title: Macrophage metalloelastase (MMP-12) deficiency mitigates retinal inflammation and pathological angiogenesis in ischemic retinopathy.
abstract: Pathological angiogenesis is a major cause of vision loss in ischemic and inflammatory retinal diseases. Recent evidence implicates macrophage metalloelastase (MMP-12), a macrophage-derived elastinolytic protease in inflammation, tissue remodeling and angiogenesis. However, little is known about the role of MMP-12 in retinal pathophysiology. The present study aims to explore the enzyme's contributions to retinal angiogenesis in oxygen-induced retinopathy (OIR) using MMP-12 knockout (KO) mice. We find that MMP-12 expression was upregulated in OIR, accompanied by elevated macrophage infiltration and increased inflammatory markers. Compared to wildtype mice, MMP-12 KO mice had decreased levels of adhesion molecule and inflammatory cytokines and reduced vascular leakage in OIR. Concomitantly, these mice had markedly reduced macrophage content in the retina with impaired macrophage migratory capacity. Significantly, loss of MMP-12 attenuated retinal capillary dropout in early OIR and mitigated pathological retinal neovascularization (NV). Similar results were observed in the study using MMP408, a pharmacological inhibitor of MMP-12. Intriguingly, in contrast to reducing pathological angiogenesis, lack of MMP-12 accelerated revascularization of avascular retina in OIR. Taken together, we conclude that MMP-12 is a key regulator of macrophage infiltration and inflammation, contributing to retinal vascular dysfunction and pathological angiogenesis.
authors.affiliation: Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
authors.forename: Jingming
authors.initials: J
authors.lastname: Li
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: Wang
authors.forename: Qisheng
authors.initials: Q
authors.lastname: Peng
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Humphrey
authors.forename: Jay
authors.initials: J
authors.lastname: Heinecke
authors.forename: Sarah X
authors.initials: SX
authors.lastname: Zhang
mesh_terms: D000818:Animals; D002199:Capillary Permeability / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007511:Ischemia; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D053508:Matrix Metalloproteinase 12 / Q000172:deficiency* / Q000235:genetics; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000235:genetics*; D012160:Retina / Q000378:metabolism* / Q000473:pathology*; D012171:Retinal Vessels / Q000378:metabolism / Q000473:pathology; D012173:Retinitis / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; D042461:Vascular Endothelial Growth Factor A; D053508:Matrix Metalloproteinase 12