MMP-3 Deficiency Alleviates Endotoxin-Induced Acute Inflammation in the Posterior Eye Segment

Int J Mol Sci. 2016 Nov 1;17(11):1825. doi: 10.3390/ijms17111825.

Abstract

Matrix metalloproteinase-3 (MMP-3) is known to mediate neuroinflammatory processes by activating microglia, disrupting blood-central nervous system barriers and supporting neutrophil influx into the brain. In addition, the posterior part of the eye, more specifically the retina, the retinal pigment epithelium (RPE) and the blood-retinal barrier, is affected upon neuroinflammation, but a role for MMP-3 during ocular inflammation remains elusive. We investigated whether MMP-3 contributes to acute inflammation in the eye using the endotoxin-induced uveitis (EIU) model. Systemic administration of lipopolysaccharide induced an increase in MMP-3 mRNA and protein expression level in the posterior part of the eye. MMP-3 deficiency or knockdown suppressed retinal leukocyte adhesion and leukocyte infiltration into the vitreous cavity in mice subjected to EIU. Moreover, retinal and RPE mRNA levels of intercellular adhesion molecule 1 (Icam1), interleukin 6 (Il6), cytokine-inducible nitrogen oxide synthase (Nos2) and tumor necrosis factor α (Tnfα), which are key molecules involved in EIU, were clearly reduced in MMP-3 deficient mice. In addition, loss of MMP-3 repressed the upregulation of the chemokines monocyte chemoattractant protein (MCP)-1 and (C-X-C motif) ligand 1 (CXCL1). These findings suggest a contribution of MMP-3 during EIU, and its potential use as a therapeutic drug target in reducing ocular inflammation.

Keywords: LPS; MMP-3; blood–retinal barrier; inflammation; leukostasis; retina; retinal pigment epithelium.

MeSH terms

  • Acute Disease
  • Animals
  • Blotting, Western
  • Cell Adhesion / genetics
  • Chemokine CCL2 / genetics*
  • Chemokine CCL2 / metabolism
  • Chemokine CXCL1 / genetics*
  • Chemokine CXCL1 / metabolism
  • Gene Expression Profiling / methods
  • Gene Expression Regulation*
  • Intercellular Adhesion Molecule-1 / genetics
  • Intercellular Adhesion Molecule-1 / metabolism
  • Interleukin-6 / genetics
  • Interleukin-6 / metabolism
  • Leukocytes / metabolism
  • Lipopolysaccharides
  • Matrix Metalloproteinase 3 / deficiency
  • Matrix Metalloproteinase 3 / genetics*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nitric Oxide Synthase Type II / genetics
  • Nitric Oxide Synthase Type II / metabolism
  • Retina / metabolism
  • Retina / pathology
  • Retinal Pigment Epithelium / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tomography, Optical Coherence
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism
  • Uveitis / chemically induced
  • Uveitis / genetics*
  • Uveitis / metabolism
  • Vitreous Body / metabolism

Substances

  • Ccl2 protein, mouse
  • Chemokine CCL2
  • Chemokine CXCL1
  • Icam1 protein, mouse
  • Interleukin-6
  • Lipopolysaccharides
  • Tumor Necrosis Factor-alpha
  • Intercellular Adhesion Molecule-1
  • Nitric Oxide Synthase Type II
  • Nos2 protein, mouse
  • Matrix Metalloproteinase 3