Rewiring immunity: How macrophage steroid metabolism directs inflammatory disease

Macrophages are highly adaptable innate immune cells whose functional states are shaped by microenvironmental cues, including locally generated steroids. Beyond systemic hormone effects, intracrine steroid metabolism within macrophages, particularly glucocorticoid activation by 11β-HSD1, emerges as a key regulator of inflammatory polarisation. Local glucocorticoid regeneration promotes a pro-resolving, tissue-repair phenotype by suppressing pro-inflammatory cytokines and enhancing phagocytic clearance. Inflammatory cues also remodel androgen metabolism through coordinated regulation of 11β-HSD1, AKR1C3 and 5α-reductase, enabling intracrine production of testosterone, dihydrotestosterone and aromatase-dependent oestradiol. Although sex steroids likely contribute to sexual dimorphism in inflammatory disease, their macrophage-specific functions remain incompletely defined. Overall, macrophage steroid metabolism represents a critical yet underappreciated determinant of inflammatory and malignant disease, with exciting biomarker and therapeutic application.