Toll-like receptor activation reveals developmental reorganization and unmasks responder subsets of microglia.
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 TNFα 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 TNFα production or to TLR-triggered functions. Also, clearance activities for myelin under physiological and pathophysiological conditions, IFNγ-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.
Institute of Neuropathology, University of Göttingen, Göttingen, Germany.
Jörg
J
Scheffel
Tommy
T
Regen
Denise
D
Van Rossum
Stefanie
S
Seifert
Sandra
S
Ribes
Roland
R
Nau
Roham
R
Parsa
Robert A
RA
Harris
Hendrikus W G M
HW
Boddeke
Han-Ning
HN
Chuang
Tobias
T
Pukrop
Johannes T
JT
Wessels
Tanja
T
Jürgens
Doron
D
Merkler
Wolfgang
W
Brück
Mareike
M
Schnaars
Mikael
M
Simons
Helmut
H
Kettenmann
Uwe-Karsten
UK
Hanisch
D000368:Aged; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000145:classification* / Q000378:metabolism* / Q000473:pathology; D051197:Toll-Like Receptor 4 / Q000378:metabolism* / Q000502:physiology
C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4