Matrilysin Shedding of Syndecan-1 Regulates Chemokine Mobilization and Transepithelial Efflux of Neutrophils in Acute Lung Injury

Abstract

The influx of inflammatory cells to sites of injury is largely directed by signals from the epithelium, but how these cells form chemotactic gradients is not known. In matrilysin null mice, neutrophils remained confined in the interstitium of injured lungs and did not advance into the alveolar space. Impaired transepithelial migration was accompanied by a lack of both shed syndecan-1, a heparan sulfate proteoglycan, and KC, a CXC chemokine, in the alveolar fluid. KC was bound to shed syndecan-1, and it was not detected in the lavage of syndecan-1 null mice. In vitro, matrilysin cleaved syndecan-1 from the surface of cells. Thus, matrilysin-mediated shedding of syndecan-1/KC complexes from the mucosal surface directs and confines neutrophil influx to sites of injury.

Matrix metalloproteinases and the regulation of tissue remodelling

“…Cleavage of other membrane proteins, such as Ecadherin and CD44, results in the release of specific, biologically active fragments of their extra cellular domains, and in increased invasive behaviour 29,30 . Cell-surface-adhesion molecules, such as syndecan-1, are also shed by soluble and membrane MMPs 31,32 . MMP9 and MMP12 contribute to proteolytic shedding of the lipopolysaccharide (LPS) receptor CD14, and therefore influence innate host defense 33 .…”

“…• Increase in chemokine activity following cleavage: interleukin-8 (IL8, also known as CXC-motif ligand-8 (CXCL8); the mouse LIX) 93,94 • Decrease in chemokine activity following cleavage: monocyte chemotactic protein-1 (MCP1, also known as CCL2 or JE) 92,[99][100][101] • Change in chemotaxis: gradients form by shedding of syndecan 32,141 …”

“…Subsequent chemokine release results in the migration of leukocytes into the air spaces and epithelial repair. In the absence of MMP7, neutrophils remain stuck outside the epithelia in injured lungs, and subsequent inflammation-mediated lung damage is attenuated 32 . Neutrophil migration is defective in Mmp7 mutants owing to the absence of the neutrophil attractant CXC-motif ligand-1 (CXCL1; also known as keratinocyte-derived chemokine (KC); or GROα in humans) in the fluid of the alveolar lumens.…”

Induction of a CXCL8 binding site on endothelial syndecan‐3 in rheumatoid synovium

“…It not only determines when and where the HS chains are expressed but also plays a direct role in signaling. Recent studies in gene-deleted mice have presented some evidence of the involvement of syndecan-1 and -4 in inflammation (37,38); however, little is known about the role of syndecans and glypicans in autoimmune diseases such as RA. The aim of the present study was to determine the expression of HSPGs by endothelial cells in the RA synovium and to determine which of these molecules bind the chemokine CXCL8.…”

Multiple expression of matrix metalloproteinases in murine neurocysticercosis: Implications for leukocyte migration through multiple central nervous system barriers

“…In addition, direct contact between leukocytes accumulated in these infiltrates can induce additional expression of MMPs [17]. Moreover, MMPs also modulate the expression and secretion of cytokines and chemokines that promote or restrict further leukocyte extravasation and immune cell interaction in inflammatory infiltrates [19,30,34]. As the immune infiltrates found during the course of murine NCC are composed of a heterogeneous population of immune cells including macrophages, γδ T cells, αβ T cells, neutrophils, and B cells [2,12], mechanisms that upregulate or downregulate the overall immune response via cleavage of cytokine, chemokine and adhesion molecules could be accomplished by the multiple expression of MMPs.…”