A hispanolone-derived diterpenoid inhibits M2-Macrophage polarization in vitro via JAK/STAT and attenuates chitin induced inflammation in vivo
A hispanolone-derived diterpenoid inhibits M2-Macrophage polarization in vitro via JAK/STAT and attenuates chitin induced inflammation in vivo
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DOI：
10.1016/j.bcp.2018.06.002
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发表时间：
2018-08-01
影响因子：
5.8
通讯作者：
Hortelano, Sonsoles
中科院分区：
文献类型：
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作者：
Jimenez-Garcia, Lidia;Angeles Higueras, Maria;Hortelano, Sonsoles
巨噬细胞是高度可塑性的细胞，它们响应环境信号而采用不同的功能表型。经典活化的巨噬细胞（M1）表现出促炎作用，介导宿主防御微生物或肿瘤细胞;而替代活化的巨噬细胞（M2）执行一系列生理过程，包括炎症，伤口修复和组织重塑。有趣的是，M2巨噬细胞参与了肿瘤进展、寄生虫感染和呼吸系统疾病等病理环境。因此，寻找能够控制巨噬细胞极化的新药物是基于新的治疗策略。在本研究中，我们评估了hispanolone衍生物8，9-dehydrohispanolone 15，16-lactol（DHHL）对M2巨噬细胞极化的影响。我们的研究结果表明，DHHL显着抑制IL-4或IL-13刺激的M2巨噬细胞活化，如M2标志物的表达减少所示。此外，DHHL抑制IL-4诱导的STAT-6和JAK-1酪氨酸磷酸化，表明该化合物通过抑制JAK-STAT信号通路抑制M2极化。最后，在体内M2极化模型中，DHHL通过给予几丁质阻止嗜酸性粒细胞募集和F4/80（+）-CD 206（+）M2样巨噬细胞的存在。总的来说，这些结果证实DHHL是一种新的巨噬细胞极化调节剂，适用于设计针对M2-巨噬细胞介导的病理的未来疗法。
Macrophages are highly plastic cells that adopt different functional phenotypes in response to environmental signals. Classically activated macrophages (M1) exhibit a pro-inflammatory role, mediating host defense against microorganisms or tumor cells; whereas alternatively activated macrophages (M2) perform a range of physio logical processes, including inflammation, wound repair and tissue remodeling. Interestingly, M2 macrophages have been involved in pathological settings such as tumor progression, parasitic infection and respiratory disorders. Consequently, the search of new agents able to control macrophage polarization is on the basis of new therapeutic strategies.In the present study, we have evaluated the effect of the hispanolone derivative 8,9-dehydrohispanolone 15,16-lactol (DHHL) on M2 macrophage polarization. Our results reveal that DHHL significantly inhibited IL-4 or IL-13-stimulated M2 macrophage activation, as showed by reduced expression of M2 markers. In addition, DHHL suppressed IL-4-induced STAT-6 and JAK-1 tyrosine phosphorylation, suggesting that this compound inhibited M2 polarization by suppressing the JAK-STAT signaling pathway. Finally, DHHL prevented eosinophil recruitment and the presence of F4/80(+)-CD206(+) M2-like macrophages in an in vivo model of M2 polarization via administration of chitin. Collectively, these results confirm DHHL as a novel regulator of macrophage polarization suitable to design future therapies towards M2-macrophages mediated pathologies.