Arfath Yassir, Kotra Tusharika, Faizan Md Imam, Akhtar Areej, Abdullah Sheikh Tasduq, Ahmad Tanveer, Ahmed Zabeer, Rayees Sheikh
Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, 180001, India.
Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.
Inflamm Res. 2024 Oct;73(10):1687-1697. doi: 10.1007/s00011-024-01923-3. Epub 2024 Aug 5.
Transient receptor potential vanilloid type 4 (TRPV4) is a versatile ion channel with diverse roles in immune cells, including macrophages. While its function in inflammation remains debated, we investigated its role in regulating IL-10 production and its impact on macrophage reprogramming during inflammation.
We investigated the connection between TRPV4 activation and CREB-mediated IL-10 production during inflammation. Notably, this signaling pathway was found to reprogram macrophages and enhance their ability to resist inflammatory damage. The experiments were conducted on primary macrophages and were further corroborated by animal studies.
In response to TRPV4 activation during inflammation, we observed a significant increase in intracellular Ca levels, which triggered the activation of the transcription factor CREB, subsequently upregulating IL-10 production. This IL-10 played a pivotal role in reprogramming macrophages to withstand inflammatory damage. Using a mouse model of acute lung injury (ALI), we confirmed that TRPV4 activation during ALI led to IL-10 secretion, but this increase did not significantly contribute to inflammation resolution. Moreover, we found that TRPV4 prevented the accumulation of dysfunctional mitochondria in macrophages through the CREB-IL-10 axis during inflammation. Suppression of CREB or TRPV4 inhibition exacerbated mitochondrial dysfunction, while treatment with recombinant IL-10 mitigated these effects. Additionally, IL-10 induced mitophagy and cleared dysfunctional mitochondria in LPS-exposed cells.
Our study highlights the essential role of TRPV4 in regulating IL-10 production and mitochondrial health in macrophages during inflammation. These findings contribute to understand the role of TRPV4 in immune responses and suggest potential therapeutic targets for modulating inflammation-induced cellular dysfunction.
瞬时受体电位香草酸亚型4（TRPV4）是一种多功能离子通道，在免疫细胞（包括巨噬细胞）中发挥多种作用。虽然其在炎症中的功能仍存在争议，但我们研究了其在调节白细胞介素-10（IL-10）产生中的作用及其在炎症期间对巨噬细胞重编程的影响。
我们研究了炎症期间TRPV4激活与CREB介导的IL-10产生之间的联系。值得注意的是，发现该信号通路可使巨噬细胞重编程并增强其抵抗炎症损伤的能力。实验在原代巨噬细胞上进行，并通过动物研究进一步证实。
在炎症期间对TRPV4激活作出反应时，我们观察到细胞内钙水平显著升高，这触发了转录因子CREB的激活，随后上调了IL-10的产生。这种IL-10在使巨噬细胞重编程以耐受炎症损伤中起关键作用。使用急性肺损伤（ALI）小鼠模型，我们证实ALI期间TRPV4激活导致IL-10分泌，但这种增加对炎症消退没有显著贡献。此外，我们发现TRPV4在炎症期间通过CREB-IL-10轴防止巨噬细胞中功能失调的线粒体积累。抑制CREB或抑制TRPV4会加剧线粒体功能障碍，而用重组IL-10治疗可减轻这些影响。此外，IL-10诱导线粒体自噬并清除脂多糖暴露细胞中的功能失调线粒体。
我们的研究强调了TRPV4在炎症期间调节巨噬细胞中IL-10产生和线粒体健康方面的重要作用。这些发现有助于理解TRPV4在免疫反应中的作用，并提示了调节炎症诱导的细胞功能障碍的潜在治疗靶点。
