Sex Differences in Metabolite-Immune Circuits of Neuroinflammation

Abstract

Sex is a fundamental yet underexplored determinant of human neuroinflammation. Across autoimmune, neurodegenerative, and post-infectious neurological syndromes, males and females exhibit consistent differences in disease vulnerability, progression, and immune tone. While sex hormones and chromosomes strongly shape immune development and function in health and disease, they do not fully explain the magnitude or disease-specific patterns of these disparities, nor do they provide sufficient mechanistic information for developing novel therapeutics. Emerging evidence suggests that sex-defining factors interact with age and environment to shape downstream metabolite-immune circuits, networks in which metabolic enzymes, metabolites, and immune cells tune inflammatory set points. Pathways spanning purine metabolism, glycolytic remodeling, lipid sensing, mitochondrial stress, and nucleic-acid sensing can recalibrate microglial activation thresholds, T-cell cytokine programs, innate type I interferon antiviral responses, and shape overall CNS resilience in a sex-dependent manner. Here, we synthesize mechanistic and human systems-level studies to propose an integrated framework in which sex-biased immunometabolism serves as a mechanistic bridge between biological sex and neuroimmune disease risk, progression, and responses to injury. We highlight key knowledge gaps and discuss how targeting metabolite-immune pathways may enable sex-informed biomarkers and therapeutic strategies in neuroinflammatory disease.

Keywords: bio‐active lipids; immunometabolism; microglia; neuroinflammation; purine metabolism; sex differences.

FIGURE 1

Sex‐biased immunometabolic programs shape microglial IFN signaling and neuroinflammatory vulnerability. This figure summarizes sex‐associated differences in microglial immunometabolic programs that shape innate immune signaling and neuroinflammatory outcomes across neurodegenerative and neuroinflammatory diseases. Male‐ and female‐associated features are shown as enriched tendencies across models and disease contexts, rather than mutually exclusive states. Male‐biased microglial programs are characterized by increased reliance on lipid catabolism and oxidative phosphorylation (OXPHOS), enhanced inflammasome‐associated signaling, and androgen‐modulated eicosanoid pathways. Higher ADA1/ADA2 activity promotes efficient purine clearance and is associated with a lower basal type I interferon (IFN‐I) tone. Functionally, these programs bias microglia toward lipid‐ and inflammasome‐driven inflammatory states, increased chronic lesion burden, and heightened sensitivity to mitochondrial and oxidative stress. Female‐biased microglial programs preferentially engage glycolytic and ECAR‐high metabolic states, coupled to stronger IFN‐responsive transcriptional programs. Reduced ADA1/ADA2 activity permits purine accumulation, facilitating SAM‐dependent derepression of endogenous retroelements and amplification of IFN‐β and interferon‐stimulated gene expression. These states are associated with early IFN priming, increased phagolysosomal activity, impaired plaque clearance, and enhanced synaptic engulfment or pruning. Together, these sex‐biased immunometabolic programs converge on the purine‐interferon axis, providing a conceptual framework for how biological sex modulates microglial IFN tone, inflammatory trajectories, and susceptibility to neurodegenerative pathology.