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Journal of Virology, September 2009, p. 8604-8615, Vol. 83, No. 17
0022-538X/09/$08.00+0     doi:10.1128/JVI.02477-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Gamma Interferon Signaling in Macrophage Lineage Cells Regulates Central Nervous System Inflammation and Chemokine Production {triangledown}

Adora A. Lin,1 Pulak K. Tripathi,1 Allyson Sholl,1 Michael B. Jordan,1,2 and David A. Hildeman1*

Divisions of Immunobiology,1 Hematology/Oncology, Cincinnati Children's Hospital, Department of Pediatrics at the University of Cincinnati College of Medicine, Cincinnati, Ohio 452292

Received 2 December 2008/ Accepted 28 May 2009

Intracranial (i.c.) infection of mice with lymphocytic choriomeningitis virus (LCMV) results in anorexic weight loss, mediated by T cells and gamma interferon (IFN-{gamma}). Here, we assessed the role of CD4+ T cells and IFN-{gamma} on immune cell recruitment and proinflammatory cytokine/chemokine production in the central nervous system (CNS) after i.c. LCMV infection. We found that T-cell-depleted mice had decreased recruitment of hematopoietic cells to the CNS and diminished levels of IFN-{gamma}, CCL2 (MCP-1), CCL3 (MIP-1{alpha}), and CCL5 (RANTES) in the cerebrospinal fluid (CSF). Mice deficient in IFN-{gamma} had decreased CSF levels of CCL3, CCL5, and CXCL10 (IP-10), and decreased activation of both resident CNS and infiltrating antigen-presenting cells (APCs). The effects of IFN-{gamma} signaling on macrophage lineage cells was assessed using transgenic mice, called "macrophages insensitive to interferon gamma" (MIIG) mice, that express a dominant-negative IFN-{gamma} receptor under the control of the CD68 promoter. MIIG mice had decreased levels of CCL2, CCL3, CCL5, and CXCL10 compared to controls despite having normal numbers of LCMV-specific CD4+ T cells in the CNS. MIIG mice also had decreased recruitment of infiltrating macrophages and decreased activation of both resident CNS and infiltrating APCs. Finally, MIIG mice were significantly protected from LCMV-induced anorexia and weight loss. Thus, these data suggest that CD4+ T-cell production of IFN-{gamma} promotes signaling in macrophage lineage cells, which control (i) the production of proinflammatory cytokines and chemokines, (ii) the recruitment of macrophages to the CNS, (iii) the activation of resident CNS and infiltrating APC populations, and (iv) anorexic weight loss.

* Corresponding author. Mailing address: Department of Pediatrics, Division of Immunobiology MLC 7038, Children's Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH 45229. Phone: (513) 636-3923. Fax: (513) 636-4278. E-mail: david.hildeman{at}cchmc.org

{triangledown} Published ahead of print on 10 June 2009.

Journal of Virology, September 2009, p. 8604-8615, Vol. 83, No. 17
0022-538X/09/$08.00+0     doi:10.1128/JVI.02477-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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