CLEC-2 promotes inflammatory peritoneal macrophage emigration to draining lymph nodes during endotoxemia

Bourne, J. H.; Beristain Covarrubias, N.; zuidscherwoude, M.; Campos, J.; Di, Y.; Garlick, E.; Colicchia, M.; Terry, L. V.; Thomas, S. G.; Brill, A.; Barry, J.; Watson, S. P.; Rayes, J.

doi:10.1101/2020.12.21.423770

bioRxiv · 10.1101/2020.12.21.423770

CLEC-2 promotes inflammatory peritoneal macrophage emigration to draining lymph nodes during endotoxemia

Bourne, J. H.·Beristain Covarrubias, N.·zuidscherwoude, M.·Campos, J.·Di, Y.·Garlick, E.·Colicchia, M.·Terry, L. V.·Thomas, S. G.·Brill, A.·Barry, J.·Watson, S. P.·Rayes, J.

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Abstract

Macrophage recruitment during sterile inflammation and infection is essential to clear pathogens, apoptotic cells and debris. However, persistent macrophage accumulation leads to chronic inflammation. Platelets are emerging as key modulators of the inflammatory response. Here, we identify that platelet C-type-lectin-like receptor-2 (CLEC-2) is a crucial immunomodulatory receptor through the interaction with podoplanin, upregulated on inflammatory macrophages. Mechanistically, platelet CLEC-2 upregulates the expression of podoplanin and its co-ligands CD44 and ERM proteins, leading to actin rearrangement and promotion of cell migration; this is mimicked by recombinant CLEC-2-Fc (rCLEC-2-Fc). Treatment of LPS-challenged mice with rCLEC-2-Fc induces a rapid emigration of peritoneal macrophages to mesenteric lymph nodes, through a gradient generated by the podoplanin ligand, CCL21, to prime T cells. We propose that crosslinking podoplanin using rCLEC-2-Fc is a novel, cell-specific strategy to accelerate macrophage removal from the site of inflammation, and hence promote the resolution of the inflammatory response. Visual Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=188 SRC="FIGDIR/small/423770v1_ufig1.gif" ALT="Figure 1"> View larger version (54K): org.highwire.dtl.DTLVardef@e37acborg.highwire.dtl.DTLVardef@92a5e1org.highwire.dtl.DTLVardef@1c8832eorg.highwire.dtl.DTLVardef@11c5c97_HPS_FORMAT_FIGEXP M_FIG C_FIG SummaryPersistent macrophage accumulation in inflamed tissue leads to chronic inflammation and organ damage. Bourne et al. identify recombinant CLEC-2-Fc crosslinking podoplanin on inflammatory macrophages, as a cell-specific strategy to accelerate their emigration to draining lymph nodes, and reduce local inflammation.

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Bourne, J. H., Beristain Covarrubias, N., zuidscherwoude, M., Campos, J., Di, Y., Garlick, E., Colicchia, M., Terry, L. V., Thomas, S. G., Brill, A., Barry, J., Watson, S. P., Rayes, J.. 2020-12-22. CLEC-2 promotes inflammatory peritoneal macrophage emigration to draining lymph nodes during endotoxemia. https://doi.org/10.1101/2020.12.21.423770

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