Cytokine Substrates: MMP Regulation of Inflammatory Signaling Molecules

Abstract

Inflammation is a highly regulated process involving tissue parenchyma, vascular and connective tissues, as well as host defense and immune cells, and is an essential component of both innate and acquired immunity. MMPs were traditionally considered to assist in the inflammatory response through the breakdown of extracellular matrix molecules, providing an environment condusive to leukocyte infiltration, edema, wound healing, and tissue repair with continued upregulation contributing to the onset of chronic inflammation. It is now evident, however, that the repertoire of MMP substrates, the substrate degradome, extends far beyond the extracellular matrix and includes many key bioactive molecules, the processing of which results in altered actions. In the context of inflammation, several MMPs have been shown biochemically to efficiently and selectively process cytokines and chemokines, as well as associated molecules, thereby changing their bioactive properties. Many of these substrates have been validated physiologically in genetic models of inflammatory disease, where a remarkable array of inflammatory phenotypes has been observed. As a whole, research involving MMPs in inflammation has demonstrated their integral role in orchestrating both the initiation and the termination of inflammatory processes, rather than only tissue degradation.