Korean Red Ginseng, a regulator of NLRP3 inflammasome, in the COVID-19 pandemic

Abstract

Coronavirus disease 2019 (COVID-19) exhibits various symptoms, ranging from asymptomatic to severe pneumonia or death. The major features of patients in severe COVID-19 are the dysregulation of cytokine secretion, pneumonia, and acute lung injury. Consequently, it leads to acute respiratory distress syndrome, disseminated intravascular coagulation, multiple organ failure, and death. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative virus of COVID-19, influences nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain containing 3 (NLRP3), the sensor of inflammasomes, directly or indirectly, culminating in the assembly of NLRP3 inflammasome and activation of inflammatory caspases, which induce the inflammatory disruption in severe COVID-19. Accordingly, the target therapeutics for inflammasome has attracted attention as a treatment for COVID-19. Korean Red Ginseng (KRG) inhibits several inflammatory responses, including the NLRP3 inflammasome signaling. This review discusses the role of KRG in the treatment and prevention of COVID-19 based on its anti-NLRP3 inflammasome efficacy.

Keywords: Ginsenoside; Inflammasome; Korean Red Ginseng extract; NLRP3; Pyroptosis.

Graphical abstract

Fig. 1

Molecular mechanisms of NLRP3 inflammasome activation by SARS-CoV-2 infection. SARS-CoV-2 enters the macrophages and monocytes, and activates NLRP3 inflammasome through K⁺ efflux, cytosolic Ca²⁺ influx, and mitochondrial ROS production. Viral E protein stimulates K⁺ efflux and cytosolic Ca²⁺ influx. ORF3a increases K⁺ efflux and mitochondrial ROS production. ORF3a also interacts with ASC leading to assembly NLRP3 inflammasome. The viral S protein disrupts the mitochondrial integrity, resulting in ROS generation, and binds with the NLRP3 protein leading to inflammasome assembly. E protein and ORF3a upregulate the NLRP3 and IL-1β transcripts through NF-κB signaling. KRG and ginsenosides attenuate the activation of caspase-1 (Casp1) and the formation of ASC pyroptosome through the inhibition of NLRP3 inflammasome assembly.

Fig. 2

Role of KRG on NLRP3 inflammasome activation in macrophages and monocytes. Saponins of KRG inhibit TLR4/NF-κB signaling leading attenuation of inflammatory cytokines and enzymes. On the other hand, non-saponin components of KRG upregulate cytokines and induce the priming step of the inflammasome activation through stimulation of TLR4/NF-κB signals. KRG attenuates the production of mitochondrial ROS (mitROS) followed by rotenone, a chemical to disrupt mitochondrial integrity (unpublished data). KRG interrupts the formation of ASC pyroptosome, a part of the inflammasome assembly. As KRG inhibits NLRP3 inflammasome activation, it is decreased the maturation of IL-1β and IL-18, the cleavage of GSDMD, and the secretion of LDH. Accordingly, the excessive inflammatory responses because the positive feedback loops are alleviated.