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

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.

Oligonucleotide array analysis of Toll-like receptors and associated signalling genes in Venezuelan equine encephalitis virus-infected mouse brain

“…+ T-cell responses in alphaviruses and MyD88-dependent inflammatory response to brain injury have been reported previously (Chen et al 2005;Koedel et al 2007). In this study, MyD88 expression was upregulated and was localized in and around the endothelial linings of the inflamed blood vessels.…”

Lipopolysaccharide Sensitizes Neonatal Hypoxic-Ischemic Brain Injury in a MyD88-Dependent Manner

“…1). These data suggest that MyD88 may not be critical for brain damage following sterile-induced inflammation in the immature brain (32) and imply a potential maturational-dependent role of innate immunity in brain injury.…”

Signaling through MyD88 Regulates Leukocyte Recruitment after Brain Injury

“…TNF-␣, IL-1␤, and CCL2 were examined as possible candidates because they were previously implicated in MyD88-signaled inflammatory response (39,42,49), and we have previously shown that CCL2 signaling through its receptor, CCR2, drives leukocyte entry (43) and that TNF acting via TNFR1 affects T cell recruitment (15) to the denervated hippocampus. We confirmed that CCL2 had a significant effect on leukocyte recruitment to the stab-injured EC.…”

“…Others have identified roles for endogenous TLR2 and/or TLR4 signaling in neuropathic pain (26,34), Alzheimer's disease (35,36), injury (20,30,37), and cerebral ischemia (16 -19, 27, 38). MyD88 signaling has also been implicated in CNS response to neurodegeneration or injury (32,33,37,39). Although MyD88 is known to impact leukocyte infiltration induced by adjuvant or infection (40 -42), its regulatory effects on the kinetics of macrophage and T cell recruitment after sterile injury are not known.…”