Abstract
Platelets play a key role in the development, progression and resolution of the inflammatory response during sterile inflammation and infection, although the mechanism is not well understood. Here we show that platelet CLEC-2 reduces tissue inflammation by regulating inflammatory macrophage activation and trafficking from the inflamed tissues. The immune regulatory function of CLEC-2 depends on the expression of its ligand, podoplanin, upregulated on inflammatory macrophages and is independent of platelet activation and secretion. Mechanistically, platelet CLEC-2 and also recombinant CLEC-2-Fc accelerates actin rearrangement and macrophage migration by increasing the expression of podoplanin and CD44, and their interaction with the ERM proteins. During ongoing inflammation, induced by lipopolysaccharide, treatment with rCLEC-2-Fc induces the rapid emigration of peritoneal inflammatory macrophages to mesenteric lymph nodes, thus reducing the accumulation of inflammatory macrophages in the inflamed peritoneum. This is associated with a significant decrease in pro-inflammatory cytokine, TNF-α and an increase in levels of immunosuppressive, IL-10 in the peritoneum. Increased podoplanin expression and actin remodelling favour macrophage migration towards CCL21, a soluble ligand for podoplanin and chemoattractant secreted by lymph node lymphatic endothelial cells. Macrophage efflux to draining lymph nodes induces T cell priming. In conclusion, we show that platelet CLEC-2 reduces the inflammatory phenotype of macrophages and their accumulation, leading to diminished tissue inflammation. These immunomodulatory functions of CLEC-2 are a novel strategy to reduce tissue inflammation and could be therapeutically exploited through rCLEC-2-Fc, to limit the progression to chronic inflammation.
Highlights
Alongside their role in thrombosis and haemostasis, platelets are emerging as vital regulators of the inflammatory response under sterile and infectious conditions [1, 2]
Using bone marrow-derived macrophages (BMDM), we show that addition of wild type (WT), but not C-type lectin-like receptor 2 (CLEC-2)-deficient platelets (CLEC2-/-), to LPS-challenged BMDM delayed the uptake of pH-sensitive fluorescent E
We report that crosslinking podoplanin using recombinant CLEC-2-Fc limits the inflammatory environment by reducing inflammatory macrophage accumulation in the inflamed tissue and reduces their inflammatory phenotype
Summary
Alongside their role in thrombosis and haemostasis, platelets are emerging as vital regulators of the inflammatory response under sterile and infectious conditions [1, 2]. Distinct platelet receptors are engaged in different vascular beds and differentially regulate vascular integrity, thrombosis and inflammation [3, 4]. Platelets are found in inflamed tissues, such as the lung and peritoneum, primarily in complexes with monocytes, neutrophils and macrophages [3, 9,10,11,12,13,14]. Among the receptors reported to regulate the inflammatory response, the adhesion receptors glycoprotein I (GPIb) and C-type lectin-like receptor 2 (CLEC-2) were shown to differentially regulate macrophage polarization and activation in the inflamed peritoneum, with distinct receptors engaged during the time course of the inflammatory response [10, 12, 13]. An increase in macrophage recruitment and activation, drives tissue inflammation observed in atherosclerosis and metabolic disorders, as well as non-resolved infection-driven inflammation [15]
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