Inflammatory restart: a unified framework for resolving chronic inflammation through epigenetic rejuvenation

Le résumé fourni par la source

Background: Chronic inflammation underlies a broad spectrum of human diseases, yet current therapeutic strategies predominantly rely on immunosuppression, which rarely achieves durable remission and often carries substantial adverse effects. Methods: We synthesized evidence from immunometabolism, resolution biology, mesenchymal stem cell biology, epigenetic rejuvenation, and geroscience to develop an integrative conceptual framework. References were identified through searches of PubMed, Google Scholar, and Web of Science up to April 2026. Findings: We introduce the Inflammatory Restart Paradigm—a reconceptualisation of inflammation as an evolutionarily programmed, self-organising cycle of tissue renewal rather than a pathological process to be suppressed. Central to this framework is the quantitative balance between two functionally opposing cytokine subsets operating as a molecular rheostat governing inflammatory trajectory. When balanced, the system progresses through coordinated phases of clearance, metabolic transition, regeneration, immune re-education, and epigenetic resetting. Rheostat imbalance leads to self-sustaining pathological circuits involving failed resolution, metabolic entrapment, pathological immune memory, and stromal dysregulation. We propose that the physiological purpose of inflammation extends beyond host defence to include periodic resetting of the epigenetic landscape. Interpretation: This framework reframes chronic inflammatory disease as failure of cycle completion and guides development of therapies designed to restore—rather than suppress—endogenous adaptive resolution capacity. Partial epigenetic reprogramming may represent not an exogenous intervention but an acceleration of natural regenerative mechanisms.

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