Chronic hypoxia (CH)-induced pulmonary hypertension (PH) results, in part, from T_H17 cell-mediated perivascular inflammation. However, the antigen/s involved are unknown. Cellular immunity to collagen type V (col V) develops after ischemia-reperfusion injury during lung transplant and is mediated by naturally occurring "nT_H17" cells. COL5A1 codifies for the α1 helix of col V, which is normally hidden from the immune system within type I collagen in the extracellular matrix. COL5A1 promoter analysis revealed NFATc3 binding sites. Therefore, we hypothesized that smooth muscle NFATc3 upregulates col V expression leading to nT_H17 cell-mediated autoimmunity to col V in response to CH, representing an upstream mechanism in PH development. To test our hypothesis, we measured indexes of PH in inducible, smooth muscle cell (SMC) specific NFATc3 KO mice exposed to either CH (380 mmHg) or normoxia and compared them to wild type (WT) mice. KO mice did not develop PH. In addition, COL5A1 was one of the 1792 genes differentially affected by both CH and SMC NFATc3 in isolated intrapulmonary arteries, which was confirmed by RT-PCR and immunostaining. Cellular immunity to col V was determined using a transvivo delayed-type hypersensitivity assay (Tv-DTH). Tv-DTH response was only evident when using splenocytes from control mice exposed to CH but not from KO mice, and mediated by nT_H17 cells. Our results suggest that SMC NFATc3 is important for CH-induced PH in adult mice, in part, by regulating the expression of the lung self-antigen COL5A1 contributing to col V-reactive nT_H17-mediated inflammation and hypertension.

中文翻译：

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NFATc3 对胶原蛋白 V 表达的调节有助于对 V 型胶原蛋白和缺氧性肺动脉高压的细胞免疫

慢性缺氧 (CH) 诱导的肺动脉高压 (PH) 部分是由 T _H 17 细胞介导的血管周围炎症引起的。然而，所涉及的抗原是未知的。对 V 型胶原蛋白 (col V) 的细胞免疫在肺移植过程中发生缺血-再灌注损伤后，由天然存在的“nT _H 17”细胞介导。COL5A1 编码 col V 的 α1 螺旋，它通常隐藏在细胞外基质中的 I 型胶原内的免疫系统之外。COL5A1 启动子分析揭示了 NFATc3 结合位点。因此，我们假设平滑肌 NFATc3 上调 col V 表达导致 nT _H17 细胞介导的针对 CH 的 col V 自身免疫，代表 PH 发展的上游机制。为了验证我们的假设，我们测量了暴露于 CH (380 mmHg) 或常氧的诱导型平滑肌细胞 (SMC) 特异性 NFATc3 KO 小鼠的 PH 指数，并将它们与野生型 (WT) 小鼠进行了比较。KO 小鼠没有出现 PH。此外，COL5A1 是分离的肺内动脉中受 CH 和 SMC NFATc3 差异影响的 1792 个基因之一，这通过 RT-PCR 和免疫染色得到证实。使用跨体内延迟型超敏反应试验 (Tv-DTH) 确定对 col V 的细胞免疫。仅当使用暴露于 CH 而不是来自 KO 小鼠的对照小鼠的脾细胞时，Tv-DTH 反应才明显，并且由 nT _H介导17 个细胞。我们的结果表明，SMC NFATc3 对成年小鼠 CH 诱导的 PH 很重要，部分原因是通过调节肺自身抗原 COL5A1 的表达，导致 col V 反应性 nT _H 17 介导的炎症和高血压。