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ATG5-regulated CCL2/MCP-1 production in myeloid cells selectively modulates anti-malarial CD4+Th1 responses
- Source :
- Autophagy; June 2024, Vol. 20 Issue: 6 p1398-1417, 20p
- Publication Year :
- 2024
-
Abstract
- ABSTRACTParasite-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 intensity; JAK2: Janus kinase 2; LAP: LC3-associated phagocytosis; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; pRBCs: parasitized red blood cells; RUBCN: RUN domain and cysteine-rich domain containing, Beclin 1-interacting protein; STAT4: signal transducer and activator of transcription 4; Th1: T helper 1 cell; Tfh: follicular helper cell; ULK1: unc-51 like kinase 1.
Details
- Language :
- English
- ISSN :
- 15548627 and 15548635
- Volume :
- 20
- Issue :
- 6
- Database :
- Supplemental Index
- Journal :
- Autophagy
- Publication Type :
- Periodical
- Accession number :
- ejs66741100
- Full Text :
- https://doi.org/10.1080/15548627.2024.2319512