IL-9 orchestrates MDSC expansion and inflammatory programming to amplify immunopathology during experimental cerebral malaria.

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.