Alox15 restrains glycolysis to support M2 macrophage effector function during helminth immunity

Ovezgeldiyev, D; Trefzer, V; Doolan, R; Moyat, M; Coakley, G; Wickramasinghe, LC; Daunt, C; Volpe, B; Henkel, F; Serra, A; Hartmann, M; Rezaei, S; Ubags, N; Butler, A; Chatzis, R; Marsland, BJ; Smith, AAT; Deveson Lucas, D; McGowan, ENS; Binger, KJ; McConville, MJ; Esser-von Bieren, J; Harris, NL; Bouchery, T

Author(s): Ovezgeldiyev, D; Trefzer, V; Doolan, R; Moyat, M; Coakley, G; Wickramasinghe, LC; Daunt, C; Volpe, B; Henkel, F; Serra, A; Hartmann, M; Rezaei, S; Ubags, N; Butler, A; Chatzis, R; Marsland, BJ; Smith, AAT; Deveson Lucas, D; McGowan, ENS; Binger, KJ; McConville, MJ; Esser-von Bieren, J; Harris, NL; Bouchery, T;
Details: Publication Year 2026-10-05,Volume 223,Issue #10,Page e20241620
Journal Title: Journal of Experimental Medicine
Abstract: 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.
Publisher: RUP
Keywords: *Arachidonate 15-Lipoxygenase/metabolism/genetics/immunology; *Macrophages/immunology/metabolism; Humans; Animals; *Glycolysis/immunology; Macrophage Activation
Research Division(s): Ubiquitin Signalling
PubMed ID: 42758314
Publisher's Version: https://doi.org/10.1084/jem.20241620
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2026-10-02 08:18:59

Last Modified: 2026-10-02 08:19:08