Roles of ginsenosides in inflammasome activation

Abstract

Inflammation is an innate immune response that protects the body from pathogens, toxins, and other dangers and is initiated by recognizing pathogen-associated molecular patterns or danger-associated molecular patterns by pattern-recognition receptors expressing on or in immune cells. Intracellular pattern-recognition receptors, including nucleotide-binding oligomerization domain-like receptors (NLRs), absent in melanoma 2, and cysteine aspartate-specific protease (caspase)-4/5/11 recognize various pathogen-associated molecular patterns and danger-associated molecular patterns and assemble protein complexes called "inflammasomes." These complexes induce inflammatory responses by activating a downstream effector, caspase-1, leading to gasdermin D -mediated pyroptosis and the secretion of proinflammatory cytokines, such as interleukin (IL)-1β and IL-18. Ginsenosides are natural steroid glycosides and triterpene saponins found exclusively in the plant genus Panax. Various ginsenosides have been identified, and their abilities to regulate inflammatory responses have been evaluated. These studies have suggested a link between ginsenosides and inflammasome activation in inflammatory responses. Some types of ginsenosides, including Rh1, Rg3, Rb1, compound K, chikusetsu saponin IVa, Rg5, and Rg1, have been clearly demonstrated to inhibit inflammatory responses by suppressing the activation of various inflammasomes, including the NLRP3, NLRP1, and absent in melanoma 2 inflammasomes. Ginsenosides have also been shown to inhibit caspase-1 and to decrease the expression of IL-1β and IL-18. Given this body of evidence, the functional relationship between ginsenosides and inflammasome activation provides new insight into the understanding of the molecular mechanisms of ginsenoside-mediated antiinflammatory actions. This relationship also has applications regarding the development of antiinflammatory remedies by ginsenoside-mediated targeting of inflammasomes, which could be used to prevent and treat inflammatory diseases.

Keywords: Antiinflammatory; Ginsenosides; Inflammasomes; Inflammation.

Fig. 1

Structures of canonical inflammasomes. (A) NLRP1 directly binds to pro-caspase-1 through their CARD motifs without the help of the adaptor molecule ASC. The N-terminal CARD motif is absent in the mouse NLRP1 isoforms. (B) Binding of NLRP3 to pro-caspase-1 is mediated by ASC. NLRP3 directly binds to ASC through their PYD motifs, whereas pro-caspase-1 directly binds to ASC through their CARD motifs. (C) NLRC4 directly binds to pro-caspase-1 through their CARD motifs without the help of the adaptor molecule ASC. (D) The binding of AIM2 to pro-caspase-1 is mediated by ASC. AIM2 directly binds to ASC through their PYD motifs, whereas pro-caspase-1 directly binds to ASC through their CARD motifs. AIM2, absent in melanoma 2; ASC, apoptosis-associated speck-like protein containing caspase recruitment domain; CARD, caspase recruit domain; caspase, cysteine aspartate–specific protease; FIIND, function-to-find domain; NACHT, nucleotide binding and oligomerization domain; NLR, nucleotide-binding oligomerization domain-like receptor; LRR, leucine-rich repeat; PYD, pyrin domain. *Autocatalytic cleavage.

Fig. 2

Structures of noncanonical inflammasomes. (A) Mouse caspase-11 and human caspase-4/5 directly bind through their CARD motifs and the lipid A moieties of intracellular LPS derived from Gram (−) bacteria. (B) Caspase-4/5/11 and LPS complexes are activated by oligomerization. Oligomerization involves binding of the caspase-4/5/11 molecules through their CARD motifs. CARD, caspase recruit domain; caspase, cysteine aspartate–specific protease; LPS, lipopolysaccharide.

Fig. 3

Chemical structures of ginsenosides. (A) Rh1. (B) Rg3. (C) Rb1. (D) Compound K. (E) CS IVa. (F) Rg5. (G) Rg1. CS IVa, chikusetsu saponin IVa.