Laboratory of Cancer Immunometabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland, USA.
Laboratory of Cancer Immunometabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland, USA; Department of Ophthalmology, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China; Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai, China; National Clinical Research Center for Eye Diseases, Shanghai, China; Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, China.
J Invest Dermatol. 2021 Jun;141(6):1404-1415. doi: 10.1016/j.jid.2020.10.016. Epub 2020 Nov 11.
Patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy show diverse endocrine and nonendocrine manifestations initiated by self-reactive T cells because of AIRE mutation-induced defective central tolerance. A large number of American patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy suffer from early-onset cutaneous inflammatory lesions accompanied by an infiltration of T cells and myeloid cells. The role of myeloid cells in this setting remains to be fully investigated. In this study, we characterize the autoinflammatory phenotypes in the skin of both autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy-like kinase-dead Ikkα knockin mice and patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. We found a marked infiltration of autoreactive CD4 T cells, macrophages, and neutrophils; elevated uric acid; and increased NLRP3, a major inflammasome component. Depleting autoreactive CD4 T cells or ablating Ccl2/Cxcr2 genes significantly attenuated the inflammasome activity, inflammation, and skin phenotypes in kinase-dead Ikkα knockin mice. Importantly, treatment with an NLRP3 inhibitor reduced skin phenotypes and decreased infiltration of CD4 T cells, macrophages, and neutrophils. These results suggest that increased myeloid cell infiltration contributes to autoreactive CD4 T cell-mediated skin autoinflammation. Thus, our findings reveal that the combined infiltration of macrophages and neutrophils is required for autoreactive CD4 T cell-mediated skin disease pathogenesis and that the NLRP3-dependent inflammasome is a potential therapeutic target for the cutaneous manifestations of autoimmune diseases.
自身免疫性多内分泌腺病-念珠菌病-外胚层营养不良患者表现出多种内分泌和非内分泌表现，这是由于 AIRE 突变诱导的中枢耐受缺陷导致自身反应性 T 细胞的作用。大量患有自身免疫性多内分泌腺病-念珠菌病-外胚层营养不良的美国患者患有早期发病的皮肤炎症性病变，伴有 T 细胞和髓样细胞浸润。髓样细胞在这种情况下的作用仍有待充分研究。在这项研究中，我们描述了自身免疫性多内分泌腺病-念珠菌病-外胚层营养不良样激酶失活 IKKα 敲入小鼠和自身免疫性多内分泌腺病-念珠菌病-外胚层营养不良患者皮肤中的自身炎症表型。我们发现存在明显的自身反应性 CD4 T 细胞、巨噬细胞和中性粒细胞浸润；尿酸升高；以及 NLRP3（主要炎症小体成分）增加。耗竭自身反应性 CD4 T 细胞或敲除 Ccl2/Cxcr2 基因可显著减轻激酶失活 IKKα 敲入小鼠中的炎症小体活性、炎症和皮肤表型。重要的是，NLRP3 抑制剂的治疗可减轻皮肤表型并减少 CD4 T 细胞、巨噬细胞和中性粒细胞的浸润。这些结果表明，髓样细胞浸润的增加有助于自身反应性 CD4 T 细胞介导的皮肤自身炎症。因此，我们的发现表明，巨噬细胞和中性粒细胞的联合浸润是自身反应性 CD4 T 细胞介导的皮肤疾病发病机制所必需的，并且 NLRP3 依赖性炎症小体是自身免疫性疾病皮肤表现的潜在治疗靶点。
