The extracellular matrix and cytokines regulate microglial integrin expression and activation.
Microglia are the primary immune effector cells resident within the CNS, whose activation into migratory, phagocytic cells is associated with increased expression of cell adhesion molecules of the integrin family. To determine which specific factors are important regulators of microglial activation and integrin expression, we have examined the influence of individual cytokines and extracellular matrix (ECM) substrates by quantifying cell surface expression of MHC and individual integrins by flow cytometry. We found that the proinflammatory cytokines TNF and IFN-alpha promoted microglial activation, as assessed by amoeboid morphology and increased expression of MHC class I, and also increased expression of the alpha(4)beta(1) and Mac-1 integrins. In contrast, TGF-beta1 had the opposite effect and was dominant over the other cytokines. Furthermore, the ECM substrates fibronectin and vitronectin, but not laminin, also promoted microglial activation and increased expression of the alpha(4)beta(1), alpha(5)beta(1) and Mac-1 integrins, but significantly, the influence of fibronectin and vitronectin was not diminished by TGF-beta1. Taken together, this work suggests that, in addition to cytokines, the ECM represents an important regulatory influence on microglial activity. Specifically, it implies that increases in the local availability of fibronectin or vitronectin, as a result of blood-brain barrier breakdown or increased expression in different pathological states of the CNS, could induce microglial activation and increased expression of integrins.
Milner
Richard
R
Department of Neuropharmacology, The Scripps Research Institute, La Jolla, CA 92037, USA. drm27@hermes.cam.ac.uk
Campbell
Iain L
IL
D000818:Animals; D018821:CD18 Antigens / Q000096:biosynthesis / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology / Q000502:physiology*; D015536:Down-Regulation / Q000502:physiology; D005109:Extracellular Matrix / Q000502:physiology*; D005353:Fibronectins / Q000037:antagonists & inhibitors / Q000494:pharmacology; D039564:Integrin alphaV / Q000096:biosynthesis / Q000378:metabolism; D019012:Integrin beta1 / Q000096:biosynthesis / Q000378:metabolism; D016023:Integrins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000378:metabolism; D016898:Interferon-alpha / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D051379:Mice; D017628:Microglia / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D016548:Prosencephalon / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation / Q000502:physiology; D019096:Vitronectin / Q000037:antagonists & inhibitors / Q000494:pharmacology
D018821:CD18 Antigens; D016207:Cytokines; D005353:Fibronectins; D039564:Integrin alphaV; D019012:Integrin beta1; D016023:Integrins; D016898:Interferon-alpha; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D019096:Vitronectin; D007371:Interferon-gamma