Frontiers in Immunology (Jun 2021)

CLEC-2 Prevents Accumulation and Retention of Inflammatory Macrophages During Murine Peritonitis

  • Joshua H. Bourne,
  • Nonantzin Beristain-Covarrubias,
  • Malou Zuidscherwoude,
  • Malou Zuidscherwoude,
  • Joana Campos,
  • Ying Di,
  • Evelyn Garlick,
  • Evelyn Garlick,
  • Martina Colicchia,
  • Lauren V. Terry,
  • Steven G. Thomas,
  • Steven G. Thomas,
  • Alexander Brill,
  • Alexander Brill,
  • Jagadeesh Bayry,
  • Jagadeesh Bayry,
  • Steve P. Watson,
  • Steve P. Watson,
  • Julie Rayes,
  • Julie Rayes

DOI
https://doi.org/10.3389/fimmu.2021.693974
Journal volume & issue
Vol. 12

Abstract

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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.

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