Czárán Domonkos, Sasvári Péter, Lőrincz Kende, Ella Krisztina, Gellén Virág, Csépányi-Kömi Roland
Semmelweis University, Department of Physiology, Budapest, Hungary.
Semmelweis University, Department of Dermatology, Venereology and Dermatooncology, Budapest, Hungary.
Front Immunol. 2025 Feb 26;16:1509713. doi: 10.3389/fimmu.2025.1509713. eCollection 2025.
Contact hypersensitivity (CHS), or allergic contact dermatitis (ACD), is an inflammatory skin disorder characterized by an exaggerated allergic reaction to specific haptens. During this delayed-type allergic reaction, the first contact with the allergen initiates the sensitization phase, forming memory T cells. Upon repeated contact with the hapten, the elicitation phase develops, activating mostly macrophages, cytotoxic T cells, and neutrophilic granulocytes. Our group previously demonstrated that the leukocyte-specific GTPase-activating protein ARHGAP25 regulates phagocyte effector functions and is crucial in the pathomechanism of autoantibody-induced arthritis. Here, we investigate its role in the pathogenesis of the more complex inflammatory process of contact hypersensitivity.
For sensitization, the abdomens of wild-type and ARHGAP25 deficient (KO) mice on a C57BL/6 background, as well as bone marrow chimeric mice, were coated with 3% TNCB (2-chloro-1,3,5-trinitrobenzene) or acetone in the control group. After five days, ears were treated with 1% TNCB for elicitation. Swelling of the ears caused by edema formation was evaluated by measuring the ear thickness. Afterward, ears were harvested, and histological analysis, investigation of leukocyte infiltration, cytokine production, and changes in relevant signaling pathways were carried out. ARHGAP25 expression at the mRNA and protein levels was measured using murine ear and human skin samples.
ARHGAP25 expression increased in human patients suffering from contact dermatitis and in contact hypersensitivity induced in mice. Our data suggest that ARHGAP25 expression is infinitesimal in keratinocytes. In the CHS mouse model, the absence of ARHGAP25 mitigated the severity of inflammation in a leukocyte-dependent manner by reducing the infiltration of phagocytes and cytotoxic T cells. ARHGAP25 altered cytokine composition in the sensitization and elicitation phase of the disease. However, this protein did not affect T cell homing and activation in the sensitization phase.
Our findings suggest that ARHGAP25 is essential in developing contact hypersensitivity by modulating the cytokine environment and leukocyte infiltration. Based on these findings, we propose ARHGAP25 as a promising candidate for future therapeutic approaches and a potential ACD biomarker.
接触性超敏反应（CHS），即过敏性接触性皮炎（ACD），是一种炎症性皮肤病，其特征为对特定半抗原产生过度的过敏反应。在这种迟发型过敏反应中，首次接触过敏原会启动致敏阶段，形成记忆T细胞。再次接触半抗原时，激发阶段开始，主要激活巨噬细胞、细胞毒性T细胞和嗜中性粒细胞。我们的研究小组之前证明，白细胞特异性鸟苷三磷酸酶激活蛋白ARHGAP25调节吞噬细胞效应功能，并且在自身抗体诱导的关节炎发病机制中起关键作用。在此，我们研究其在更复杂的接触性超敏反应炎症过程发病机制中的作用。
为进行致敏，在C57BL/6背景的野生型和ARHGAP25缺陷（KO）小鼠以及骨髓嵌合小鼠的腹部涂抹3%三硝基氯苯（2-氯-1,3,5-三硝基苯），对照组涂抹丙酮。五天后，用1%三硝基氯苯处理耳朵以进行激发。通过测量耳朵厚度评估由水肿形成导致的耳朵肿胀。之后，采集耳朵，进行组织学分析、白细胞浸润研究、细胞因子产生情况以及相关信号通路变化的研究。使用小鼠耳朵和人类皮肤样本测量ARHGAP25在mRNA和蛋白质水平的表达。
在患有接触性皮炎的人类患者以及小鼠诱导的接触性超敏反应中，ARHGAP25表达增加。我们的数据表明，ARHGAP25在角质形成细胞中的表达极少。在CHS小鼠模型中，ARHGAP25的缺失通过减少吞噬细胞和细胞毒性T细胞的浸润，以白细胞依赖的方式减轻了炎症的严重程度。ARHGAP25在疾病的致敏和激发阶段改变了细胞因子组成。然而，这种蛋白质在致敏阶段不影响T细胞归巢和激活。
我们的研究结果表明，ARHGAP25通过调节细胞因子环境和白细胞浸润在接触性超敏反应的发展中至关重要。基于这些发现，我们提出ARHGAP25作为未来治疗方法的有希望的候选者以及潜在的ACD生物标志物。
