Opposing roles for CXCR3 signaling in central nervous system versus ocular inflammation mediated by the astrocyte-targeted production of IL-12.
Opposing roles for CXCR3 signaling in central nervous system versus ocular inflammation mediated by the astrocyte-targeted production of IL-12.
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DOI：
10.1016/j.ajpath.2011.07.041
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发表时间：
2011-11
期刊：
影响因子：
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通讯作者：
M. Krauthausen;S. Ellis;J. Zimmermann;M. Sarris;D. Wakefield;M. Heneka;I. Campbell;M. Müller
中科院分区：
文献类型：
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作者：
M. Krauthausen;S. Ellis;J. Zimmermann;M. Sarris;D. Wakefield;M. Heneka;I. Campbell;M. Müller
CXCR 3及其配体对于炎症期间活化的CD 4 + TH 1 T细胞、CD 8 +T细胞和自然杀伤细胞的运输非常重要。最近的功能研究表明，CXCR 3在中枢神经系统（CNS）的炎性疾病中的作用更加多样化。我们研究了CXCR 3对CNS中不太复杂的干扰素-γ依赖性1型细胞介导的免疫应答的影响，该免疫应答是通过星形胶质细胞和视网膜Müller细胞转基因产生胶质细胞酸性蛋白IL-12（GF-IL 12）诱导的。GF-IL 12小鼠由于严重的小脑炎症而发展共济失调，但几乎没有明显的眼部疾病。令人惊讶的是，CXCR 3缺陷型GF-IL 12小鼠（GF-IL 12/CXCR 3 KO）具有显著降低的共济失调，但发展为白内障、严重的眼部炎症和眼萎缩。大多数GF-IL 12/CXCR 3 KO小鼠具有最小的小脑炎症，但具有严重的视网膜紊乱、光感受器损失和眼睛中的透镜破坏。与GF-IL 12小鼠相比，GF-IL 12/CXCR 3 KO小鼠CNS中的CD 3+、CD 11b+和自然杀伤1.1+细胞数量减少，但眼睛中的CD 3+、CD 11b+和自然杀伤1.1+细胞数量显著增加。在GF-IL 12小脑和GF-IL 12/CXCR 3 KO眼中发现高水平的干扰素-γ、IL-1、肿瘤坏死因子α、CXCL 9、CXCL 10和CCL 5。我们的研究结果证明了CXCR 3在IL-12诱导的CNS免疫疾病中的关键但矛盾的功能，促进大脑中的炎症，但限制眼睛中的炎症。我们的结论是，CXCR 3在细胞免疫疾病中的功能是由一个共同的触发器驱动，并由组织特异性因素控制。
CXCR3 and its ligands are important for the trafficking of activated CD4+TH1 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.