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Ly-6G⁺CCR2^– Myeloid Cells Rather Than Ly-6C^highCCR2⁺ Monocytes Are Required for the Control of Bacterial Infection in the Central Nervous System¹

Alexander Mildner^2,*, Marija Djukic^2,, David Garbe, Andreas Wellmer, William A. Kuziel, Matthias Mack, Roland Nau^,¶ and Marco Prinz^3,*

^* Department of Neuropathology, University of Freiburg, Freiburg, Germany; Department of Neurology, Georg-August-University, Göttingen, Germany; Protein Design Labs, Inc., Fremont, CA 94555; Department of Internal Medicine, University of Regensburg, Regensburg, Germany; ^¶ Department of Geriatrics, Evangelisches Krankenhaus, Göttingen-Weende, Germany

Myeloid cell recruitment is a characteristic feature of bacterial meningitis. However, the cellular mechanisms important for the control of Streptococcus pneumoniae infection remain largely undefined. Previous pharmacological or genetic studies broadly depleted many myeloid cell types within the meninges, which did not allow defining the function of specific myeloid subsets. Herein we show that besides CD11b⁺Ly-6G⁺CCR2^– granulocytes, also CD11b⁺Ly-6C^highCCR2⁺ but not Ly-6C^lowCCR2^– monocytes were recruited in high numbers to the brain as early as 12 h after bacterial challenge. Surprisingly, CD11b⁺Ly-6C^highCCR2⁺ inflammatory monocytes modulated local CXCL2 and IL-1β production within the meninges but did not provide protection against bacterial infection. Consistent with these results, CCR2 deficiency strongly impaired monocyte recruitment to the infected brains but was redundant for disease pathogenesis. In contrast, specific depletion of polymorphonuclear granulocytes caused elevated local bacterial titer within the brains, led to an aggravated clinical course, and enhanced mortality. These findings demonstrate that Ly-6C^highCCR2⁺ inflammatory monocytes play a redundant role for the host defense during bacterial meningitis and that predominantly CD11b⁺Ly-6G⁺CCR2^– myeloid cells are involved in the restriction of the extracellular bacteria.

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 Fritz-Thyssen-Stiftung, the Gemeinnützige Hertie-Stiftung (to M.P.). The Deutsche Forschungsgemeinschaft (DFG) (to M.D. and R.N.). A.M. is a fellow of the Gertrud Reemtsma foundation.

² A.M. and M.D. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Marco Prinz, Department of Neuropathology, University of Freiburg, Breisacher Strasse 64, D-79106 Freiburg, Germany. E-mail address: marco.prinz{at}uniklinik-freiburg.de

⁴ Abbreviations used in this paper: CSF, cerebrospinal fluid; p.i., postinfection; wt, wild type.

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