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MyD88-Dependent Signals Are Essential for the Host Immune Response in Experimental Brain Abscess¹

Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, Little Rock, AR 72205

Brain abscesses form in response to a parenchymal infection by pyogenic bacteria, with Staphylococcus aureus representing a common etiologic agent of human disease. Numerous receptors that participate in immune responses to bacteria, including the majority of TLRs, the IL-1R, and the IL-18R, use a common adaptor molecule, MyD88, for transducing activation signals leading to proinflammatory mediator expression and immune effector functions. To delineate the importance of MyD88-dependent signals in brain abscesses, we compared disease pathogenesis using MyD88 knockout (KO) and wild-type (WT) mice. Mortality rates were significantly higher in MyD88 KO mice, which correlated with a significant reduction in the expression of several proinflammatory mediators, including but not limited to IL-1, TNF-, and MIP-2/CXCL2. These changes were associated with a significant reduction in neutrophil and macrophage recruitment into brain abscesses of MyD88 KO animals. In addition, microglia, macrophages, and neutrophils isolated from the brain abscesses of MyD88 KO mice produced significantly less TNF-, IL-6, MIP-1/CCL3, and IFN--induced protein 10/CXCL10 compared with WT cells. The lack of MyD88-dependent signals had a dramatic effect on the extent of tissue injury, with significantly larger brain abscesses typified by exaggerated edema and necrosis in MyD88 KO animals. Interestingly, despite these striking changes in MyD88 KO mice, bacterial burdens did not significantly differ between the two strains at the early time points examined. Collectively, these findings indicate that MyD88 plays an essential role in establishing a protective CNS host response during the early stages of brain abscess development, whereas MyD88-independent pathway(s) are responsible for pathogen containment.

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 work was supported by National Institutes of Health, National Institute of Mental Health Grant R01 MH65297, and National Institute of Neurological Disorders and Stroke Grant P30 NS047546 (to the Core Facility at University of Arkansas for Medical Sciences, Little Rock, AR).

² Address correspondence and reprint requests to Dr. Tammy Kielian, University of Arkansas for Medical Sciences, Department of Neurobiology and Developmental Sciences, 4301 West Markham Street, Slot 846, Little Rock, AR 72205. E-mail address: KielianTammyL{at}uams.edu

³ Abbreviations used in this paper: KO, knockout; AQP4, aquaporin 4; IP-10, IFN--induced protein 10; WT, wild type.

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