Phytomedicine : international journal of phytotherapy and phytopharmacology · 2025
Mechanism of Dihydroartemisinin in activating macrophages to enhance host resistance to malaria.
СтатьяНазвание и аннотация: Перевод пока не подготовлен
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Li Xin, Li Qilong, Jiang Ning, Zheng Kexin, Zhang Yiwei, Sang Xiaoyu, Feng Ying, Chen Ran, Chen Qijun
Аннотация
BACKGROUND: The property of dihydroartemisinin (DHA) in promoting host immunohomeostasis, apart from its potent antimalarial activity, has been well-recognized. However, the mechanism of DHA in activating macrophages to enhance host resistance to malaria remains unexplored.
PURPOSE: This study investigated the molecular mechanism by which DHA promotes the polarization of macrophages toward the M1 phenotype during the treatment of malaria.
METHODS: The mouse macrophage cell line RAW 264.7 or the macrophages isolated from mice were stimulated with Plasmodium berghei ANKA infected red blood cells (iRBC) in the presence of DHA. The macrophage phenotypes in both in vivo and in vitro were determined using cytometric bead array and flow cytometry. To dissect the molecular mechanisms underlying macrophage responses to DHA, we initially profiled the expression of 90 genes associated with innate immunity, including the entire NLR family, in macrophages stimulated with DHA. This targeted screen strikingly revealed that only Nlrp12 was significantly upregulated among all tested NLR genes. The function of Nlrp12 was further dissected by Nlrp12 knockdown in macrophages with recombinant lentiviruses encoding Nlrp12-specific shRNA, within the context of DHA treatment. To comprehensively define the molecular consequences of Nlrp12 deficiency, we performed an integrated analysis by combining single-cell RNA sequencing with label-free quantitative proteomic profiling. This allowed us to systematically characterize the complex transcriptomic and proteomic dynamics in DHA-treated macrophages upon Nlrp12 deletion.
RESULTS: DHA induced macrophage polarization to M1 phenotype and enhanced phagocytosis by up-regulating the expression of NLRP12. Nlrp12-knockdown in macrophages reduced the expression of M1 type-associated genes, resulting in a significantly increased expression of the translocator protein (TSPO), which suppressed the secretion of inflammation-associated cytokines and blunting macrophage M1 polarization. The results of single cell RNA sequencing further revealed that DHA promoted the conversion of classical M1 macrophages into lipocalin-2 (Lcn2) high M1 macrophages.
CONCLUSION: The activation of NLRP12 induced by DHA is crucial for M1 macrophage polarization, which plays a significant role in the clearance of Plasmodium parasites.
PURPOSE: This study investigated the molecular mechanism by which DHA promotes the polarization of macrophages toward the M1 phenotype during the treatment of malaria.
METHODS: The mouse macrophage cell line RAW 264.7 or the macrophages isolated from mice were stimulated with Plasmodium berghei ANKA infected red blood cells (iRBC) in the presence of DHA. The macrophage phenotypes in both in vivo and in vitro were determined using cytometric bead array and flow cytometry. To dissect the molecular mechanisms underlying macrophage responses to DHA, we initially profiled the expression of 90 genes associated with innate immunity, including the entire NLR family, in macrophages stimulated with DHA. This targeted screen strikingly revealed that only Nlrp12 was significantly upregulated among all tested NLR genes. The function of Nlrp12 was further dissected by Nlrp12 knockdown in macrophages with recombinant lentiviruses encoding Nlrp12-specific shRNA, within the context of DHA treatment. To comprehensively define the molecular consequences of Nlrp12 deficiency, we performed an integrated analysis by combining single-cell RNA sequencing with label-free quantitative proteomic profiling. This allowed us to systematically characterize the complex transcriptomic and proteomic dynamics in DHA-treated macrophages upon Nlrp12 deletion.
RESULTS: DHA induced macrophage polarization to M1 phenotype and enhanced phagocytosis by up-regulating the expression of NLRP12. Nlrp12-knockdown in macrophages reduced the expression of M1 type-associated genes, resulting in a significantly increased expression of the translocator protein (TSPO), which suppressed the secretion of inflammation-associated cytokines and blunting macrophage M1 polarization. The results of single cell RNA sequencing further revealed that DHA promoted the conversion of classical M1 macrophages into lipocalin-2 (Lcn2) high M1 macrophages.
CONCLUSION: The activation of NLRP12 induced by DHA is crucial for M1 macrophage polarization, which plays a significant role in the clearance of Plasmodium parasites.