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Updated: Jun 11, 2026
Isolation and Analysis of Brain-sequestered Leukocytes from Plasmodium berghei ANKA-infected Mice
Published on: January 2, 2013
IL-9 orchestrates MDSC expansion and inflammatory programming to amplify immunopathology during experimental cerebral
Pronabesh Ghosh1, Soubhik Ghosh2, Poulomi Khamaru1
1Immunology Lab, Department of Zoology, University of Calcutta, 35, Ballygunge Circular Road, Kolkata, 700019, India.
Abstract:
Pathogenesis of cerebral malaria, the most severe form of Plasmodium infection, has been well studied in experimental rodent models by using P. falciparum homologue P. berghei ANKA (PbA). Although Th-9 (CD4+ IL-9+) cells have been reported to be expanded during PbA infection, their functional effect on other immune cells, specifically macrophages, dendritic cells, and Myeloid Derived Suppressor Cells (MDSCs), and the crucial factors behind Th-9 differentiation are yet to be deciphered, which ultimately determines the disease burden. Here, we investigate how IL-9 regulates the immune-metabolic state of MDSCs and how MDSCs, through a positive feedback loop, control Th-9 differentiation during experimental cerebral malaria (ECM) in rodents upon infection with PbA. IL-9 played an important role in MDSC expansion and particularly PMN-MDSC proliferation. It also enhanced pro-inflammatory phenotype within MDSCs. Apart from MDSCs, IL-9 also induced the inflammatory phenotypes in macrophages and dendritic cells, thus exacerbating inflammation, leading to higher host morbidity. Neutralizing IL-9 in vivo reduced immunopathology and increased host survival during PbA infection. Conversely, depleting MDSCs led to a decrease of Th-9 cell population, their transcription factors, and down-regulated their migratory potentials, thus suggesting that these two cells work in a positive feedback mechanism. Elevated secretion of IL-1β from MDSCs was defined as a pivotal factor in controlling Th-9 differentiation. The findings highlight the potent role of IL-9 as a key component in host immune response modulation during ECM and hint toward a possible new adjunct therapeutic formulation by blocking IL-9.
Insights
Interleukin-9 (IL-9) drives myeloid-derived suppressor cells (MDSCs) and exacerbates experimental cerebral malaria (ECM). Blocking IL-9 or depleting MDSCs improves survival, revealing a crucial IL-9-MDSC feedback loop in disease pathogenesis.
Area of Science:
- Immunology
- Infectious Diseases
- Pathogenesis
Background:
- Cerebral malaria (CM) pathogenesis is studied in rodent models using Plasmodium berghei ANKA (PbA).
- The role of T helper 9 (Th-9) cells and their regulation of immune cells like myeloid-derived suppressor cells (MDSCs) in CM remains unclear.
- Understanding these interactions is crucial for determining disease burden.
Purpose of the Study:
- To investigate how IL-9 influences the immune-metabolic state of MDSCs.
- To elucidate the positive feedback mechanism between MDSCs and Th-9 cells in experimental cerebral malaria (ECM).
- To identify key factors controlling Th-9 differentiation during PbA infection.
Main Methods:
- Experimental rodent models of cerebral malaria (ECM) infected with Plasmodium berghei ANKA (PbA).
- In vivo neutralization of IL-9 and depletion of MDSCs.
- Analysis of immune cell populations (Th-9, MDSCs, macrophages, dendritic cells), their phenotypes, and cytokine secretion (IL-1β).
Main Results:
- IL-9 promoted MDSC expansion, proliferation (particularly PMN-MDSCs), and pro-inflammatory phenotype.
- IL-9 induced inflammatory phenotypes in macrophages and dendritic cells, worsening immunopathology and host morbidity.
- Neutralizing IL-9 reduced ECM pathology and increased survival; depleting MDSCs decreased Th-9 populations and function, indicating a feedback loop.
- MDSC-derived IL-1β was identified as a key factor controlling Th-9 differentiation.
Conclusions:
- IL-9 plays a significant role in modulating the host immune response during ECM.
- A positive feedback loop exists between IL-9, MDSCs, and Th-9 cells, contributing to disease pathogenesis.
- Blocking IL-9 presents a potential therapeutic strategy for managing experimental cerebral malaria.
