Monocyte upregulation of podoplanin during early sepsis induces complement inhibitor release to protect liver function

Xie, Zhanli; Shao, Bojing; Hoover, Christopher; McDaniel, Michael; Song, Jianhua; Jiang, Miao; Ma, Zhengliang; Yang, Fei; Han, Jingjing; Bai, Xia; Ruan, Changgeng; Xia, Lijun

doi:10.1172/jci.insight.134749

Cited by 23 publications

(27 citation statements)

References 57 publications

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“…The increase in macrophage emigration was not due to matrix metalloprotease 9 secretion (Gong et al, 2008), or dysregulated vascular integrity, neither by increase in other chemotactic molecules such as complement C5a levels. Indeed, CLEC-2 was previously shown to regulate the inflammatory response by increasing the secretion of complement regulators from platelets (Xie et al, 2020). We now show that CCL21, constituently secreted by LECs (Farnsworth et al, 2019), is utilised by emigrating macrophages during our model of inflammation as a gradient towards the draining MLN.…”

Section: Discussionsupporting

confidence: 54%

“…During lipopolysaccharide (LPS)-induced endotoxemia, platelets dampen the inflammatory macrophage phenotype, through multiple mechanisms. These include the release of immunomodulatory molecules such as prostaglandin E2 (Xiang et al, 2013) and through the interaction of platelet C-type lectin-like receptor (CLEC-2) with podoplanin upregulated on inflammatory macrophages (Rayes et al, 2017) and monocytes (Xie et al, 2020). CLEC-2 is a hemi-immunoreceptor tyrosine-based activation motif (hemi-ITAM) receptor constituently expressed on platelets and a sub-set of dendritic cells.…”

Section: Introductionmentioning

confidence: 99%

“…Beside the role of CLEC-2-podoplanin in thrombosis (Hitchcock et al, 2015, Payne et al, 2017 CLEC-2 regulates the cytokine storm, and decreases the number of peritoneal macrophages (Rayes et al, 2017) and blood monocytes (Xie et al, 2020) during inflammation. Complexes of platelet and podoplanin-positive-macrophage are observed during atherosclerosis (Inoue et al, 2015), rheumatoid arthritis (Takakubo et al, 2017), and breast cancer (Hatzioannou et al, 2016); but how this influences macrophage phenotype and migration is not known.…”

Section: Introductionmentioning

confidence: 99%

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

Bourne

Beristain‐Covarrubias

Zuidscheroude

et al. 2020

Preprint

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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 AbstractSummaryPersistent 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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Section: Discussionsupporting

confidence: 54%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Bourne

Beristain‐Covarrubias

Zuidscheroude

et al. 2020

Preprint

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“…The absence of macrophages from the inflamed peritoneum is not secondary to (i) macrophage local death ( 49 ), (ii) increased macrophage adherence through integrin α D β 2 and α M β 2 (Mac-1) upregulation ( 50 ) but rather due to macrophage emigration to a secondary site ( 48 ), in particular draining lymph nodes. The increase in macrophage emigration was not due to matrix metalloprotease 9 secretion ( 51 ), or dysregulated vascular integrity, neither by increase in other chemotactic molecules such as complement C5a levels ( 22 ). Combining our in vitro and in vivo data suggests that a chemoattractant released from the draining lymph nodes is responsible for the directed migration.…”

Section: Discussionmentioning

confidence: 99%

“…Podoplanin is a small, transmembrane O-glycosylated mucin-type protein constituently expressed on type I lung epithelial cells, fibroblastic reticular cells, lymphatic endothelial cells and podocytes, and is upregulated on inflammatory macrophages, TH17 cells, fibroblasts and cancer cells ( 18 , 19 ). Beside the role of CLEC-2-podoplanin in thrombosis ( 20 , 21 ), deletion of platelet-CLEC-2 or haematopoietic-podoplanin increases the cytokine storm and bacterial growth and spreading during caecal ligation and puncture-mediated peritonitis ( 10 , 22 ). Whether crosslinking podoplanin can regulate macrophage phenotype, fate or resultant tissue inflammation is not known.…”

Section: Introductionmentioning

confidence: 99%

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

Bourne

Beristain‐Covarrubias

Zuidscherwoude

et al. 2021

Front. Immunol.

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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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IL-1R1 blockade attenuates liver injury through inhibiting the recruitment of myeloid-derived suppressor cells in sepsis

Luo

Wang²,

Liu³

et al. 2022

Biochemical and Biophysical Research Communications

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Monocyte upregulation of podoplanin during early sepsis induces complement inhibitor release to protect liver function

Cited by 23 publications

References 57 publications

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

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

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

IL-1R1 blockade attenuates liver injury through inhibiting the recruitment of myeloid-derived suppressor cells in sepsis

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