion of the specific pro-inflammatory cytokines from the resident peritoneal macrophages and the mouse macrophage-like cells that express SIGNR1 (RAW-SIGNR1). LPS-induced secretion of IL-6 from peritoneal macrophages suppressed in response to uptake of oligomannose-coated liposomes (OMLs), and the suppression was partly inhibited by treatment with an anti-SIGNR1 antibody. LPS-induced secretion of IL-6 from RAW-SIGNR1 cells was also clearly inhibited by treatment of the cells with OMLs >0.4μm in diameter, but treatment with OMLs <0.4μm in diameter did not affect the IL-6 secretion. In contrast, LPS-induced TNF-α secretion from the cells was not affected on treatment of the cells with OMLs. Suppression of the IL-6 secretion was not observed following treatment with oligomannose-containing soluble polymers or when cells were bound to an oligomannose-coated solid phase. Phagocytosis of oligomannose-coated liposomes did not interfere with the transcription of IL-6 mRNA, but did affect IL-6 mRNA stability, leading to suppression of IL-6 secretion. Interestingly, treatment of the cells with Ly290042, a PI3 kinase inhibitor, partly blocked the suppression of LPS-induced secretion of IL-6 by OML. Thus, we conclude that SIGNR1-mediated phagocytosis but not SIGNR1-mediated endocytosis and cell adhesion, suppresses the TLR4-mediated production of specific proinflammatory cytokines via PI3 kinase signaling.

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