Cellular and Molecular Immunology Research Unit (CMIRU), Faculty of Allied Health Sciences, Naresuan University, Phitsanulok, Thailand.
Front Immunol. 2022 Apr 19;13:856296. doi: 10.3389/fimmu.2022.856296. eCollection 2022.
Macrophages are a type of innate immune cell that activates the NLRP3 inflammasome, causing the release of the cytokine IL-1β, which is a crucial mediator of the inflammatory response. NLRP3 activation that is dysregulated worsens a variety of inflammatory and autoimmune diseases, as well as neurodegenerative diseases. Oleamide is an endogenous fatty acid amide that was first determined as a sleep-inducing molecule and later shown to have wide-ranging beneficial effects on the central nervous system. How oleamide influences human macrophage polarization and NLRP3-inflammasome activation remains unclear. The effect of oleamide on macrophage polarization was explored using an culture of primary human monocyte-derived macrophages (MDMs) supplemented with human serum-containing media. Cellular and molecular mechanisms of oleamide-regulated MDMs polarization were also investigated. Results showed that oleamide promoted naïve macrophages (M0) toward the M1 phenotype by upregulating M1-associated genes (, , ), along with downregulation of M2-associated genes (, , ). Cell surface expression indicated that oleamide enhanced CD80 expression in M0 naïve macrophages and hider CD206 and CD163 expression in M2 macrophages. Higher production of IL-1β cytokine was observed but with no alteration in IL-6 and TNF-α levels by MDMs and differentiated THP-1 models. Whether oleamide functioned as a second signal that activated the NLRP3 inflammasome and mediated IL-1β production was further investigated using LPS-primed MDMs followed by oleamide treatment that induced activation of inflammasome-related proteins including NLRP3, ASC, cleaved casp-1, and cleaved IL-1β. These findings suggested that oleamide promoted M1 macrophage polarization and increased IL-1β production by activating the NLRP3 inflammasome in primary MDMs. This research reveals a new function for oleamide as well as prospective targets for treating NLRP3-related inflammatory disorders.
巨噬细胞是先天免疫细胞的一种，可激活 NLRP3 炎性体，导致细胞因子 IL-1β 的释放，后者是炎症反应的关键介质。NLRP3 激活失调会加重各种炎症和自身免疫性疾病以及神经退行性疾病。油酸酰胺是一种内源性脂肪酸酰胺，最初被确定为诱导睡眠的分子，后来被证明对中枢神经系统有广泛的有益作用。油酸酰胺如何影响人巨噬细胞极化和 NLRP3 炎性体激活尚不清楚。使用含有人血清的培养基补充的原代人单核细胞衍生的巨噬细胞（MDM）培养物来探索油酸酰胺对巨噬细胞极化的影响。还研究了油酸酰胺调节 MDM 极化的细胞和分子机制。结果表明，油酸酰胺通过上调 M1 相关基因（、和），同时下调 M2 相关基因（、和），促进幼稚巨噬细胞（M0）向 M1 表型极化。细胞表面表达表明，油酸酰胺增强了幼稚巨噬细胞（M0）中 CD80 的表达，而在 M2 巨噬细胞中降低了 CD206 和 CD163 的表达。观察到更高水平的 IL-1β 细胞因子产生，但 MDM 和分化的 THP-1 模型中的 IL-6 和 TNF-α 水平没有改变。进一步使用 LPS 诱导的 MDM 进行研究，然后用油酸酰胺处理，以激活包括 NLRP3、ASC、切割的 caspase-1 和切割的 IL-1β 在内的炎性体相关蛋白，以研究油酸酰胺是否作为激活 NLRP3 炎性体并介导 IL-1β 产生的第二信号。这些发现表明，油酸酰胺通过激活原代 MDM 中的 NLRP3 炎性体促进 M1 巨噬细胞极化并增加 IL-1β 的产生。这项研究揭示了油酸酰胺的新功能以及治疗 NLRP3 相关炎症性疾病的潜在靶标。
