Fibronectin fragments modulate monocyte VLA-5 expression and monocyte migration

Abstract

To identify the mechanisms that cause monocyte localization in infarcted myocardium, we studied the impact of ischemia-reperfusion injury on the surface expression and function of the monocyte fibronectin (FN) receptor VLA-5 (α 5 β 1 integrin, CD49e/CD29). Myocardial infarction was associated with the release of FN fragments into cardiac extracellular fluids. Incubating monocytes with postreperfusion cardiac lymph that contained these FN fragments selectively reduced expression of VLA-5, an effect suppressed by specific immunoadsorption of the fragments. Treating monocytes with purified, 120-kDa cell-binding FN fragments (FN120) likewise decreased VLA-5 expression, and did so by inducing a serine proteinase-dependent proteolysis of this β 1 integrin. We postulated that changes in VLA-5 expression, which were induced by interactions with cell-binding FN fragments, may alter monocyte migration into tissue FN, a prominent component of the cardiac extracellular matrix. Support for this hypothesis came from experiments showing that FN120 treatment significantly reduced both spontaneous and MCP-1-induced monocyte migration on an FN-impregnated collagen matrix. In vivo, it is likely that contact with cell-binding FN fragments also modulates VLA-5/FN adhesive interactions, and this causes monocytes to accumulate at sites where the fragment concentration is sufficient to ensure proteolytic degradation of VLA-5.

Impact of Fibronectin Fragments on the Transendothelial Migration of HIV-Infected Leukocytes and the Development of Subendothelial Foci of Infectious Leukocytes

“…After exposure to FNf, monocytes shed CD49e and are less able to migrate through collagenous matrices rich in native FN (23). FNf-induced loss of CD49e may also explain the failure of treated MNLs to penetrate deeply into FN-collagen matrices below the endothelial barrier in the present report.…”

“…Recent studies have called attention to the possibility that proteolytic fragments or polymers of FN may be among the factors that influence leukocyte behavior in inflamed tissues (23)(24)(25). Certain FN fragments can stabilize and enhance the infectivity of cell-associated virus (24,25); other FN subunits can activate monocytes and cause them to release TNF-␣ through a protein kinase C-dependent signaling pathway (26 -30).…”

The extracellular matrix in myocardial injury, repair, and remodeling

“…In experimental models, release of type I collagen fragments in the serum has been documented within 30 minutes after coronary occlusion (37). Fragmentation of components of the basement membrane, such as collagen IV, and of noncollagenous matrix constituents has also been demonstrated in the infarcted myocardium (38)(39)(40)(41). Low-molecular weight hyaluronan fragments exert potent proinflammatory actions in the infarcted region; impaired clearance of these fragments has been shown to prolong and accentuate proinflammatory signaling in leukocytes and vascular cells (42,43).…”

Augmentation of RANTES-Induced Extracellular Signal-Regulated Kinase Mediated Signaling and T Cell Adhesion by Elastase-Treated Fibronectin

“…have a promigratory effect on human neutrophils (22), and fragments of FN can modify the expression of VLA-5 and affect the migration of monocytes (26). We have shown that heparinase, a heparin sulfate-specific endoglycosidase, can degrade the ECM and release a specific disaccharide that inhibits delayed-type hypersensitivity in mice, and that this effect is accompanied by attenuation of the production of TNF-␣ by activated T cells (27).…”