Fibronectin fragments modulate monocyte VLA-5 expression and monocyte migration

To identify the mechanisms that cause monocyte localization in infarcted my ocardium, we studied the impact of ischemia-reperfusion injury an the surfa ce expression and function of the monocyte fibronectin (FN) receptor VLA-5 (alpha(5)beta(1) integrin, CD49e/CD29). Myocardial infarction was associate d with the release of FN fragments into cardiac extracellular fluids. Incub ating 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 purifie d, 120-kDa cell-binding FN fragments (FN120) likewise decreased VLA-5 expre ssion, and did so by inducing a serine proteinase-dependent proteolysis of this beta(1) integrin. We postulated that changes in VLA-5 expression, whic h were induced by interactions with cell-binding FN fragments, may alter mo nocyte migration into tissue FN, a prominent component of the cardiac extra cellular matrix; Support for this hypothesis came from experiments showing that FN120 treatment significantly reduced both spontaneous and MCP-1-induc ed 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 whe re the fragment concentration is sufficient to ensure proteolytic degradati on of VLA-5.