Pharmacological control of inflammation via innate immune memory manipulation

Chronic inflammation underlies several common diseases although it is inadequately managed by conventional anti-inflammatory therapies that often suppress immune responses and have long-term adverse effects. Innate immune memory encompasses trained immunity and tolerance, which provide a comprehensive framework for persistent maladaptive innate responses that drive the pathogenesis of neurodegenerative disorders, oncological, cardiometabolic, and autoimmune diseases. This Invited Mini-Review elucidates the molecular mechanisms of innate immune memory including epigenetic reprogramming of chromatin configurations, metabolic rewiring towards glycolytic or oxidative metabolic pathways and the signaling of pattern recognition receptors (PRRs) and the NLRP3 inflammasome that reinforce either enhanced or diminished innate responsiveness. We subsequently discuss pharmacological strategies for selective modulation of innate immune memory. Epigenetic modulators including histone deacetylase (HDAC) and Bromodomain and Extra- Terminal Domain (BET) inhibitors may modify aberrant chromatin programs, while metabolic modulators like metformin and statins can influence their cellular bioenergetics and inflammatory response. Direct NLRP3 inflammasome inhibitors including MCC950 and INF-39 target maladaptive NLRP3 inflammasome signaling. MCC 950 was stopped at the preclinical stage due to hepatotoxicity. Early clinical studies of trained immunity include Bacillus Calmette-Guerin (BCG) vaccine and metabolic modulation. These studies provide evidence that innate immunity programming can be altered in humans, but clinical disease modifying efficacy has not yet been established. We examine translational obstacles and provide a strategy for precision immunopharmacology that incorporates molecular biomarkers, cell-type- and disease-specific targeting, and combinatorial methods to achieve selective immune reprogramming. The development of targeted modulators for innate immune memory will require robust biomarker frameworks. Such approaches may provide more effective and durable therapeutic advances for chronic inflammatory disorders while reducing global immunosuppression.