MMP7 cleaves remyelination-impairing fibronectin aggregates and its expression is reduced in chronic multiple sclerosis lesions.

Peng Wang,Chao Zhao,Rianne P. Gorter,Wia Baron,Dick Hoekstra,Jenny C. de Jonge,Muhammad Nazmuddin,Sandra Amor

doi:10.1002/glia.23328

Abstract

Upon demyelination, transient expression of fibronectin precedes successful remyelination. However, in chronic demyelination observed in multiple sclerosis (MS), aggregates of fibronectin persist and contribute to remyelination failure. Accordingly, removing fibronectin (aggregates) would constitute an effective strategy for promoting remyelination. Matrix metalloproteinases (MMPs) are enzymes known to remodel extracellular matrix components, including fibronectin. Here, we examined the ability of MMPs to degrade fibronectin aggregates. Our findings reveal that MMP7 cleaved fibronectin aggregates resulting into a prominent 13 kDa EIIIA (16 kDa EDA)‐containing fragment. MMP7 was upregulated during lysolecithin‐induced demyelination, indicating its potential for endogenous fibronectin clearance. In contrast, the expression of proMMP7 was substantially decreased in chronic active and inactive MS lesions compared with control white matter and remyelinated MS lesions. Microglia and macrophages were major cellular sources of proMMP7 and IL‐4‐activated, but not IFNγ+LPS‐activated, microglia and macrophages secreted significant levels of proMMP7. Also, conditioned medium of IL‐4‐activated macrophages most efficiently cleaved fibronectin aggregates upon MMP‐activating conditions. Yet, coatings of MMP7‐cleaved fibronectin aggregate fragments inhibited oligodendrocyte maturation, indicating that further degradation and/or clearance by phagocytosis is essential. These findings suggest that MMP7 cleaves fibronectin aggregates, while reduced (pro)MMP7 levels in MS lesions contribute to their persistent presence. Therefore, upregulating MMP7 levels may be key to remove remyelination‐impairing fibronectin aggregates in MS lesions.

Highlights

ProMMP7 levels were reduced in chronic active and chronic inactive multiple sclerosis (MS) lesions compared with control white matter and remyelinated MS lesions, which may explain the persistence of fibronectin aggregates in demyelinated MS lesions
Given that microglia/macrophage activation is perturbed in MS lesions (Vogel et al, 2013; Peferoen et al, 2015), upregulation of local MMP7 expression levels, for example by priming microglia/macrophages towards the alternative activated phenotype, may be an attractive approach to locally provoke degradation of fibronectin and promote remyelination in MS
FIG URE 5 Matrix metalloproteinases (MMPs) protein localization and expression in control white matter and MS lesions. (a) Serial cryosections of post-mortem control white matter (n 5 3), active MS lesions (n 5 3), chronic active MS lesions (n 5 3), chronic inactive MS lesions (n 5 3) and remyelinated MS (n 5 3) lesions of distinct MS patients were stained for PLP or luxol fast blue (LFB), and MHC II (HLA-DR), and double-stained for HLA-DR and MMP7

Summary

| INTRODUCTION

Progression (Compston & Coles, 2008; Irvine & Blakemore, 2008). Myelination of axons is essential for saltatory nerve conduc- port and retain axons, and to prevent progressive decline. In chronic MS lesions, but not in toxin-induced lesions, fibronectin is persistently present as aggregates, which frustrates OPC differentiation, and thereby impedes remyelination (Stoffels et al, 2013). MMPs are transiently involved in the regulation of ECM dynamics upon injury, and are under strict (local) control at various levels, including gene transcription, synthesis, secretion, propeptide activation, and inhibition by physiological tissue inhibitors of MMPs (TIMPs). Given the role of MMPs in ECM remodeling in injured CNS, we examined here whether a perturbed expression and/or malfunctioning of MMP3, MMP7 or MMP9 contributes to the inability to clear dimeric fibronectin and/or fibronectin aggregates in MS lesions. Local targeting of MMP7 levels in chronic MS lesions may represent a first step to remove remyelination-inhibiting fibronectin aggregates

| MATERIALS AND METHODS

| RESULTS

Findings

| DISCUSSION