Published online before print April 26, 2007

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(American Journal of Pathology. 2007;171:200-213.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.060821

Acute Brain Injury Triggers MyD88-Dependent, TLR2/4-Independent Inflammatory Responses

Uwe Koedel^*, Ulrike Michaela Merbt^*, Caroline Schmidt^*, Barbara Angele^*, Bernadette Popp^*, Hermann Wagner, Hans-Walter Pfister^* and Carsten J. Kirschning

From the Department of Neurology,^* Klinikum Grosshadern, Ludwig Maximilians-University, Munich; and the Institute of Medical Microbiology, Immunology, and Hygiene, Technical University of Munich, Munich, Germany

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.

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