Interleukin-1β (IL-1β), a key pro-inflammatory cytokine, is majorly produced by macrophages through NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome, which has been identified as the culprit to deteriorate the inflammatory crosstalk between macrophages and adipocytes. Ainsliadimer C (AC) is a disesquiterpenoid isolated from Ainsliaea macrocephala. In the current study, we investigated the effects of AC on adipose tissue inflammation in co-culture of macrophages and adipocytes in vitro as well as in LPS-treated mice in vivo. We showed that AC (20–80 µM) dose-dependently inhibited the secretion of IL-1β from LPS plus ATP-stimulated THP-1 macrophages by inhibiting the activation of NLRP3 inflammasome. Furthermore, we found that AC treatment activated NAD⁺-dependent deacetylase Sirtuin 1 (SIRT1), resulting in reduced acetylation level of NLRP3. Molecular modeling analysis revealed that binding of AC to sirtuin-activating compound-binding domain increased the affinity of the substrate to the catalytic domain of SIRT1. Moreover, AC (80 µM) significantly attenuated macrophage-conditioned medium-induced inflammatory responses in 3T3-L1 adipocytes. In LPS-induced acute inflammatory mice, administration of AC (20, 60 mg·kg⁻¹·d⁻¹, ip) for 5 days significantly suppressed the pro-inflammatory cytokine levels in serum and epididymal white adipose tissue (eWAT), attenuated macrophage infiltration into eWAT, and mitigated adipose tissue inflammation. The beneficial effects of AC were blocked by co-administration of a selective SIRT1 inhibitor EX-527 (10 mg·kg⁻¹·d⁻¹). Taken together, AC suppresses NLRP3-mediated IL-1β secretion through activating SIRT1, leading to attenuated inflammation in macrophages and adipose tissue, which might be a candidate to treat obesity-associated metabolic diseases.

白细胞介素-1β (IL-1β) 是一种关键的促炎细胞因子，主要由巨噬细胞通过含有 NOD-、LRR- 和 Pyrin 结构域的蛋白 3 (NLRP3) 炎症小体产生，已被确定为恶化病情的罪魁祸首。巨噬细胞和脂肪细胞之间的炎症串扰。Ainsliadimer C (AC) 是从Ainsliaea macrocephala中分离出来的二倍半萜类化合物。在当前的研究中，我们在体外共培养巨噬细胞和脂肪细胞以及在体内LPS处理的小鼠中研究了AC对脂肪组织炎症的影响。我们发现，AC (20–80 µM) 通过抑制 NLRP3 炎性体的激活，剂量依赖性地抑制 LPS 加 ATP 刺激的 THP-1 巨噬细胞分泌 IL-1β。此外，我们发现 AC 治疗激活了 NAD ⁺依赖的去乙酰化酶 Sirtuin 1 (SIRT1)，导致 NLRP3 乙酰化水平降低。分子模型分析表明，AC 与 Sirtuin 激活化合物结合结构域的结合增加了底物与 SIRT1 催化结构域的亲和力。此外，AC (80 µM) 显着减弱 3T3-L1 脂肪细胞中巨噬细胞条件培养基诱导的炎症反应。在 LPS 诱导的急性炎症小鼠中，给予 AC (20, 60 mg·kg ⁻¹ ·d ⁻¹，ip）连续5天显着抑制血清和附睾白色脂肪组织（eWAT）中的促炎细胞因子水平，减弱巨噬细胞对eWAT的浸润，并减轻脂肪组织炎症。^{AC 的有益作用被选择性 SIRT1 抑制剂 EX-527 (10 mg·kg -1} ·d ^-1 )的共同给药所阻断。总而言之，AC 通过激活 SIRT1 抑制 NLRP3 介导的 IL-1β 分泌，从而减轻巨噬细胞和脂肪组织的炎症，这可能是治疗肥胖相关代谢疾病的候选药物。