Matrix metalloproteinase-9 deficiency leads to prolonged foreign body response in the brain associated with increased IL-1beta levels and leakage of the blood-brain barrier.
Matrix metalloproteinases (MMPs) are enzymes with specificity towards extracellular matrix (ECM) components. MMPs, especially MMP-9, have been shown to degrade components of the basal lamina and disrupt the blood-brain barrier (BBB) and thus, contribute to neuroinflammation. In the present study we examined the role of MMP-9 in the foreign body response in the brain. Millipore filters of mixed cellulose ester were implanted into the brain cortex of wild type and MMP-9-null mice for a period of 2 d to 8 wks and the response was analyzed by histology and immunohistochemistry. We observed enhanced and prolonged neuroinflammation in MMP-9-null mice, evidenced by persistence of neutrophils, macrophages/microglia, and reactive astrocytes up to 8 wks post-implantation. In addition, blood vessel density around implants was increased in MMP-9-null mice and detection of mouse serum albumin (MSA) indicated that vessels were leaky. Immunohistochemical and western blot analyses indicated that this defect was associated with the absence of tight junction proteins zonula occludens-1 (ZO-1) and ZO-2 from vessels in proximity to implants. Analysis of brain sections and brain protein extracts revealed that the levels of the pro-inflammatory cytokine interleukin-1beta (IL-1beta), which is a substrate for MMP-9, were significantly higher in MMP-9-null mice at 8wks post-implantation. Collectively, our studies suggest that increased levels of IL-1beta and the delayed repair of BBB are associated with prolongation of the FBR in MMP-9-null mice.
Tian
Weiming
W
Vascular Biology and Therapeutics Program, Departments of Pathology and Biomedical Engineering, Yale University, New Haven, CT 06519, USA.
Kyriakides
Themis R
TR
D000818:Animals; D001253:Astrocytes / Q000166:cytology; D001812:Blood-Brain Barrier / Q000378:metabolism / Q000503:physiopathology*; D001921:Brain / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D002452:Cell Count; D005549:Foreign-Body Reaction / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D005911:Gliosis / Q000473:pathology; D007249:Inflammation / Q000473:pathology; D053583:Interleukin-1beta / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D017628:Microglia / Q000166:cytology; D008851:Micropore Filters; D009389:Neovascularization, Pathologic / Q000473:pathology; D009504:Neutrophils / Q000166:cytology; D010750:Phosphoproteins / Q000378:metabolism; D019736:Prostheses and Implants; D012709:Serum Albumin / Q000378:metabolism; D062826:Zonula Occludens-1 Protein; D062827:Zonula Occludens-2 Protein
D053583:Interleukin-1beta; D008565:Membrane Proteins; D010750:Phosphoproteins; D012709:Serum Albumin; C569043:Tjp1 protein, mouse; C569047:Tjp2 protein, mouse; D062826:Zonula Occludens-1 Protein; D062827:Zonula Occludens-2 Protein; D020780:Matrix Metalloproteinase 9