CXCR3 promotes cerebellar inflammation but prevents ocular destruction in transgenic mice with a TH1-driven neuroinflammation

CXCR3 and its ligands are important for the trafficking of activated TH1 T-cells during inflammation. Recent functional studies demonstrate a more diverse role of CXCR3 in inflammatory CNS diseases. In EAE, the animal model for MS, CXCR3 does not promote the influx of encephalitogenic T cells into the brain but restricts the invasion of effector T cells into the parenchyma, thereby exerting a protective effect. However, EAE has a very complex pathogenesis in which a multitude of different inflammatory cell types are involved. We examined the impact of CXCR3 on a less complex IFN-gamma-dependent TH1-driven CNS immune response induced in mice (GF-IL12) by the transgenic production of IL-12 by CNS astrocytes and Müller cells of the retina. GF-IL12 mice developed ataxia due to severe cerebellar inflammation but showed no overt ocular pathology. When GF-IL12 mice were crossed with CXCR3 deficient (CXCR3KO) mice, the GF-IL12/CXCR3KO animals developed ataxia only rarely but surprisingly all mice developed cataracts progressing to severe atrophy of the eye. Histological examination revealed that while immune pathology was considerably reduced in the cerebellum of GF-IL12/CXCR3 KO mice, there was severe retinal disorganization, loss of photoreceptors and lens destruction in the eyes. The numbers of CD3+ T cells was reduced in the CNS but highly increased in the eyes of GF-IL12/CXCR3KO compared with GF-IL12 mice. In addition, high levels of IFN-gamma, IL-1, TNFalpha, CXCL9, CXCL10 and CCL5 were found in the cerebellum of GF-IL12 and the eye of GF-IL12/CXCR3KO mice, whereas the levels in the cerebellum of the GF-IL12/CXCR3KO and the eyes of the GF-IL12 mice were substantially lower. Our findings demonstrate key but opposing functions for CXCR3 in the pathogenesis of IL-12-induced inflammation being proinflammatory in the brain and antiinflammatory in the eye. The presented data impressively demonstrate the critical and diverse roles of CXCR3 in neuroinflammation.