Regulatory circuits that build and sustain noninfectious granulomas.

Abstract

Noninfectious granulomas organize immune cells into persistent tissue aggregates without an identifiable pathogen. Across diverse diseases, inflammation that should resolve instead persists, producing hallmark pathologic changes in tissue architecture that compromise organ function. Here, we synthesize recent studies to move beyond linear cytokine models and propose that granulomas persist through regulatory circuits linking immune cells, metabolism, and stroma. Maintenance reflects reinforcement among these local programs rather than a single inflammatory pathway. Comparisons across granulomatous diseases, including sarcoidosis, can distinguish disease-specific wiring from conserved maintenance programs. Defining these programs should identify strategies to dismantle established lesions.