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Traditionally defined by histopathology and morphology, granulomas are now being revisited with high-throughput \u201comics approaches. The findings reveal previously unrecognized cellular diversity and cytokine gradients that together shape granuloma behavior. Across diverse pathogens, including Mycobacterium, Salmonella, Yersinia, and Brucella, bacterial effector proteins actively remodel macrophage activation states and cytokine responses to shape granuloma architecture. In parallel, host-driven programs involving IFN-mediated macrophage activation, regulatory cytokine niches, and fibroblast-dependent tissue remodeling establish an immunological landscape in which bacteria operate strategies to survive. Studies of granuloma biology reveal conserved cellular modules that transcend bacterial taxa and mirror features of noninfectious granulomatous inflammation, including iNOS+ core, fibroblast\/macrophage cuffs, neutrophil rims, and suppressive macrophage niches. In this review, we integrate these insights to propose a unifying framework in which granulomas represent adaptive but imperfect tissue responses balancing protection and pathology. Understanding how microbial effectors and host immune circuits jointly determine granuloma fate is essential for identifying mechanisms that could be targeted by host-directed strategies to therapeutically reprogram granulomatous inflammation to favor antimicrobial resolution.<\/jats:p>","DOI":"10.1093\/jleuko\/qiag045","type":"journal-article","created":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T11:41:06Z","timestamp":1775043666000},"source":"Crossref","is-referenced-by-count":1,"title":["Re-defining granulomas: bacterial effectors, host circuits, and spatially resolved immunity"],"prefix":"10.1093","volume":"118","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6717-545X","authenticated-orcid":false,"given":"Daniel S C","family":"Butler","sequence":"first","affiliation":[{"name":"Department of Clinical Sciences, Division of Infection Medicine, Lund University , BMC, B14, Klinikgatan 26, 222 42 Lund 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