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Identification of mannose receptor as receptor for hepatocyte growth factor ?-chain: novel ligand-receptor pathway for enhancing macrophage phagocytosis.

ABSTRACT: Hepatocyte growth factor (HGF), a heterodimer composed of the ?-chain and ?-chain, exerts multifunctional actions for tissue repair and homeostasis via its receptor, MET. HGF is cleaved by proteases secreted from inflammatory cells, and NK4 and ?-chain remnant (HGF-?) are generated. Here, we provide evidence that HGF-? binds to a new receptor other than MET for promoting a host cell clearance system. By an affinity cross-linking, radiolabeled HGF-? was bound to liver non-parenchymal cells, particularly to Kupffer cells and sinusoidal endothelial cells, but not to parenchymal hepatocytes. The cross-linked complex was immunoprecipitated by anti-HGF antibody, but not anti-MET antibody, implying that HGF-? binds to non-parenchymal cells at a site distinct from MET. Mass spectrometric detection of the ligand receptor complex revealed that the binding site of HGF-? was the mannose receptor (MR). Actually, an ectopic expression of MR in COS-7 cells, which express no endogenous MR or MET, enabled HGF-? to bind these cells at a K(D) of 89 nM, demonstrating that MR is the new receptor for HGF-?. Interaction of HGF-? and MR was diminished by EGTA, and by an enzymatic digestion of HGF-? sugar chains, suggesting that MR may recognize the glycosylation site(s) of HGF-? in a Ca(2+)-dependent fashion. Notably, HGF-?, but not other MR ligands, enhanced the ingestion of latex beads, or of apoptotic neutrophils, by Kupffer cells, possibly via an F-actin-dependent pathway. Thus, the HGF-?·MR complex may provide a new pathway for the enhancement of cell clearance systems, which is associated with resolution of inflammation.

SUBMITTER: Ohnishi H

PROVIDER: S-EPMC3339932 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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Identification of mannose receptor as receptor for hepatocyte growth factor β-chain: novel ligand-receptor pathway for enhancing macrophage phagocytosis.

Ohnishi Hiroyuki H Oka Kiyomasa K Mizuno Shinya S Nakamura Toshikazu T

The Journal of biological chemistry 20120221 16

Hepatocyte growth factor (HGF), a heterodimer composed of the α-chain and β-chain, exerts multifunctional actions for tissue repair and homeostasis via its receptor, MET. HGF is cleaved by proteases secreted from inflammatory cells, and NK4 and β-chain remnant (HGF-β) are generated. Here, we provide evidence that HGF-β binds to a new receptor other than MET for promoting a host cell clearance system. By an affinity cross-linking, radiolabeled HGF-β was bound to liver non-parenchymal cells, parti ...[more]

PMID: 22354962

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Project description:BackgroundMobilization of the innate immune response to clear and metabolize necrotic and apoptotic cardiomyocytes is a prerequisite to heart repair after cardiac injury. Suboptimal kinetics of dying myocyte clearance leads to secondary necrosis, and in the case of the heart, increased potential for collateral loss of neighboring non-regenerative myocytes. Despite the importance of myocyte phagocytic clearance during heart repair, surprisingly little is known about its underlying cell and molecular biology.ObjectiveTo determine if phagocytic receptor MERTK is expressed in human hearts and to elucidate key sequential steps and phagocytosis efficiency of dying adult cardiomyocytes, by macrophages.ResultsIn infarcted human hearts, expression profiles of the phagocytic receptor MER-tyrosine kinase (MERTK) mimicked that found in experimental ischemic mouse hearts. Electron micrographs of myocardium identified MERTK signal along macrophage phagocytic cups and Mertk-/- macrophages contained reduced digested myocyte debris after myocardial infarction. Ex vivo co-culture of primary macrophages and adult cardiomyocyte apoptotic bodies revealed reduced engulfment relative to resident cardiac fibroblasts. Inefficient clearance was not due to the larger size of myocyte apoptotic bodies, nor were other key steps preceding the formation of phagocytic synapses significantly affected; this included macrophage chemotaxis and direct binding of phagocytes to myocytes. Instead, suppressed phagocytosis was directly associated with myocyte-induced inactivation of MERTK, which was partially rescued by genetic deletion of a MERTK proteolytic susceptibility site.ConclusionUtilizing an ex vivo co-cultivation approach to model key cellular and molecular events found in vivo during infarction, cardiomyocyte phagocytosis was found to be inefficient, in part due to myocyte-induced shedding of macrophage MERTK. These findings warrant future studies to identify other cofactors of macrophage-cardiomyocyte cross-talk that contribute to cardiac pathophysiology.

Dataset Information

Identification of mannose receptor as receptor for hepatocyte growth factor ?-chain: novel ligand-receptor pathway for enhancing macrophage phagocytosis.

Publications

Identification of mannose receptor as receptor for hepatocyte growth factor β-chain: novel ligand-receptor pathway for enhancing macrophage phagocytosis.

Similar Datasets

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