Matrix metalloproteinase 28 is regulated by TRIF- and type I IFN-dependent signaling in macrophages

Abstract

Matrix metalloproteinases (MMPs) are transcriptionally regulated proteases that have multiple roles in modifying the extracellular matrix (ECM) and inflammatory response. Our previous work identified Mmp28 as a key regulator of inflammation and macrophage polarization during experimental models of pulmonary infection, fibrosis, and chronic smoke exposure. However, the signaling pathways responsible for regulation of macrophage Mmp28 expression remain undefined. This study utilized murine macrophages obtained from wild type, Tlr2 À/À , Tlr4(Trif mutant ), and Ifnar1 À/À mice to test the hypothesis that macrophage Mmp28 expression was dependent on TRIF and type I IFN. Our results support the hypothesis, demonstrating that increased macrophage Mmp28 expression was dependent on type I IFN after LPS and poly(I:C) stimulation. To gain further insight into the function of MMP28, we explored the inflammatory response of macrophages derived from wild type or Mmp28 À/À mice to stimulation with poly(I:C). Our data support a role for MMP28 in regulating the macrophage inflammatory response to poly(I:C) because expression of Ccl2, Ccl4, Cxcl10, and Il6 were increased in Mmp28 À/À macrophages. Together, these data support a model in which macrophages integrate TRIF-and type I IFN-dependent signaling to coordinate regulation of proteins with the capacity to modify the ECM.

Microglial activation in an amyotrophic lateral sclerosis-like model caused by Ranbp2 loss and nucleocytoplasmic transport impairment in retinal ganglion neurons

“…For example, loss of Ranbp2 in Thy1 + -motoneurons promotes the downregulation of Mmp28 in the sciatic nerve without affecting the secretion of Mmp28 from the soma of Thy1 + -motoneurons[34]. Mmp28 is a regulator of macrophage activation and myelination[75][76][77][78]. In light of the foregoing findings, including that Mmp28 likely mediates neural-type selective paracrine responses upon loss of Ranbp2, we examined the effects of lossof Ranbp2 in YFP + -RGNs in the proteostasis and subcellular distribution of Mmp28.…”

“…In naive mice lacking Ranbp2 in RGNs, the upregulation of Acc1 was accompanied by the multiphasic activation of microglia. 4) RGNs and motoneurons share the dysregulation of the proteostasis of Mmp28, which is another modulator of immunity and possibly myelination[75][76][77][78], but this effect likely arises by distinct mechanisms between RGNs and spinal motoneurons.…”

Continuous Developmental and Early Life Trichloroethylene Exposure Promoted DNA Methylation Alterations in Polycomb Protein Binding Sites in Effector/Memory CD4+ T Cells

“…One region, CpG 32 on Chr11 encodes matrix metalloproteinase 28 (epilysin) or MMP-28. Although not thoroughly studied in T cells, MMP-28 has been shown to be a key regulatory of inflammation and macrophage differentiation (42). The other distinct island region, CpG 30 on Chr7, is a binding site for the transcription factor, Bhlhe40, known to control cytokine production by T cells and has been identified as a critical regulator of autoreactive T cell pathology (43).…”

Matrix Metalloproteinases: From Molecular Mechanisms to Physiology, Pathophysiology, and Pharmacology

“…MMP28 mRNA is typically expressed in epithelial cells of many tissues in both mice and humans, with a high expression in the lungs and skin, as well as in macrophages (Lohi et al, 2001;Rodgers et al, 2009;Gharib et al, 2018). Interestingly, MMP28 appears to contain limited ability to cleave ECM proteins, as very few substrates have been identified to date, but it has been shown to stimulate chemokine expression (Ma et al, 2013;Manicone et al, 2017;Gharib et al, 2018;Long et al, 2018).…”