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Toll-like receptor activation reveals developmental reorganization and unmasks responder subsets of microglia

Item Type:Article
Title:Toll-like receptor activation reveals developmental reorganization and unmasks responder subsets of microglia
Creators Name:Scheffel, J. and Regen, T. and Van Rossum, D. and Seifert, S. and Ribes, S. and Nau, R. and Parsa, R. and Harris, R.A. and Boddeke, H.W.G.M. and Chuang, H.N. and Pukrop, T. and Wessels, J.T. and Juergens, T. and Merkler, D. and Brueck, W. and Schnaars, M. and Simons, M. and Kettenmann, H. and Hanisch, U.K.
Abstract:The sentinel and immune functions of microglia require rapid and appropriate reactions to infection and damage. Their Toll-like receptors (TLRs) sense both as threats. However, whether activated microglia mount uniform responses or whether subsets conduct selective tasks is unknown. We demonstrate that murine microglia reorganize their responses to TLR activations postnatally and that this process comes with a maturation of TLR4-organized functions. Although induction of MHCI for antigen presentation remains as a pan-populational feature, synthesis of TNF{alpha} becomes restricted to a subset, even within adult central nervous system regions. Response heterogeneity is evident ex vivo, in situ, and in vivo, but is not limited to TNF{alpha} production or to TLR-triggered functions. Also, clearance activities for myelin under physiological and pathophysiological conditions, IFN{gamma}-enforced upregulation of MHCII, or challenged inductions of other proinflammatory factors reveal dissimilar microglial contributions. Notably, response heterogeneity is also confirmed in human brain tissue. Our findings suggest that microglia divide by constitutive and inducible capacities. Privileged production of inflammatory mediators assigns a master control to subsets. Sequestration of clearance of endogenous material versus antigen presentation in exclusive compartments can separate potentially interfering functions. Finally, subsets rather than a uniform population of microglia may assemble the reactive phenotypes in responses during infection, injury, and rebuilding, warranting consideration in experimental manipulation and therapeutic strategies.
Keywords:Cytokines, Heterogeneity, MHC, Myelin, Phagocytosis, Phenotype, Subpopulation, TLR, Animals, Mice
Page Range:1930-1943
Date:December 2012
Official Publication:https://doi.org/10.1002/glia.22409
PubMed:View item in PubMed

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