New insights into fibrosis from the ECM degradation perspective: the macrophage-MMP-ECM interaction

Abstract

Fibrosis is a pathological feature of a variety of chronic inflammatory diseases that can affect almost all organs, which can cause severe consequences and even lead to death. Fibrosis is characterized by the excessive accumulation of extracellular matrix (ECM) due to disruption of the balance between ECM production and degradation. Although overabundance of ECM proteins has long been the focus of studies on fibrosis, another facet of the problem-impaired degradation of the ECM-is gaining increasing attention. Matrix metalloproteinase (MMP) and the tissue inhibitor of metalloproteinase (TIMP) system is the main molecular system contributing to ECM degradation, and macrophages are the major regulators of ECM. However, the relationship among macrophages, the MMP/TIMP system and the ECM is not fully understood in the context of fibrosis. Here, we discuss in detail the role played by the ECM in the development of fibrosis and highlight the macrophage-MMP-ECM interaction that is involved in fibrogenesis and may be a potential therapeutic target for fibrosis.

Keywords: Extracellular matrix; Fibrosis; Macrophage; Matricryptin; Matrix metalloprotease.

Fig. 1

Macrophage-MMP-ECM interaction in fibrosis. Fibrolytic macrophages can degrade the ECM by secreting MMPs and phagocytizing ECM components in fibrotic sites. Regulated at the transcriptional and secretory levels, MMPs are released by fibrolytic macrophages to hydrolyze ECM components. Matricryptins, hydrolysis products of ECM degradation, are ingested by fibrolytic macrophages through the lysosomal pathway. Both MMPs and matricryptins can regulate the function of fibrolytic macrophages, enhancing their ability to resolve fibrosis. In addition, matricryptins exert a chemotactic effect on monocytes in peripheral blood, which may induce the transformation into fibrolytic macrophages due to inducing stimuli in the microenvironment