<br>壳聚糖包被青蒿琥酯通过 STAT6 介导的巨噬细胞 M2 极化和肠道屏障保护来预防溃疡性结肠炎,International Journal of Biological Macromolecules

当前位置： X-MOL 学术 › Int. J. Biol. Macromol. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

壳聚糖包被青蒿琥酯通过 STAT6 介导的巨噬细胞 M2 极化和肠道屏障保护来预防溃疡性结肠炎
International Journal of Biological Macromolecules ( IF 7.7 ) Pub Date : 2023-10-27 , DOI: 10.1016/j.ijbiomac.2023.127680
Ya Tao ₁ , Lei Xu ₁ , Xiaopan Liu ₁ , Peijia Wang ₁ , Simin Wei ₁ , Yinmo Huang ₁ , Wenyi Gu ₂ , Ruonan Bo ₁ , Mingjiang Liu ₁ , Jie Yu ₃ , Jingui Li ₁

Affiliation

口服壳聚糖包衣青蒿琥酯（CPA）已被证明可有效预防小鼠溃疡性结肠炎（UC）。然而，抗炎机制尚不完全清楚。STAT6 是一种关键的转录因子，通过诱导 M2 和 Th2 显性表型来促进抗炎作用，因此我们假设 STAT6 可能在此过程中发挥关键作用。为了证明这一点，在小鼠 UC 模型中建立并研究了 STAT6 基因敲除巨噬细胞系（STAT6−/− RAW264.7，通过 CRISPR/Cas9 方法）及其相应的 Caco-2/RAW264.7 共培养系统联合 STAT6 抑制剂（AS1517499，AS）。结果显示，CPA 显著抑制 TLR-4/NF-κB 通路的激活和促炎细胞因子的 mRNA 水平，同时增加 RAW264.7 中的 IL-10 水平。CPA 的这种作用有助于保护 Caco-2 中的 ZO-1，而 ZO-1 在刺激巨噬细胞时被破坏。同时，CPA 降低了 CD86 的表达，但增加了 LPS 刺激的 RAW264.7 细胞中 CD206 和 p-STAT6 的表达。然而，上述改变并不像 STAT6−/− RAW264.7 及其共培养系统那样明显，表明 STAT6 起关键作用。此外，CPA 处理显著抑制了 DSS 诱导的 TLR-4/NF-κB 活化、肠道巨噬细胞 M1 极化和粘膜屏障损伤，同时促进了 UC 小鼠模型中 STAT6 磷酸化，但这种作用也被 AS 显着抵消。因此，我们的数据表明，STAT6 是 CPA 的 M1/M2 极化平衡、肠道屏障完整性和抗结肠炎作用的主要调节因子。这些发现拓宽了我们对 CPA 如何对抗 UC 的理解，并暗示了通过该途径治疗 UC 的替代治疗策略。

"点击查看英文标题和摘要"

Chitosan-coated artesunate protects against ulcerative colitis via STAT6-mediated macrophage M2 polarization and intestinal barrier protection

Oral delivery of chitosan-coated artesunate (CPA) has been proven to be effective at preventing ulcerative colitis (UC) in mice. However, the anti-inflammatory mechanism is not fully understood. STAT6 is a key transcription factor that promotes anti-inflammatory effects by inducing M2 and Th2 dominant phenotypes, therefore we hypothesized STAT6 might play a key role in the process. To prove it, a STAT6 gene knockout macrophage cell line (STAT6−/− RAW264.7, by CRISPR/Cas9 method), and its corresponding Caco-2/RAW264.7 co-culture system combined with the STAT6 inhibitor (AS1517499, AS) in a mouse UC model were established and studied. The results showed that CPA remarkably suppressed the activation of TLR-4/NF-κB pathway and the mRNA levels of proinflammatory cytokines, while increased the IL-10 levels in RAW264.7. This effect of CPA contributed to the protection of the ZO-1 in Caco-2 which was disrupted upon the stimulation to macrophages. Simultaneously, CPA reduced the expression of CD86 but increase the expression of CD206 and p-STAT6 in LPS-stimulated RAW264.7 cells. However, above alterations were not obvious as in STAT6−/− RAW264.7 and its co-culture system, suggesting STAT6 plays a key role. Furthermore, CPA treatment significantly inhibited TLR-4/NF-κB activation, intestinal macrophage M1 polarization and mucosal barrier injury induced by DSS while promoted STAT6 phosphorylation in the UC mouse model, but this effect was also prominently counteracted by AS. Therefore, our data indicate that STAT6 is a major regulator in the balance of M1/M2 polarization, intestinal barrier integrity and then anti-colitis effects of CPA. These findings broaden our understanding of how CPA fights against UC and imply an alternative treatment strategy for UC via this pathway.

更新日期：2023-10-27

点击分享查看原文

点击收藏

阅读更多本刊新发论文本刊介绍/投稿指南