Alox15 diminishes inflammation by inducing STING and Type I Interferon production in response to schistosome eggs in dendritic cells 2259492

Abstract

Abstract Introduction Schistosomes are trematode helminths that cause widespread. Schistosoma mansoni (S. mansoni) infection causes a spectrum of hepato-intestinal disease driven largely by host CD4+ T cell responses to egg antigens: CBA mice develop severe, Th17-biased hepatic granulomas, while C57BL/6 (BL/6) mice show smaller, Th2-dominant lesions. The host factors that determine this divergent pathology remain unclear. Arachidonate 15-lipoxygenase (ALOX15) produces specialized pro-resolving mediators (SPMs) from polyunsaturated fatty acids that limit inflammation. Separately, STING signaling promotes type I interferon responses and can shape downstream immune programs. We hypothesize that STING-mediated induction of ALOX15 generates SPMs that restrain egg-induced inflammation and thereby modulate disease severity. Methods Alox15 mRNA/protein in bone marrow—derived dendritic cells (BMDCs) from high-pathology CBA and low-pathology BL/6 mice, including BL/6 STING Knockouts were assessed by RT-qPCR and immunoblot analysis. Functional effects were assessed by inhibiting ALOX15 with ML351 and measuring cytokine output after egg stimulation. Results BMDCs from CBA mice showed substantially reduced Alox15 expression at both transcript and protein levels compared with BL/6 controls. Importantly, STING deficiency in BL/6 BMDCs led to a marked drop in Alox15 expression after egg stimulation, supporting a model in which STING activity promotes Alox15 expression. Functionally, pharmacologic blockade of ALOX15 with ML351 potentiated IL-1β production by egg-stimulated DCs, shifting the cytokine milieu toward a pro-inflammatory profile known to favor Th17 differentiation and enhanced immunopathology. Conclusion ALOX15 is a STING-regulated checkpoint in DCs that limits pro-inflammatory cytokine output and may protect against exaggerated egg-driven hepatic pathology. Enhancing ALOX15—SPM signaling or restoring STING-dependent ALOX15 induction warrants exploration as a host-directed strategy to promote resolution in schistosomiasis. Funding Source NIH NIAID R01 AI018919 Topic Categories Innate Immune Responses and Host Defense: Molecular Mechanisms (INM)