Manni Giorgia, Barcelos Estevao Carlos Silva, Ricciuti Doriana, Pieroni Benedetta, Gargaro Marco, Mencarelli Giulia, Acha-Orbea Hans, Talesa Vincenzo Nicola, Mezzasoma Letizia, Fallarino Francesca
Department of Medicine and Surgery, University of Perugia, Perugia, Italy.
Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy.
Cell Mol Life Sci. 2025 Jul 11;82(1):273. doi: 10.1007/s00018-025-05769-8.
Natriuretic Peptides (NPs), including atrial (ANP) and brain (BNP) types, exert pleiotropic effects in regulating immune responses via the Natriuretic Peptide Receptor-1 (NPR1), expressed across various immune cells. While NPs are established inhibitors of inflammasome activation and IL-1β secretion in human monocytes, their role in dendritic cells (DCs)-key regulators of innate and adaptive immunity-remains unclear. Inflammasome activation in DCs can yield both protective and detrimental outcomes depending on the context of the disease, suggesting that modulating this pathway could offer a promising pharmacological strategy for controlling immune responses. This study explored the regulation of the NLRP3 inflammasome by NPs in two conventional DC subsets: cDC1 and cDC2. We found that both subsets express basal levels of the NPR1 receptor, which increase under inflammatory conditions. Additionally, cDCs themselves produce ANP and BNP during inflammation. Although both subsets express basal levels of NLRP3 inflammasome proteins, cDC2 display a more robust NLRP3/IL-1β activation in response to LPS + ATP stimulation compared to cDC1. Notably, the NPs/NPR1 axis suppresses NLRP3 activation more effectively in the cDC2 subset by acting at translational and post-translational levels. These findings highlight NPs as a novel mechanism for controlling the inflammatory phenotype of cDCs and underscores NPs/NPR1 axis as therapeutic target for immune modulation of DC subsets.
利钠肽（NPs），包括心房利钠肽（ANP）和脑利钠肽（BNP），通过在各种免疫细胞中表达的利钠肽受体-1（NPR1），在调节免疫反应中发挥多效性作用。虽然NP是人类单核细胞中已确定的炎性小体激活和白细胞介素-1β分泌的抑制剂，但其在树突状细胞（DCs）——先天性和适应性免疫的关键调节因子——中的作用仍不清楚。DCs中的炎性小体激活根据疾病背景可产生保护性和有害性两种结果，这表明调节该途径可能为控制免疫反应提供一种有前景的药理学策略。本研究探讨了NP对两种传统DC亚群：cDC1和cDC2中NLRP3炎性小体的调节作用。我们发现这两个亚群均表达基础水平的NPR1受体，在炎症条件下其表达会增加。此外，cDCs自身在炎症期间会产生ANP和BNP。虽然两个亚群均表达基础水平的NLRP3炎性小体蛋白，但与cDC1相比，cDC2在受到脂多糖+三磷酸腺苷刺激时表现出更强的NLRP3/白细胞介素-1β激活。值得注意的是，NP/NPR1轴通过在翻译和翻译后水平发挥作用，在cDCs2亚群中更有效地抑制NLRP3激活。这些发现突出了NP作为控制cDCs炎症表型的一种新机制，并强调NP/NPR1轴作为DC亚群免疫调节治疗靶点的重要性。
