Correia-Silva Rebeca D, Corrêa Mab P, de Castro Maria Eduarda, Almeida Joaquim S, D'Ávila Solange C G P, Oliani Sonia M, Greco Karin V, Gil Cristiane D
Departamento de Morfologia E Genética, Escola Paulista de Medicina (EPM), Universidade Federal de São Paulo (UNIFESP), Rua Botucatu 740, Ed. Lemos Torres - 3º andar, São Paulo, SP, 04023-900, Brazil.
Departamento de Patologia, EPM-UNIFESP, São Paulo, SP, 04023-900, Brazil.
J Mol Med (Berl). 2025 Apr;103(4):435-451. doi: 10.1007/s00109-025-02529-w. Epub 2025 Mar 18.
Despite the well-documented regulatory role of annexin A1 (ANXA1) in numerous stages of the inflammatory response, its involvement in regulating the NLRP3 inflammasome in the context of allergic responses has not been extensively investigated to date. This study evaluated the expression patterns of the ANXA1 and NLRP3 proteins in human skin samples obtained from patients with atopic dermatitis (AD) and in mice with ovalbumin (OVA)-induced experimental AD. Furthermore, the in vitro effect of the ANXA1 mimetic peptide Ac2-26 on IL-4-stimulated human keratinocytes was evaluated. IL-4-stimulated keratinocytes were treated with Ac2-26 (a mimetic peptide of ANXA1) in two different concentrations: 5 and 25 ng/mL. Additionally, some cells were treated with the pan-formyl peptide receptor antagonist Boc2 at a concentration of 10 µM, administered 15 min before Ac2-26. The NLRP3 protein demonstrated intense immunoreactivity in both murine and human AD skin samples, with NLRP3 and ANXA1 exhibiting particularly high coexpression in keratinocytes. A significant increase in ANXA1 and NLRP3 transcripts was observed in AD skins (GSE16161 study). ANXA1 transcript levels were elevated in the AD epidermis relative to the non-lesional epidermis, while NLRP3 transcript levels were reduced in the AD epidermis (GSE120721 study). The Ac2-26 treatment reduced the proliferation rate of IL-4-stimulated keratinocytes, an effect abolished by Boc2 and IL-1β and ROS production. In conclusion, our findings indicate that ANXA1 plays a role in regulating NLRP3 activation in keratinocytes, contributing to the pathogenesis of AD. KEY MESSAGES: ANXA1 and NLRP3 levels are upregulated and exhibit coexpression in murine and human AD skins. ANXA1-FPR axis regulates the proliferation of human keratinocytes under IL-4 stimulation. ANXA1-derived peptide Ac regulates oxidative stress and NLRP3 activation in human keratinocytes.
尽管膜联蛋白A1（ANXA1）在炎症反应的多个阶段的调节作用已有充分记录，但迄今为止，其在过敏反应背景下对NLRP3炎性小体的调节作用尚未得到广泛研究。本研究评估了从特应性皮炎（AD）患者获取的人类皮肤样本以及卵清蛋白（OVA）诱导的实验性AD小鼠中ANXA1和NLRP3蛋白的表达模式。此外，还评估了ANXA1模拟肽Ac2-26对IL-4刺激的人角质形成细胞的体外作用。用两种不同浓度（5和25 ng/mL）的Ac2-26（ANXA1的模拟肽）处理IL-4刺激的角质形成细胞。此外，一些细胞用浓度为10 μM的泛甲酰肽受体拮抗剂Boc2处理，在Ac2-26处理前15分钟给药。NLRP3蛋白在小鼠和人类AD皮肤样本中均显示出强烈的免疫反应性，NLRP3和ANXA1在角质形成细胞中表现出特别高的共表达。在AD皮肤中观察到ANXA1和NLRP3转录本显著增加（GSE16161研究）。相对于非病变表皮，AD表皮中ANXA1转录水平升高，而AD表皮中NLRP3转录水平降低（GSE120721研究）。Ac2-26处理降低了IL-4刺激的角质形成细胞的增殖率，Boc2、IL-1β和ROS产生消除了这种作用。总之，我们的研究结果表明ANXA1在调节角质形成细胞中NLRP3激活方面发挥作用，这有助于AD的发病机制。关键信息：ANXA1和NLRP3水平在小鼠和人类AD皮肤中上调并表现出共表达。ANXA1-FPR轴在IL-4刺激下调节人角质形成细胞的增殖。ANXA1衍生肽Ac调节人角质形成细胞中的氧化应激和NLRP3激活。
