Sant'Ana Monielle, da Silva Rafael André, Ferreira Luiz Philipe S, Gil Cristiane D, Primo Fernando L, Girol Ana Paula, Greco Karin V, Oliani Sonia M
Structural and Functional Biology Graduated Program, Federal University of São Paulo (UNIFESP), São Paulo 09913-030, SP, Brazil.
Department of Biology, School of Biosciences, Humanities and Exact Sciences, São Paulo State University (UNESP), São José do Rio Preto 15054-000, SP, Brazil.
Cells. 2025 Jun 30;14(13):999. doi: 10.3390/cells14130999.
Chronic, non-resolving inflammation is a major contributor to impaired wound healing in diabetes. Annexin A1 (AnxA1), a pro-resolving mediator, and its mimetic peptide Ac have demonstrated therapeutic potential in modulating inflammatory responses. In this study, we evaluated the effects of topical Ac hydrogel in a streptozotocin-induced diabetic wound model. Treatment significantly accelerated wound closure, improved tissue architecture, and reduced leukocyte infiltration. Immunohistochemical analysis revealed diminished mast cell accumulation and IL-1β expression in treated wounds. Complementary transcriptomic profiling supported the downregulation of pro-inflammatory genes, including Il1b and mast cell-related mediators, confirming the peptide's regulatory effect on the wound immune landscape. Mounting evidence suggests that dysregulated mast cell activity plays a role in the heightened inflammatory tone and delayed tissue repair observed in diabetic wounds. In our model, Ac hydrogel treatment attenuated IL-1β expression, suggesting an indirect downregulation of NLRP3 inflammasome activation, potentially mediated through mast cell modulation, though effects on other cell types within the wound microenvironment cannot be excluded. While definitive causality cannot be assigned, the integration of histological and transcriptomic data highlights mast cells as contributors to the IL-1β-driven inflammatory burden in diabetic wounds. These findings underscore the immunomodulatory capacity of Ac and its potential to restore resolution pathways in chronic wound settings, positioning it as a promising candidate for future therapeutic development.
慢性、难愈性炎症是导致糖尿病患者伤口愈合受损的主要因素。膜联蛋白A1（AnxA1）是一种促消退介质，其模拟肽Ac已显示出在调节炎症反应方面的治疗潜力。在本研究中，我们评估了局部应用Ac水凝胶在链脲佐菌素诱导的糖尿病伤口模型中的作用。治疗显著加速了伤口愈合，改善了组织结构，并减少了白细胞浸润。免疫组织化学分析显示，治疗后的伤口中肥大细胞积聚和IL-1β表达减少。补充的转录组分析支持了包括Il1b和肥大细胞相关介质在内的促炎基因的下调，证实了该肽对伤口免疫格局的调节作用。越来越多的证据表明，肥大细胞活性失调在糖尿病伤口中观察到的炎症增强和组织修复延迟中起作用。在我们的模型中，Ac水凝胶治疗减弱了IL-1β的表达，提示NLRP3炎性小体激活可能通过肥大细胞调节间接下调，尽管不能排除对伤口微环境中其他细胞类型的影响。虽然无法确定明确的因果关系，但组织学和转录组数据的整合突出了肥大细胞是糖尿病伤口中IL-1β驱动的炎症负担的促成因素。这些发现强调了Ac的免疫调节能力及其在慢性伤口环境中恢复消退途径的潜力，使其成为未来治疗开发的有希望的候选者。
