Dovran Ovezgeldiyev

Macrophage polarization by type-2 cytokines is central to anti-helminth immunity and tissue repair. While some hallmark changes in macrophages are well-characterized and associated with protection against helminths, it is still unclear how macrophages exert their anti-helminth effects. In this context, we investigated arachidonate 15-lipoxygenase (LOX) (Alox15), a LOX well known for its role in macrophage polarization in the context of metabolic diseases, and a hallmark of type-2 macrophage (M2) human polarization. We show that in the absence of Alox15, M2 cannot trap and kill helminths. Surprisingly, expression of M2 markers was normal despite a loss of function. Instead, we found a concomitant increase in pro-inflammatory responses due to an uncontrolled activation of glycolysis. We further show that activation of Peroxisome proliferator-activated receptor-delta (PPAR-δ) by lipids downstream of docosapentaenoic acid (DPA) can restore normal glycolysis control, highlighting a novel role of lipids in the fine-tuning of the metabolic support required for optimal macrophage polarization.

Schistosomiasis remains a major global health burden, with praziquantel as the only available treatment despite limitations such as reduced efficacy against juvenile stages. Aryl hydantoins such as Ro 13-3978 (AR02) and its derivative AR102, exhibit potent in vivo activity against all major human schistosome species, yet lack direct in vitro efficacy, suggesting a host-directed mechanism. Here, we identify neutrophils as critical mediators of aryl hydantoin activity. In a murine model of Schistosoma mansoni infection, neutrophil depletion or enzymatic degradation of extracellular DNA significantly impaired drug efficacy. Using human neutrophil co-cultures, we show that schistosomes suppress extracellular trap formation (NETosis), but aryl hydantoins restore this response without directly inducing NETs. Proteomics revealed compound-dependent modulation of neutrophil activation pathways, including chromatin remodeling and degranulation, specifically in the presence of parasite-derived products. Compound effects were limited to PMA-induced NETosis, implicating a pathway downstream of ROS production. While the precise molecular target remains elusive, our findings provide key mechanistic insight into a unique host-directed anthelmintic strategy, highlighting a neutrophil-dependent mode of action that restores NETosis suppressed by schistosomes -offering a promising pathway for immunomodulatory anti-parasitic therapies.