B7.2 on activated and phagocytic microglia in the facial axotomy model: regulation by interleukin-1 receptor type 1, tumor necrosis factor receptors 1 and 2 and endotoxin.
Co-stimulatory factors are involved in different forms of brain pathology and play an important role in the activation of T-cells. In the current study, we explored the regulation of B7.2, a prominent member of the B7 family of costimulatory factors, in the facial motor nucleus (FMN) following facial axotomy and systemic application of lipopolysaccharide (LPS, endotoxin) using light and electron immunohistochemistry and cytokine-receptor-deficient mice. Facial axotomy led to a gradual increase of B7.2 immunoreactivity (IR) on microglial cell surface; similar effects were also observed following application of LPS, but both effects were not additive, suggesting overlapping or saturated signaling pathways. Some B7.2-IR was already present on activated microglia surrounding injured neurons at days 1-4 after injury, but became particularly intense during neuronal cell death, peaking at day 14. Previous studies revealed that these late microglial changes are accompanied by a strong increase in the expression of proinflammatory cytokines such as interleukin-1 beta (IL1beta) tumor necrosis factor-alpha (TNFalpha) and interferon gamma (IFNgamma) [J. Neurosci. 18 (1998a) 5804]. Here, deletion of the receptors for these cytokines-IL1R1, TNFR1 or TNFR2, but not IFNgammaR1-caused a strong and significant reduction in B7.2-IR in reactive microglial cells, compared with their wild type (WT) controls on the same genetic strain background, with a 31% decrease in IL1R1-/- , 39% in TNFR1-/- and 49% in TNFR2-/- mice. These data underscore the significance of IL1beta, TNFalpha and LPS, and their receptors, as potent inflammatory signals that regulate the cellular response in the injured brain as well as the interaction with the rapidly recruited immune system. The broad susceptibility of B7.2 regulation to a wide range of different inflammatory signals also points to its role as a sensor of molecular pathology, and a factor that plays an important accessory role in allowing and shaping the microglia/T-cell interaction in the injured central nervous system.
Department Neuromorphology, Max-Planck Institute for Neurobiology, Martinsried, Germany.
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Bohatschek
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Kloss
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Pfeffer
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Bluethmann
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Raivich
D000818:Animals; D015703:Antigens, CD / Q000502:physiology*; D019771:Axotomy; D051940:B7-2 Antigen; D004731:Endotoxins / Q000494:pharmacology*; D020220:Facial Nerve Injuries / Q000276:immunology* / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D010586:Phagocytes / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D017472:Receptors, Interleukin-1 / Q000502:physiology*; D053573:Receptors, Interleukin-1 Type I; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000502:physiology*; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000502:physiology*
D015703:Antigens, CD; D051940:B7-2 Antigen; C497965:Cd86 protein, mouse; D004731:Endotoxins; D008562:Membrane Glycoproteins; D017472:Receptors, Interleukin-1; D053573:Receptors, Interleukin-1 Type I; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II