MMP-25 Metalloprotease Regulates Innate Immune Response through NF-κB Signaling

Abstract

Matrix metalloproteases (MMPs) regulate innate immunity acting over proinflammatory cytokines, chemokines, and other immune-related proteins. MMP-25 (membrane-type 6-MMP) is a membrane-bound enzyme predominantly expressed in leukocytes whose biological function has remained largely unknown. We have generated Mmp25-deficient mice to elucidate the in vivo function of this protease. These mutant mice are viable and fertile and do not show any spontaneous phenotype. However, Mmp25-null mice exhibit a defective innate immune response characterized by low sensitivity to bacterial LPS, hypergammaglobulinemia, and reduced secretion of proinflammatory molecules. Moreover, these immune defects can be tracked to a defective NF-κB activation observed in Mmp25-deficient leukocytes. Globally, our findings provide new mechanistic insights into innate immunity through the activity of MMP-25, suggesting that this proteinase could be a potential therapeutic target for immune-related diseases.

Tobacco exposure-related alterations in DNA methylation and gene expression in human monocytes: the Multi-Ethnic Study of Atherosclerosis (MESA)

“…P2RY6 has also been implicated in mediating release of pro-inflammatory cytokines and chemokines in monocytes [ 34 ] and macrophages [ 35 ] and promoting vascular inflammation [ 37 ]. MMP25 deficiency has been linked to an defective NF-κB activation and impaired innate immune response in mice [ 38 ]. Future monitoring of these alterations in gene expression, which are linked to inflammatory processes, may offer avenues for regulatory scientists and tobacco companies to measure early toxicity responses to tobacco product use.…”

Epigenetic hypomethylation and upregulation of matrix metalloproteinase 9 in Kawasaki disease

“…Interestingly, Soria-Valles at al. showed that MMP-25 could activate the innate immune response [ 33 ]. Similarly, our study has also found increased transcripts of MMP-8, MMP-9, and MMP-25 in KD, indicating that these proteinases may be potential therapeutic targets for KD.…”

Virus-host interactome and proteomic survey of PMBCs from COVID-19 patients reveal potential virulence factors influencing SARS-CoV-2 pathogenesis

“…CXCR2 is a subunit of IL-8 receptor and facilitates IL-8-induced neutrophil chemotaxis while PRG3 has been reported to stimulate neutrophil superoxide production and IL-8 release 25,26 . LBP positively regulates neutrophil response upon LPS stimulation and MMP25 inactivates alpha-1 proteinase inhibitor to facilitate the trans-endothelial migration of neutrophil to inflammatory sites during infection 27,28 . These differentially expressed proteins support a model by which SARS-CoV-2 triggers cytokine release, such as IL-8, in the early stage of infection, resulting in uncontrolled infiltration and activation of neutrophils to the sites of infection followed by eventual progression to cytokine storm and respiratory distress.…”