Korean Red Ginseng Saponins Play an Anti-Inflammatory Role by Targeting Caspase-11 Non-Canonical Inflammasome in Macrophages

Abstract

We previously reported that Korean red ginseng (KRG) exerts an anti-inflammatory role through inhibiting caspase-11 non-canonical inflammasome in macrophages; however, the components responsible for the anti-inflammatory role remained unclear. This study explored the anti-inflammatory activity of the KRG saponin fraction (KRGSF) in caspase-11 non-canonical inflammasome-activated macrophages. KRGSF inhibited pyroptosis, pro-inflammatory cytokine secretion, and inflammatory mediator production in caspase-11 non-canonical inflammasome-activated J774A.1 cells. A mechanism study revealed that KRGSF-induced anti-inflammatory action was mediated via suppressing the proteolytic activation of caspase-11 and gasdermin D (GSDMD) in caspase-11 non-canonical inflammasome-activated J774A.1 cells. Moreover, KRGSF increased the survival of lethal septic mice. Taken together, these results reveal KRGSF-mediated anti-inflammatory action with a novel mechanism, by inhibiting caspase-11 non-canonical inflammasome in macrophages.

Regulatory Roles of Flavonoids in Caspase-11 Non-Canonical Inflammasome-Mediated Inflammatory Responses and Diseases

“…Third, although over 6000 naturally occurring flavonoids have been identified [ 84 ], only a few have been demonstrated to attenuate non-canonical inflammasome-associated inflammatory responses and diseases. Since substantial evidence has emphasized that non-canonical inflammasomes are key players in inducing inflammation, leading to the exacerbation of multiple inflammatory and infectious diseases [ 13 , 14 , 15 , 24 , 37 , 197 , 198 , 199 , 200 ], further studies to identify new flavonoids targeting non-canonical inflammasomes and to demonstrate their pharmacological roles in diseases associated with non-canonical inflammasomes need to be undertaken. Fourth, most of the studies demonstrated the preventive effect of flavonoids in the inflammatory responses and diseases, and the therapeutic effect of flavonoids should also be examined in the inflammatory responses and diseases.…”

Critical review on anti‐inflammation effects of saponins and their molecular mechanisms

“…Moreover, the influence of saponins extends to the inhibition of downstream effector functions, where interference with the proteolytic cleavage and activation of key inflammasome components, including caspase‐1, GSDMD (Gasdermin D), and pro‐inflammatory cytokines such as IL‐1β and IL‐18, is observed. Although the specific mechanisms underlying saponin modulation of inflammasome signaling pathways remain unspecified in the provided text, potential avenues include transcriptional inhibition, interference with proteolytic cleavage, and competitive inhibition of ligand–PRR interactions (Cho et al, 2023). The diverse effects exhibited by different saponins, sourced from Panax ginseng, Panax notoginseng, Panax japonicus , and Panax quinquefolius , further underscore their distinct impact on inflammasome activation.…”

Pharmacological potential of ginseng and ginsenosides in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis

“…Among them, ginsenosides, which are steroidal saponins, have been identified as major compounds that modulate numerous biological and physiological conditions in the body. Ginsenosides also have been reported to have pharmacological roles in multiple diseases by regulating various pathological conditions, such as inflammation, oxidative stress, lipogenesis, fibrosis, hypoxia, infection, and cellular apoptosis [ [12] , [13] , [14] , [15] , [16] , [17] , [18] , [19] , [20] ]. Recently, an increasing number of studies have demonstrated that ginsengs and ginsenosides play a pharmacological role in the pathogenesis and progression of NAFLD and NASH.…”