Department of Dermatology and.
Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA.
JCI Insight. 2023 Aug 22;8(16):e166076. doi: 10.1172/jci.insight.166076.
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.
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，这些细胞强烈参与组织损伤。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。在狼疮肾炎中，我们之前在肾脏浸润 T 细胞中鉴定出一个炎症基因程序，该程序依赖于 HIF-1，HIF-1 是一种转录因子，对于细胞和发育对缺氧以及炎症相关信号的反应至关重要。在我们目前使用狼疮皮肤疾病小鼠模型进行的研究中，我们发现皮肤浸润的 CD4+和 CD8+T 细胞也表达高水平的 HIF-1。皮肤浸润的 T 细胞在转录和蛋白水平上表现出强烈的细胞毒性特征，并且 HIF-1 抑制与 T 细胞细胞毒性活性降低相关联，可减轻皮肤和全身疾病。我们还在人类 CLE 组织中证明，富含 T 细胞的炎症浸润显示出增加的 HIF-1 含量和细胞毒性特征。在 CLE 中，颗粒酶 B 表达的 T 细胞集中在皮肤组织损伤部位，表明该途径与人类疾病有关。
