2. Academic Validation
  3. Mechanism of Dihydroartemisinin in activating macrophages to enhance host resistance to malaria

Mechanism of Dihydroartemisinin in activating macrophages to enhance host resistance to malaria

  • Phytomedicine. 2025 Jul 25:143:156913. doi: 10.1016/j.phymed.2025.156913.
Xin Li 1,  Qilong Li 1,  Ning Jiang 1,  Kexin Zheng 1,  Yiwei Zhang 1,  Xiaoyu Sang 1,  Ying Feng 1,  Ran Chen 1,  Qijun Chen 2
Affiliations

Affiliations

  • 1 Key Laboratory of Livestock Infectious Diseases, Ministry of Education, and Key Laboratory of Ruminant Infectious Disease Prevention and Control (East), Ministry of Agriculture and Rural Affairs, College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, 120 Dongling Road, Shenyang 110866, PR China; Research Unit for Pathogenic Mechanisms of Zoonotic Parasites, Chinese Academy of Medical Sciences, 120 Dongling Road, Shenyang 110866, PR China.
  • 2 Key Laboratory of Livestock Infectious Diseases, Ministry of Education, and Key Laboratory of Ruminant Infectious Disease Prevention and Control (East), Ministry of Agriculture and Rural Affairs, College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, 120 Dongling Road, Shenyang 110866, PR China; Research Unit for Pathogenic Mechanisms of Zoonotic Parasites, Chinese Academy of Medical Sciences, 120 Dongling Road, Shenyang 110866, PR China. Electronic address: qijunchen759@syau.edu.cn.
PMID: 40450979 DOI: 10.1016/j.phymed.2025.156913
Abstract

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.

Keywords

Dihydroartemisinin; Immunoregulation; Macrophage; Malaria; Plasmodium.

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