Effective-component compatibility of Bufei Yishen formula alleviates chronic obstructive pulmonary disease inflammation by regulating GSK3β-mediated NLRP3 inflammasome activation

Abstract

Glycogen synthase kinase 3β (GSK3β) has been associated with sensing many different stimuli to trigger the NLRP3 inflammasome, which plays a crucial role in promoting the inflammatory response in diseases, including chronic obstructive pulmonary disease (COPD). Bufei Yishen formula (BYF), a traditional Chinese herbal medicine, has beneficial effects on COPD. Effective-component compatibility of BYF (ECC-BYF), optimized from BYF, is equally effective as BYF in inhibiting COPD inflammation. However, the exact mechanism by which ECC-BYF regulates the activation of NLRP3 inflammasome to inhibit COPD inflammation remains unclear. Hence, we investigated the mechanisms underlying the alleviation of COPD inflammation by ECC-BYF through the inhibition of GSK3β-mediated NLRP3 inflammasome activation by experimental rat model of COPD and lipopolysaccharide/adenosine triphosphate (LPS/ATP) induced macrophages. The data showed that ECC-BYF significantly improved the lung function, attenuated histopathological damage, and alleviated inflammatory cell infiltration and alveolar destruction. Further, it significantly inhibited inflammatory cytokine production and downregulated the phosphorylation of GSK3β by inhibiting the activation of NLRP3 inflammasome in the rat model of COPD. Moreover, ECC-BYF suppressed the activation of the NLRP3 inflammasome by increasing the phosphorylation at serine 9 and decreasing the phosphorylation at tyrosine 216 of GSK3β, followed by the inhibition of IL-1β secretion in macrophages. Together, ECC-BYF effectively ameliorates COPD by suppressing inflammation, which is dependent on the regulation of GSK3β-mediated NLRP3 inflammasome activation.

Keywords

• COPD
• ECC-BYF
• Inflammation
• GSK3β
• NLRP3 inflammasome