Secoisolariciresinol diglucoside ameliorates muscarinic acetylcholine receptor mediated activation of NLRP3 inflammasome in cardiomyocytes.

BACKGROUND

Secoisolariciresinol diglucoside (SDG), the main lignan found in flaxseed, contributes to cardioprotection. However, its molecular mechanism of action remains unknown. NOD-like receptor protein containing domain 3 (NLRP3), a critical mediator in inflammatory pathways, is one of the key players in cardiovascular disease progression and is a promising target for cardioprotective interventions. This study investigated the immunomodulatory effect of SDG in regulating acetylcholine receptor-mediated activation of the NLRP3 inflammasome.

METHODS AND

RESULTS

HL-1 mouse cardiomyocytes were treated with carbachol, a cholinergic agonist, and analyzed for the expression and activation of NLRP3 family members (NLRP3, ASC, Caspase-1, IL-18, and IL-1beta). Investigations included preconditioning with SDG, NF-kappa B (NF-κB) inhibitor, or antagonists for acetylcholine receptors. NLRP3 components and NF-κB were analyzed by immunostaining and immunofluorescence. Caspase-1 activity and gasdermin D expression were studied as the functional endpoints of NLRP3 activation. Carbachol induced the activation of NLRP3 inflammasomes in HL-1 cardiomyocytes. Pre-treatment with SDG significantly attenuated the carbachol-induced activation of NLRP3 inflammasome. NLRP3 activation was also subdued in the presence of atropine, and NF-κB activation inhibitor, confirming the role of the muscarinic receptor and the NF-κB pathway, respectively.

CONCLUSION

The study revealed the beneficial therapeutic properties of SDG as an anti-inflammatory agent that can help prevent NLRP3-induced inflammation. Further, the findings highlight the pro-inflammatory property of muscarinic cholinergic system, in contrast to the known nicotinic cholinergic anti-inflammatory system.