Inflammation is the most visible operational mode of immunity in tissues, translating danger sensing into coordinated vascular, cellular, and metabolic responses that restrict injury and initiate repair. However, the same pathways that protect acutely can become pathogenic when amplification is mis-tuned, tolerance checkpoints fail, or resolution programs stall. This Review synthesizes a circuit-level view of immune inflammation, integrating tissue-encoded cellular networks with modular molecular switches that govern initiation, escalation, and termination. First, it outlines how barrier tissues and tissue-resident immune populations establish local inflammatory set points and explain context-dependent outcomes, exemplified by microbiota-diet interactions that can either support interleukin-22-dependent homeostasis or exacerbate colitis. Then, by describing myeloid circuits as the primary link between perception and systemic consequences, highlighting emerging control layers in RNA metabolism, chromatin remodeling, regulated cell death, and efferocytosis that shape persistence versus regression. Next, it elucidates specific and memory lymphocyte programs that can also lead to tissue damage through tolerance disruption, checkpoint remodeling, or an immunosuppressive microenvironment. Finally, the focus is on the active phase of inflammation resolution, regulated by phased leukocyte degradation, apoptotic cell clearance, and tissue repair, including specific pro-resolution mediators acting as lipid instructions. These mediators complement anti-inflammatory blockade therapies. Across infection, immunometabolic disease, neuroinflammation, fibrosis, and cancer, a unifying principle emerges: durable therapy requires combining selective suppression of maladaptive amplification with restoration of resolution capacity and preservation of protective immune competence.

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