Fibroblast‐Macrophage Interactions: Regulation by Modification of Extracellular Matrix

Abstract

Inflammation is associated with modifications of the extracellular matrix (ECM) that are recognized by receptors expressed by a variety of inflammatory cells. During inflammation, fibroblasts are activated and increase their expression of type I collagen and Fibroblast Activation Protein (FAP). FAP is a member of the post‐prolyl peptidase family and is primarily expressed by activated fibroblasts. Although the biological role of FAP is not clear, deletion of FAP in mice is associated with decreasing the immune response in cancer. To understand the mechanism underlying the immunomodulatory role of FAP, we examined the relative ability of FAP to cleave collagen and regulate macrophage adhesion. Using quenched fluorescent substrates, we show that FAP, but not the related post‐prolyl proteases DPPIV and POP, selectively cleaves type I collagen. When used as an adhesion substrate, FAP‐cleaved type I collagen increased the adhesion of primary macrophages in comparison to native collagen. Chelating divalent cations did not inhibit macrophage adhesion to FAP‐cleaved collagen indicating that this effect is independent of integrins. In contrast, FAP‐mediated cleavage of collagen did not increase the adhesion of macrophages isolated from mice lacking the Class A Scavenger Receptor (SR‐A). Together, our results identify an unknown biological role for FAP in modifying the ECM and increasing macrophage adhesion. Taken further, our study describes a novel way of communication between activated fibroblasts and macrophages, which relies on modifications of ECM.