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Administration of rIL-33 Restores Altered mDC/pDC Ratio, MDSC Frequency, and Th-17/Treg Ratio during Experimental
Saikat Mukherjee1, Pronabesh Ghosh1, Soubhik Ghosh1
1Immunology Laboratory, Department of Zoology, University of Calcutta, 35, Ballygunge Circular Road, Kolkata 700019, West Bengal, India.
Abstract:
The onset of malaria causes the induction of various inflammatory markers in the host's body, which in turn affect the body's homeostasis and create several cerebral complications. Polarization of myeloid-derived suppressor cells (MDSCs) from the classically activated M1 to alternatively activated M2 phenotype increases the secretion of pro-inflammatory molecules. Treatment with recombinant IL-33 (rIL-33) not only alters this MDSC's polarization but also targets the glycolysis pathway of the metabolism in MDSCs, rendering them less immunosuppressive. Along with that, the Helper T-cells subset 17 (Th17)/T regulatory cells (Tregs) ratio is skewed towards Th17, which increases inflammation by producing more IL-17. However, treating with rIL-33 also helps to restore this ratio, which brings back homeostasis. During malaria infection, there is an upregulation of IL-12 production from dendritic cells along with a distorted myeloid dendritic cells (mDC)/plasmacytoid dendritic cells (pDC) ratio towards mDCs promoting inflammation. Administering rIL-33 will also subvert this IL-12 production and increase the population of pDC in the host's immune system during malaria infection, thus restoring mDC/pDC to homeostasis. Therefore, treatment with rIL-33 to reduce the pro-inflammatory signatures and maintenance of immune homeostasis along with the increase in survivability could be a potential therapeutic approach for cerebral malaria.
Insights
Recombinant IL-33 (rIL-33) therapy combats malaria-induced inflammation by modulating immune cell polarization and restoring homeostasis. This approach shows promise for treating cerebral malaria and improving patient survival.
Area of Science:
- Immunology
- Infectious Diseases
- Molecular Biology
Background:
- Malaria infection triggers inflammatory responses, disrupting host homeostasis and causing cerebral complications.
- Myeloid-derived suppressor cells (MDSCs) polarization to M2 phenotype and skewed T-helper 17 (Th17)/T regulatory cells (Tregs) ratio exacerbate inflammation.
- Dendritic cell imbalance, with increased myeloid dendritic cells (mDCs) and elevated IL-12, further promotes inflammation during malaria.
Purpose of the Study:
- To investigate the therapeutic potential of recombinant IL-33 (rIL-33) in managing malaria-induced inflammation and immune dysregulation.
- To assess the effects of rIL-33 on MDSC polarization, Th17/Tregs balance, and dendritic cell populations in malaria infection.
Main Methods:
- Treatment of malaria-infected hosts with rIL-33.
- Analysis of MDSC polarization from M1 to M2 phenotype.
- Evaluation of Th17/Tregs cell ratios and IL-17 production.
- Assessment of dendritic cell populations (mDC/pDC ratio) and IL-12 levels.
Main Results:
- rIL-33 treatment altered MDSC polarization, reducing their immunosuppressive function by targeting glycolysis.
- rIL-33 restored the Th17/Tregs ratio, mitigating IL-17-driven inflammation and promoting homeostasis.
- rIL-33 administration decreased IL-12 production and normalized the mDC/pDC ratio, favoring pDCs.
Conclusions:
- rIL-33 treatment effectively reduces pro-inflammatory signatures associated with malaria infection.
- rIL-33 helps maintain immune homeostasis and increases host survivability, presenting a potential therapeutic strategy for cerebral malaria.
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