Professor Qijun Chen's research team at Shenyang Agricultural University revealed the regulatory mechanism of dihydroartemisinin on Ly6G+ neutrophils in immune responses to malaria

Background:

Malaria, an infectious disease caused by Plasmodium parasites, is pathologically linked to the dynamic equilibrium of host innate immune responses. Neutrophils, as pivotal effector cells of the innate immune system, constitute the first line of defense against pathogen invasion. Previous work by Professor Qijun Chen's team demonstrated that neutrophils significantly suppress Plasmodium proliferation during early infection through the release of neutrophil extracellular traps (NETs). However, the precise functional specialization and regulatory dynamics of neutrophil subsets during malaria infection have yet to be fully elucidated. Building upon these findings, the team's preliminary investigations revealed that oral gavage administration of dihydroartemisinin (DHA)—a widely deployed antimalarial drug—in murine models induced a marked elevation in the proportion of splenic Ly6G⁺ neutrophils. Nevertheless, the mechanistic basis underlying the antimalarial efficacy of this specific neutrophil subpopulation, particularly its immunomodulatory capacity, remains deep exploration.

Advance:

The research team led by Professor Qijun Chen at Shenyang Agricultural University found that Plasmodium berghei-infected mice exhibit a striking expansion of Ly6G⁺ neutrophils in both peripheral blood and splenic compartments. Strikingly, antibody-mediated depletion of this specific neutrophil subpopulation resulted in exacerbated parasitemia and significantly abbreviated survival compared to the control groups (Figure 1).

They also observed a marked elevation of serum IL-17 following Plasmodium berghei infection. IL-17 neutralization resulted in exacerbated parasitemia and substantially diminished survival rates. Mechanistic investigations revealed a mutually regulatory interplay between Ly6G⁺ neutrophils and IL-17: antibody-mediated depletion of Ly6G⁺ neutrophils triggered a paradoxical surge in systemic IL-17 levels, whereas IL-17 blockade reciprocally amplified neutrophil activation, establishing a bidirectional immunoregulatory axis critical for malaria pathogenesis (Figure 2).

To investigate DHA-mediated regulation on neutrophils, they administered DHA via oral gavage over sequential days in murine models. Pharmacological profiling revealed that DHA augmented transcriptional activation of CD18 and CXCR4, thereby orchestrating bone marrow-derived Ly6G⁺ neutrophils mobilization to peripheral circulation and splenic niches, which potentiated their antimalarial effector functions. Mechanistically, this process appears governed by the p38 mitogen-activated protein kinase (MAPK)/monocyte chemoattractant protein-1 (MCP-1) signaling axis, as evidenced by pathway inhibition assays (Figure 3). Critically, neutrophil-depletion experiments established the centrality of Ly6G⁺ cells in DHA-induced immunomodulation. Following using anti-Ly6G for deleting Ly6G⁺ neutrophils and oral administration of DHA, a marked reduction in splenic T-cell subsets (CD3⁺, CD4⁺, CD8⁺) was observed, concomitant with a significant expansion of myeloid cell populations including dendritic cells, macrophages, and monocytes (Figure 3).

These findings elucidated the pivotal role of Ly6G⁺ neutrophils and IL-17 signaling in counteracting Plasmodium infection, and delineated DHA's mechanism of action through augmentation of neutrophil-mediated immunity. Collectively, this work provides paradigm-shifting insights into malaria immunopathology, redefining neutrophil-cytokine crosstalk as a central immunological axis governing host-parasite equilibrium.

Future directions:

This study establishes novel therapeutic paradigms and druggable targets for malaria intervention. Elucidating the crosstalk between Ly6G⁺ neutrophils and IL-17 signaling during Plasmodium infection provides a framework for developing precision immunotherapies by amplification of host protective responses to malaria.