HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Data Supplement Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Nichols, J. R. Articles by Kielian, T. PubMed PubMed Citation Articles by Nichols, J. R. Articles by Kielian, T. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Substance via MeSH

TLR2 Deficiency Leads to Increased Th17 Infiltrates in Experimental Brain Abscesses¹

Jessica R. Nichols^*, Amy L. Aldrich, Monica M. Mariani, Debbie Vidlak, Nilufer Esen and Tammy Kielian^2,

^* Department of Pediatrics, Arkansas Children’s Hospital, Little Rock, AR 72205; Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198; and Department of Neurology, University of Michigan Medical Center, Ann Arbor, MI 48109

TLR2 plays a pivotal role in recognizing Staphylococcus aureus, a common etiologic agent of CNS parenchymal infections, such as brain abscess. We previously reported that brain abscesses of TLR2 knockout (KO) mice exhibited elevated IL-17 levels, suggesting the presence of an alternative pathway available to respond to S. aureus infection that may involve Th17 cells. Both CD4⁺ and CD8⁺ T cell infiltrates were elevated in brain abscesses of TLR2 KO mice at days 3, 7, and 14 postinfection compared with wild-type animals. Intracellular cytokine staining revealed a significant increase in the frequency of IL-17-producing Th17 cells in TLR2 KO mice with relatively few IFN--positive cells. T cells were also a source of IL-17 in brain abscesses. Microglia, astrocytes, and macrophages were shown to express both IL-17RA and IL-17RC. Despite receptor expression, IL-17 was relatively ineffective at eliciting glial activation, whereas the cytokine augmented the ability of TNF- to induce CXCL2 and CCL2 expression by macrophages. Based on the ability of IL-17 to elicit the release of chemokines and other proinflammatory mediators, we propose that the exaggerated IL-17 response that occurs in TLR2 KO mice functions in a compensatory manner to control brain abscess pathogenesis, with cells other than glia as targets for IL-17 action. This is supported by our findings in which innate immune infiltrates were not significantly different between TLR2 KO and wild-type mice in conjunction with the lack of prolonged alterations in the synthesis of other proinflammatory molecules during the course of infection.

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 Neurological Disorders and Stroke (R01 NS055385) to T.K.

² Address correspondence and reprint requests to Dr. Tammy Kielian, University of Nebraska Medical Center, Department of Pathology and Microbiology, 985120 Nebraska Medical Center, Omaha, NE 68198-5120. E-mail address: tkielian{at}unmc.edu

³ Abbreviations used in this paper: PGN, peptidoglycan; DC, dendritic cell; KO, knockout; MDP, muramyl dipeptide; NOD2, nucleotide-binding oligomerization domain 2; PMN, polymorphonuclear cell; qRT-PCR, quantitative real-time RT-PCR; WT, wild type; PRR, pattern recognition receptor.

⁴ The online version of this article contains supplemental material.