1. Opposing roles for CXCR3 signaling in central nervous system versus ocular inflammation mediated by the astrocyte-targeted production of IL-12.
- Author
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Krauthausen M, Ellis SL, Zimmermann J, Sarris M, Wakefield D, Heneka MT, Campbell IL, and Müller M
- Subjects
- Animals, Blindness immunology, Cerebellar Ataxia pathology, Encephalitis immunology, Encephalitis pathology, Endophthalmitis immunology, Endophthalmitis pathology, Eye Diseases pathology, Genotype, Glial Fibrillary Acidic Protein, Interferon-gamma metabolism, Lymphocyte Subsets immunology, Mice, Mice, Inbred C57BL, Phosphorylation, RNA, Messenger metabolism, Receptors, CCR5 metabolism, Receptors, Interleukin-12 metabolism, STAT4 Transcription Factor metabolism, Signal Transduction, Astrocytes metabolism, Cerebellar Ataxia immunology, Eye Diseases immunology, Immunity, Cellular immunology, Interleukin-12 biosynthesis, Nerve Tissue Proteins metabolism, Receptors, CXCR3 deficiency
- Abstract
CXCR3 and its ligands are important for the trafficking of activated CD4(+) T(H)1 T cells, CD8(+) T cells, and natural killer cells during inflammation. Recent functional studies demonstrate a more diverse role of CXCR3 in inflammatory diseases of the central nervous system (CNS). We examined the impact of CXCR3 on a less complex interferon-γ-dependent, type 1 cell-mediated immune response in the CNS, induced in mice by the transgenic production of glial fibrillary acidic protein IL-12 (GF-IL12) by astrocytes and retinal Müller cells. GF-IL12 mice develop ataxia because of severe cerebellar inflammation but have little overt ocular disease. Surprisingly, CXCR3-deficient GF-IL12 mice (GF-IL12/CXCR3KO) have drastically reduced ataxia but developed cataracts, severe ocular inflammation, and eye atrophy. Most GF-IL12/CXCR3KO mice had minimal cerebellar inflammation but severe retinal disorganization, loss of photoreceptors, and lens destruction in the eye. The number of CD3(+), CD11b(+), and natural killer 1.1(+) cells were reduced in the CNS but highly increased in the eyes of GF-IL12/CXCR3KO compared with GF-IL12 mice. High levels of interferon-γ, IL-1, tumor necrosis factor α, CXCL9, CXCL10, and CCL5 were found in GF-IL12 cerebelli and GF-IL12/CXCR3KO eyes. Our findings demonstrate key but paradoxical functions for CXCR3 in IL-12-induced immune disease in the CNS, promoting inflammation in the brain yet restricting it in the eye. We conclude that the function of CXCR3 in cellular immune disease is driven by a common trigger and is controlled by tissue-specific factors., (Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2011
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