HIF-1 regulates pathogenic cytotoxic T cells in lupus skin disease.
HIF-1 regulates pathogenic cytotoxic T cells in lupus skin disease.
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DOI：
10.1172/jci.insight.166076
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发表时间：
2023-08-22
期刊：
影响因子：
8
通讯作者：
Craft, Joe
中科院分区：
文献类型：
--
作者：
Little, Alicia J.;Chen, Ping-Min;Vesely, Matthew D.;Khan, Rahanna N.;Fiedler, Jacob;Garritano, James;Maisha, Fahrisa I.;Mcniff, Jennifer M.;Craft, Joe
皮肤红斑狼疮 (CLE) 是一种毁容性自身免疫性皮肤病，其特征是富含 T 细胞的炎症浸润，T 细胞与组织损伤密切相关。这些细胞如何适应皮肤环境并促进组织炎症和损伤尚不清楚。在狼疮性肾炎中，我们之前在肾脏浸润性 T 细胞中发现了一个依赖于 HIF-1 的炎症基因程序，HIF-1 是一种转录因子，对于细胞和发育对缺氧的反应以及炎症相关信号至关重要。在我们目前使用狼疮皮肤病小鼠模型的研究中，我们发现皮肤浸润的 CD4+ 和 CD8+ T 细胞也表达高水平的 HIF-1。皮肤浸润 T 细胞在转录物和蛋白质水平上表现出强烈的细胞毒性特征，HIF-1 抑制消除了与 T 细胞细胞毒性活性降低相关的皮肤和全身疾病。我们还在人类 CLE 组织中证明，富含 T 细胞的炎症浸润表现出 HIF-1 含量增加和细胞毒性特征。表达粒酶 B 的 T 细胞集中在 CLE 皮肤组织损伤部位，表明该途径与人类疾病相关。
Cutaneous lupus erythematosus (CLE) is a disfiguring autoimmune skin disease characterized by an inflammatory infiltrate rich in T cells, which are strongly implicated in tissue damage. How these cells adapt to the skin environment and promote tissue inflammation and damage is not known. In lupus nephritis, we previously identified an inflammatory gene program in kidney-infiltrating T cells that is dependent on HIF-1, a transcription factor critical for the cellular and developmental response to hypoxia as well as inflammation-associated signals. In our present studies using a mouse model of lupus skin disease, we find that skin-infiltrating CD4+ and CD8+ T cells also express high levels of HIF-1. Skin-infiltrating T cells demonstrated a strong cytotoxic signature at the transcript and protein levels, and HIF-1 inhibition abrogated skin and systemic diseases in association with decreased T cell cytotoxic activity. We also demonstrate in human CLE tissue that the T cell–rich inflammatory infiltrate exhibited increased amounts of HIF-1 and a cytotoxic signature. Granzyme B–expressing T cells were concentrated at sites of skin tissue damage in CLE, suggesting relevance of this pathway to human disease.
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