Activated microglia in the human glaucomatous optic nerve head.
To investigate the distribution and potential participation of microglia, the resident defense cells of the central nervous system, in the optic nerve head (ONH) in glaucoma, histological paraffin sections of optic nerves from normal and glaucoma patients with mild to advanced nerve damage were studied using double labeling immunohistofluorescence. A monoclonal antibody for HLA-DR, indicating activated microglia, was colocalized with antibodies for functional proteins. In normal ONHs, microglia do not contain TGF-beta2, COX-2, or TNF-alpha and are not positive for PCNA; however, in glaucomatous ONHs, microglia contain abundant TGF-beta2, TNF-alpha, and PCNA. In glaucomatous eyes, a few microglia are usually positive for COX-2. In normal ONHs, there are rarely microglia containing TGF-beta1, NOS-2, TSP, TIMP-2, and CD68, but, in glaucomatous tissue, a few microglia are positive from the prelaminar to the postlaminar regions. MMP-1, MMP-2, MMP-3, and MMP-14 are constitutively present in the perivascular microglia in normal ONHs and appear to be more abundant in glaucomatous tissue. COX-1, TNF-R1, TIMP-1, and c-fms are constitutively present in normal tissues and appear to be increased in microglia in the glaucomatous ONHs. HSP27 is not present in microglia. In glaucomatous ONHs, microglia become activated and phagocytic and produce cytokines, mediators, and enzymes that can alter the extracellular matrix. Our findings suggest that activated microglia may participate in stabilizing the tissue early in the disease process, but, as the severity of the glaucomatous damage increases, the activities of microglia may have detrimental consequences for the pathological course of glaucomatous optic neuropathy.
Yuan
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Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
Neufeld
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AH
D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD / Q000378:metabolism; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D005901:Glaucoma / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D006801:Humans; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008565:Membrane Proteins; D017628:Microglia / Q000378:metabolism / Q000473:pathology*; D008875:Middle Aged; D008938:Mitosis / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D009898:Optic Disk / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D010587:Phagocytosis / Q000502:physiology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I; D019699:Thrombospondins / Q000378:metabolism; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1; D053781:Transforming Growth Factor beta2; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D015703:Antigens, CD; D007527:Isoenzymes; D008565:Membrane Proteins; D011956:Receptors, Cell Surface; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; C508960:TGFB1 protein, human; C509041:TGFB2 protein, human; D019699:Thrombospondins; D019714:Tissue Inhibitor of Metalloproteinases; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D053781:Transforming Growth Factor beta2; D014409:Tumor Necrosis Factor-alpha; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases; D020782:Matrix Metalloproteinases