ATG5-regulated CCL2/MCP-1 production in myeloid cells selectively modulates anti-malarial CD4 + Th1 responses

作者：Yuanli Gao, Suilin Chen, Shiming Jiao, Yongling Fan, Xiuxiu Li, Nie Tan, Jiaqin Fang, Luming Xu, Yi Huang, Jing Zhao, Shuai Guo, Taiping Liu, Wenyue Xu · 发表于：Autophagy · 年份：2024 · DOI：10.1080/15548627.2024.2319512 · 被引用次数：7 · 研究领域：Immune Cell Function and Interaction、Phagocytosis and Immune Regulation、HIV Research and Treatment

Parasite-specific CD4+ Th1 cell responses are the predominant immune effector for controlling malaria infection; however, the underlying regulatory mechanisms remain largely unknown. This study demonstrated that ATG5 deficiency in myeloid cells can significantly inhibit the growth of rodent blood-stage malarial parasites by selectively enhancing parasite-specific CD4+ Th1 cell responses. This effect was independent of ATG5-mediated canonical and non-canonical autophagy. Mechanistically, ATG5 deficiency suppressed FAS-mediated apoptosis of LY6G− ITGAM/CD11b+ ADGRE1/F4/80− cells and subsequently increased CCL2/MCP-1 production in parasite-infected mice. LY6G− ITGAM+ ADGRE1− cell-derived CCL2 selectively interacted with CCR2 on CD4+ Th1 cells for their optimized responses through the JAK2-STAT4 pathway. The administration of recombinant CCL2 significantly promoted parasite-specific CD4+ Th1 responses and suppressed malaria infection. Conclusively, our study highlights the previously unrecognized role of ATG5 in modulating myeloid cells apoptosis and sequentially affecting CCL2 production, which selectively promotes CD4+ Th1 cell responses. Our findings provide new insights into the development of immune interventions and effective anti-malarial vaccines.Abbreviations: ATG5: autophagy related 5; CBA: cytometric bead array; CCL2/MCP-1: C-C motif chemokine ligand 2; IgG: immunoglobulin G; IL6: interleukin 6; IL10: interleukin 10; IL12: interleukin 12; MFI: mean fluorescence intensi...