Acute brain injury triggers MyD88-dependent, TLR2/4-independent inflammatory responses.
Endogenous molecules released from disrupted cells and extracellular matrix degradation products activate Toll-like receptors (TLRs) and, thus, might contribute to immune activation after tissue injury. Here, we show that aseptic, cold-induced cortical injury triggered an acute immune response that involves increased production of multiple cytokines/chemokines accompanied by neutrophil recruitment to the lesion site. We observed selective reductions in injury-induced cytokine/chemokine expression as well as in neutrophil accumulation in mice lacking the common TLR signaling adaptor MyD88 compared with wild-type mice. Notably, attenuation of the immune response was paralleled by a reduction in lesion size. Neutrophil depletion of wild-type mice and transplantation of MyD88-deficient bone marrow into lethally irradiated wild-type recipients had no substantial impact on injury-induced expression of cytokines/chemokines and on lesion development. In contrast to MyD88 deficiency, double deficiency of TLR2 and TLR4 -- despite the two receptors being activated by specific endogenous molecules associated to danger and signal through MyD88 -- altered neither immune response nor extent of tissue lesion size on injury. Our data indicate modulation of the neuroinflammatory response and lesion development after aseptic cortical injury through MyD88-dependent but TLR2/4-independent signaling by central nervous system resident nonmyeloid cells.
Koedel
Uwe
U
Department of Neurology, Klinikum Grosshadern, Ludwig Maximilians-University, Marchioninistr 15, Munich, Germany. uwe.koedel@med.uni-muenchen.de
Merbt
Ulrike Michaela
UM
Schmidt
Caroline
C
Angele
Barbara
B
Popp
Bernadette
B
Wagner
Hermann
H
Pfister
Hans-Walter
HW
Kirschning
Carsten J
CJ
D000818:Animals; D001930:Brain Injuries / Q000235:genetics* / Q000276:immunology*; D018925:Chemokines / Q000378:metabolism; D003080:Cold Temperature; D016207:Cytokines / Q000378:metabolism; D007111:Immunity, Cellular / Q000235:genetics*; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics*; D009504:Neutrophils / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000502:physiology*
D018925:Chemokines; D016207:Cytokines; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C495345:TLR4 protein, human; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4