Exploratory Analysis of the Inhibitory Effects of Propranolol on NLRP3 and Pyrin Inflammasomes.

OBJECTIVE: Propranolol, a nonselective beta receptor blocking agents, impacts cAMP levels and is commonly used to treat hypertension and hemangioma in children and adults. Although there are reports indicating its anti-inflammatory properties, the exact mechanism is not fully understood. METHODS: Murine and human monocytes and macrophages were exposed to ATP and lipopolysaccharide (LPS), as well as Clostridioides difficile toxin A (TcdA) and LPS in the presence or absence of propranolol. Levels of interleukin-1β (IL-1β), tumor necrosis factor α, and IL-6 were then measured. This same process was repeated with monocytes obtained from six different patients with familial Mediterranean fever (FMF). In a murine atherosclerosis model, a model known to be highly impacted by inflammasome activation, propranolol was administered through drinking water, and the size of aortic plaques was measured. RESULTS: Propranolol was found to decrease the production and secretion of IL-1β in both murine and human monocytes and macrophages following activation of the NLRP3 inflammasome, accompanied by reduced caspase-1 levels in human cells. Propranolol treatment effectively prevented IL-1β production in monocytes from healthy donors and patients with FMF after stimulation with the NLRP3 inflammasome activators LPS and ATP, as well as the pyrin inflammasome activator TcdA. In mice, propranolol treatment also resulted in reduced aortic plaque formation. CONCLUSION: This exploratory study suggests that propranolol inhibits both the NLRP3 and pyrin inflammasomes in murine and human monocytes and macrophages. Given its established safety profile and approval for pediatric use, propranolol warrants further investigation as a potential treatment for refractory FMF, particularly in regions with limited access to IL-1β blockade.