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ASN NEURO (2009) 1(2):art:e00007.doi:10.1042/AN20090004

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MyD88 expression by CNS-resident cells is pivotal for eliciting protective immunity in brain abscesses

Sarita Garg*¹, Jessica R Nichols†¹, Nilufer Esen‡, Shuliang Liu§, Nirmal K Phulwani§, Mohsin Md. Syed§, William H Wood||, Yongqing Zhang||, Kevin G Becker||, Amy Aldrich¶ and Tammy Kielian¶²

^*Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR 72205, U.S.A.
^†Department of Pediatrics, Arkansas Children's Hospital, Little Rock, AR 72205, U.S.A.
^‡Department of Neurology, University of Michigan Medical Center, Ann Arbor, MI 48109, U.S.A.
^§Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, Little Rock, AR 72205, U.S.A.
^||Gene Expression and Genomics Unit, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, U.S.A.
^¶Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, U.S.A.

MyD88 KO (knockout) mice are exquisitely sensitive to CNS (central nervous system) infection with Staphylococcus aureus, a common aetiological agent of brain abscess, exhibiting global defects in innate immunity and exacerbated tissue damage. However, since brain abscesses are typified by the involvement of both activated CNS-resident and infiltrating immune cells, in our previous studies it has been impossible to determine the relative contribution of MyD88-dependent signalling in the CNS compared with the peripheral immune cell compartments. In the present study we addressed this by examining the course of S. aureus infection in MyD88 bone marrow chimaera mice. Interestingly, chimaeras where MyD88 was present in the CNS, but not bone marrow-derived cells, mounted pro-inflammatory mediator expression profiles and neutrophil recruitment equivalent to or exceeding that detected in WT (wild-type) mice. These results implicate CNS MyD88 as essential in eliciting the initial wave of inflammation during the acute response to parenchymal infection. Microarray analysis of infected MyD88 KO compared with WT mice revealed a preponderance of differentially regulated genes involved in apoptotic pathways, suggesting that the extensive tissue damage characteristic of brain abscesses from MyD88 KO mice could result from dysregulated apoptosis. Collectively, the findings of the present study highlight a novel mechanism for CNS-resident cells in initiating a protective innate immune response in the infected brain and, in the absence of MyD88 in this compartment, immunity is compromised.

Key words: bone marrow chimaera mice, brain abscess, central nervous system, MyD88, Staphylococcus aureus, Toll-like receptor

Abbreviations: CFU, colony forming unit, CNS, central nervous system, GAPDH, glyceraldehyde-3-phosphate dehydrogenase, GFP, green fluorescent protein, Ier3/IEX, immediate early response 3, IL, interleukin, IL-1R etc., IL-1 receptor, KO, knockout, Lcn2, lipocalin-2, NF-κB, nuclear factor κB, Pacsin3, protein kinase C and casein kinase substrate in neurons 3, Pfc, complement factor properdin, qRT-PCR, quantitative real-time RT (reverse transcriptase)-PCR, ROS, reactive oxygen species, SOCS3, suppressor of cytokine signalling 3, TLR, Toll-like receptor, TNF-α, tumour necrosis factor-α, WT, wild-type

¹Both of these authors contributed equally to this work.

²To whom correspondence should be addressed (email tkielian@unmc.edu).

Received 23 January 2009/25 February 2009; accepted 3 March 2009

Published as ASN NEURO Immediate Publication 3 March 2009, doi:10.1042/AN20090004

©2009 The Author(s) This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial Licence (http://creativecommons.org/licenses/by-nc/2.5/) which permits unrestricted non-commerical use, distribution and reproduction in any medium, provided the original work is properly cited.