Macrophage diversity in different types of leprosy: a systematic review

Leprosy shows a clinicopathological spectrum that reflects divergent host responses to Mycobacterium leprae, with macrophages playing a central role in lesion immunopathology. This systematic review synthesised in situ evidence on marker-defined macrophage phenotypes in human leprosy skin lesions. A PRISMA-guided search identified 14 observational studies published between 1996 and 2023 that examined macrophage-associated markers in clinically classified skin biopsies using immunohistochemistry or lesion-based molecular approaches. Because the included studies were heterogeneous in marker panels, lesion classification, laboratory methods, and outcome reporting, findings were synthesised narratively rather than by meta-analysis. Tuberculoid-spectrum lesions were consistently associated with M1-related marker patterns, including NOS2 (iNOS), TNF-α, IL-6, and MMP-9, in keeping with preserved granuloma organisation and bacillary containment. Lepromatous lesions more often showed dominant M2-associated and M4-like marker-defined phenotypes, characterised by IL-10, CD163, ARG1, PPARG, STAT6, IDO, MRP8, and MMP7, consistent with immuno-regulatory, tissue-remodelling, and bacillus-permissive lesion environments. These findings improve lesion-level biological interpretation across the leprosy spectrum, but they do not yet support routine diagnostic, prognostic, or reaction-prediction use. Macrophage phenotypic reprogramming remains a hypothesis-generating translational direction requiring longitudinal validation.