Modulating inflammation

"Modulating inflammation" describes pharmacological approaches to control excessive inflammatory responses rather than a discrete molecular target like a receptor or enzyme. Inflammasomes, multiprotein complexes (e.g., NLRP3, Pyrin) that activate caspase-1 to process pro-IL-1β and pro-IL-18 into mature cytokines, serve as key upstream mediators in these strategies, driving pyroptosis and innate immune amplification during pathogen or sterile insults.[1] Dysregulated inflammasome activation contributes to autoinflammatory diseases (e.g., CAPS, FMF), metabolic disorders, cancer, and neurodegeneration by promoting chronic IL-1 signaling.[1] Approved therapies indirectly modulate this via IL-1 blockade: anakinra (IL-1 receptor antagonist) for CAPS/FMF/gout, canakinumab (anti-IL-1β monoclonal antibody) for CAPS and post-MI inflammation (CANTOS trial), and rilonacept (IL-1 trap) for CAPS.[1] Experimental agents target upstream (e.g., NLRP3 inhibitors) or IL-18 (e.g., tadekinig alfa, GSK1070806).[1] Challenges include infection risks from innate immunity suppression, though lower than TNF inhibitors.[1] No single canonical target exists; efforts focus on pathway-selective inhibition to balance host defense and pathology.[1]

Strategies primarily involve targeting inflammasome pathways and IL-1/IL-18 cytokines. Approved therapies indirectly modulate this via IL-1 blockade (e.g., IL-1 receptor antagonism, anti-IL-1β monoclonal antibodies, IL-1 traps). Experimental agents target upstream components (e.g., NLRP3 inhibitors) or IL-18.