Schmidt Christina, Harit Kunjan, Traidl Stephan, Naumann Michael, Werfel Thomas, Roesner Lennart M, Nishanth Gopala, Schlüter Dirk
Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany.
Department of Dermatology and Allergy, Hannover Medical School, Hannover, Germany.
Front Immunol. 2025 Jan 28;16:1507989. doi: 10.3389/fimmu.2025.1507989. eCollection 2025.
In atopic dermatitis (AD), lesional skin is frequently colonized by , which promotes clinical symptoms of the disease. The inflammatory milieu in the skin is characterized by a Th2 response, including M2 macrophages, which cannot eradicate . Therefore, repolarization of macrophages toward the M1 phenotype may foster control of . Our data show that the deubiquitinating enzyme cylindromatosis () is strongly expressed in macrophages of AD patients and prevents the clearance of . Mechanistically, impaired M1 macrophage polarization by K63-specific deubiquitination of STAT1 and activation of the NF-κB pathway via its interaction with TRAF6, NEMO, and RIPK2. Inhibition of STAT1 and NF-κB, independently, abolished the differences between -infected -deficient and -competent M1 macrophages. Infection of -deficient and wild-type mice with confirmed the protective CYLD function. Collectively, our study shows that impairs the control of in macrophages of AD patients, identifying CYLD as a potential therapeutic target.
在特应性皮炎（AD）中，病变皮肤常被[具体微生物名称未给出]定植，这会加重该疾病的临床症状。皮肤中的炎症环境以Th2反应为特征，包括M2巨噬细胞，而M2巨噬细胞无法清除[具体微生物名称未给出]。因此，将巨噬细胞重新极化至M1表型可能有助于控制[具体微生物名称未给出]。我们的数据表明，去泛素化酶圆柱瘤蛋白（CYLD）在AD患者的巨噬细胞中强烈表达，并阻止[具体微生物名称未给出]的清除。从机制上讲，CYLD通过对STAT1进行K63特异性去泛素化以及通过与TRAF6、NEMO和RIPK2相互作用激活NF-κB途径来损害M1巨噬细胞极化。单独抑制STAT1和NF-κB消除了感染[具体微生物名称未给出]的CYLD缺陷型和CYLD功能正常的M1巨噬细胞之间的差异。用[具体微生物名称未给出]感染CYLD缺陷型和野生型小鼠证实了CYLD的保护功能。总体而言，我们的研究表明CYLD损害了AD患者巨噬细胞对[具体微生物名称未给出]的控制，确定CYLD为潜在的治疗靶点。
