Published online before print April 26, 2007

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Copyright © 2007 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2007.060821

Accepted for publication March 16, 2007.

Article

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

^@ To whom correspondence should be addressed. E-mail: uwe.koedel{at}med.uni-muenchen.de.

	Abstract

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.