Effect of IL-10 Deficiency on TGFβ Expression during Fatal Alphavirus Encephalomyelitis in C57Bl/6 Mice.
Effect of IL-10 Deficiency on TGFβ Expression during Fatal Alphavirus Encephalomyelitis in C57Bl/6 Mice.
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DOI：
10.3390/v14081791
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发表时间：
2022-08-16
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辛德毕斯病毒（SINV）在小鼠中引起病毒性脑炎，具有毒株依赖性毒力。用SINV的神经适应株（NSV）感染的C57 Bl/6小鼠中的致死性脑脊髓炎是涉及由调节细胞因子IL-10调节的Th 17细胞的免疫病理过程。为了进一步表征对NSV的致病性免疫应答，我们分析了野生型（WT）和IL-10缺陷小鼠中转化生长因子（TGF）-B的调节。NSV感染可上调中枢神经系统TGF β 1和TGF β 3的表达。在不存在IL-10的情况下，脑Tgfb 1 mRNA以及脑和脊髓成熟活性TGFβ1和TGFβ3蛋白的水平高于WT小鼠。与WT小鼠相比，IL-10缺陷小鼠具有更多的TGFβ1表达型3先天淋巴细胞（ILC 3）和浸润CNS的CD 4 + T细胞，但颈部淋巴结中的数量相似。在IL-10缺陷小鼠的CNS细胞上，结合调节性T细胞表面上的pro-TGFb的糖蛋白A重复优势蛋白（GARP）的表达降低。较高的CNS TGFb伴随着更多的TGFbRII受体表达，SMAD转录因子的激活，PCKα mRNA的增加，以及更多的RORγ t阳性和IL-17 A表达细胞。这些结果表明，在IL-10不存在的情况下，TGFβ的代偿作用促进了Th 17相关的免疫病理学和NSV感染后更快的死亡。
Sindbis virus (SINV) causes viral encephalitis in mice with strain-dependent virulence. Fatal encephalomyelitis in C57Bl/6 mice infected with a neuroadapted strain of SINV (NSV) is an immunopathogenic process that involves Th17 cells modulated by the regulatory cytokine IL-10. To further characterize the pathogenic immune response to NSV, we analyzed the regulation of transforming growth factor (TGF)-b in both wild-type (WT) and IL-10-deficient mice. NSV infection upregulated the expression of TGFb1 and TGFb3 in the central nervous system (CNS). In the absence of IL-10, levels of brain Tgfb1 mRNA and brain and spinal cord mature active TGFβ1 and TGFβ3 proteins were higher than in WT mice. Compared to WT mice, IL-10-deficient mice had more TGFβ1-expressing type 3 innate lymphoid cells (ILC3s) and CD4+ T cells infiltrating the CNS, but similar numbers in the cervical lymph nodes. Expression of glycoprotein A repetitions predominant protein (GARP) that binds pro-TGFb on the surface of regulatory T cells was decreased on CNS cells from IL-10-deficient mice. Higher CNS TGFb was accompanied by more expression of TGFbRII receptor, activation of SMAD transcription factors, increased PCKα mRNA, and more RORγt-positive and IL-17A-expressing cells. These results suggest a compensatory role for TGFβ in the absence of IL-10 that fosters Th17-related immunopathology and more rapid death after NSV infection.