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E.M. Cantin, D. Gehman, H. Openshaw, P. Lundberg; Lack of CXCR3 Signaling Differentially Affects HSV Corneal and Skin Disease, and Fatal Encephalitis in Mice Depending on the Genetic Background of the Strain . Invest. Ophthalmol. Vis. Sci. 2005;46(13):3590.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose:To determine a role for CXCR3 signaling in HSV–induced corneal disease and fatal encephalitis. CD4+ Th1 responses contribute to protection against HSV encephalitis (HSE) and to immune pathology associated with HSK and periocular skin disease. Thus, interference with the CXCR3 axis (a known TH1 recruitment pathway) would be expected to ameliorate HSK and possibly modify mortality due to HSE. Methods: HSV infected mice were monitored for mortality or sacrificed for collection of corneas, trigeminal ganglia and brainstems (BS) for gene expression (RT–PCR assays and cDNA microarrays) or flow cytometric analysis. CXCR3–/– mice and in vivo neutralization of MIG and IP10 was used to assess the role of CXCR3 signaling in infection. Results:BALB–CXCR3–/– mice (susceptible) showed delayed mortality (median survival +1.5 days, p=0.02), while mortality was unchanged for B6–CXCR3–/– mice. Additionally, we showed that MIG and IP10 depletion abrogated mortality in susceptible 129S6 mice but was without effect in B6 mice. Surprisingly, a dramatic increase in corneal and periocular disease was noted in B6–CXCR3–/– mice in contrast to the relatively mild disease in B6 mice. The few surviving BALB–CXCR3–/– mice developed corneal and periocular disease to the extent expected for BALB/c mice. On day 6, BS infiltrates in BALB–CXCR3–/– mice included CD4+ T–cells; this population was absent in B6–CXCR3–/– mice. Conversely, a resident (CD45INT) CD8LO population was abundant in B6–CXCR3–/– compared to BALB–CXCR3–/– mice. Both CXCR3–/– strains had infiltrating (CD45HI) CD8+ T–cells although to differing extents. Despite CXCR3 deficiency, CD4+ T cells infiltrated the corneas of these mice that also had infiltrating Gr–1+ neutrophils as expected. Interestingly, a fraction of the Gr–1+ cells stained positive for the high affinity IgE receptor, suggesting that they may be mast cells or basophils. The role of these cellular infiltrates will be discussed in the context of corneal disease and development of fatal encephalitis. Conclusions:In HSV infected B6 mice lack of CXCR3 signaling exacerbates immune pathology in the cornea and skin, while in BALB/c mice CXCR3 deficiency reduces fatal encephalitis. We conclude that the CXCR3 pathway can have opposing effects depending on strain background and that its role differs depending on the target tissue.
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