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Signaling through MyD88 Regulates Leukocyte Recruitment after Brain Injury¹

Medical Biotechnology Center, University of Southern Denmark, Odense, Denmark and Neuroimmunology Unit, Montreal Neurological Institute, Montreal, Quebec, Canada

Injury to the CNS provokes an innate inflammatory reaction that engages infiltrating leukocytes with the capacity to repair and/or exacerbate tissue damage. The initial cues that orchestrate leukocyte entry remain poorly defined. We have used flow cytometry to investigate whether MyD88, an adaptor protein that transmits signals from TLRs and receptors for IL-1 and IL-18, regulates leukocyte infiltration into the stab-injured entorhinal cortex (EC) and into sites of axonal degeneration in the denervated hippocampus. We have previously established the kinetics of leukocyte entry into the denervated hippocampus. We now show that significant leukocyte entry into the EC occurs within 3–12 h of stab injury. Whereas T cells showed small, gradual increases over 8 days, macrophage infiltration was pronounced and peaked within 12–24 h. MyD88 deficiency significantly reduced macrophage and T cell recruitment to the stab-injured EC and the denervated hippocampus at 5 days post-injury. Whereas macrophage and T cell entry remained impaired into the denervated hippocampus of MyD88-deficient mice at 8 days, leukocyte infiltration into the stab-injured EC was restored to levels observed in wild-type mice. Transcripts for TNF-, IL-1β, and CCL2, which increased >50-fold after stab injury in C57BL/6 mice at the time of peak expression, were severely reduced in injured MyD88 knockout mice. Leukocyte recruitment and gene expression were unaffected in TLR2-deficient or TLR4 mutant mice. No significant differences in gene expression were observed in mice lacking IL-1R or IL-18R. These data show that MyD88-dependent signaling mediates proinflammatory gene expression and leukocyte recruitment after CNS injury.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This research was supported by the Multiple Sclerosis Society of Canada.

² Address correspondence and reprint requests to Dr. Alicia Babcock or Dr. Trevor Owens, Medical Biotechnology Center, University of Southern Denmark, Winsløwparken 25, 2. Sal, 5000 Odense C, Denmark. E-mail addresses: ababcock{at}health.sdu.dk and towens{at}health.sdu.dk

³ Abbreviations used in this paper: EC, entorhinal cortex; ADAM, a disintegrin and metalloproteinase; EAE, experimental autoimmune encephalomyelitis; KO, knockout; MMP, matrix metalloproteinase; qPCR, quantitative real-time RT-PCR.