Regulatory roles of ginseng on inflammatory caspases, executioners of inflammasome activation

Abstract

Inflammation is an immune response that protects against pathogens and cellular stress. The hallmark of inflammatory responses is inflammasome activation in response to various stimuli. This subsequently activates downstream effectors, that is, inflammatory caspases such as caspase-1, 4, 5, 11, and 12. Extensive efforts have been made on developing effective and safe anti-inflammatory therapeutics, and ginseng has long been traditionally used as efficacious and safe herbal medicine in treating various inflammatory and inflammation-mediated diseases. Many studies have successfully shown that ginseng plays an anti-inflammatory role by inhibiting inflammasomes and inflammasome-activated inflammatory caspases. This review discusses the regulatory roles of ginseng on inflammatory caspases in inflammatory responses and also suggests new research areas on the anti-inflammatory function of ginseng, which provides a novel insight into the development of ginseng as an effective and safe anti-inflammatory herbal medicine.

Keywords: AIM2, Absent in melanoma 2; ASC, Apoptosis-associated speck-like protein containing CARD; CARD, C-terminal caspase recruit domain; COX-2, Cyclooxygenase-2; Caspase, Cysteine aspartate–specific protease; DAMP, Danger-associated molecular pattern; FIIND, Functional-to-find domain; GSDMD, Gasdermin D; Ginseng; Ginsenoside; HIN, Hematopoietic interferon-inducible nuclear protein; IL, Interleukin; Inflammasome; Inflammation; Inflammatory caspase; LPS, Lipopolysaccharide; LRR, Leucine-rich repeat; NACHT, Nucleotide-binding and oligomerization domain; NF-κB, Nuclear factor-kappa B; NLR, Nucleotide-binding oligomerization domain-like receptor; NO, Nitric oxide; PAMP, Pathogen-associated molecular pattern; PGE2, Prostaglandin E2; PRR, Pattern-recognition receptor; PYD, N-terminal pyrin domain; RGE, Korean Red Ginseng; ROS, Reactive oxygen species.

Fig. 1

Structures of human and mouse inflammatory caspases. The members of the inflammatory caspases are caspase-1, 4, 5, 11, and 12 in humans and mice. These inflammatory caspases share an N-terminal CARD, a large catalytic subunit (p20), and a C-terminal small catalytic subunit (p10). Unlike other caspases, human caspase-12 consists of only an N-terminal CARD and a C-terminal large catalytic subunit (p20) and does not have a small catalytic subunit (p10). Phylogenetically and structurally, mouse caspase-12 belongs to an inflammatory caspase family. CARD, caspase recruitment domain.

Fig. 2

Roles of the inflammatory caspases in inflammasome-activated inflammatory responses. Canonical inflammasomes, such as NLRP1, NLRP3, NLRC4, and AIM2 inflammasomes assemble in response to their specific ligands, leading to proteolytic activation of caspase-1 to form p20–p10 dimers. Caspase-4/5/11 noncanonical inflammasomes assemble by direct recognition of intracellular LPS, followed by oligomerization of LPS–caspase-4/5/11 complexes. Active caspase-1 and caspase-4/5/11 noncanonical inflammasomes, in turn, cleave GSDMD to produce N-terminal GSDMD fragments, and cleaved N-terminal GSDMD fragments move to the cell membrane, generate GSDMD pores, and induce pore-mediated pyroptosis. Active caspase-1 also maturates inactive pro–IL-1β and pro–IL-18 by proteolytic processing to produce active IL-1β and IL-18, which are secreted through GSDMD pores. NLR, nucleotide-binding and oligomerization domain-like receptor; AIM2, absent in melanoma 2; LPS, lipopolysaccharide; GSDMD, gasdermin D; IL, interleukin.

Fig. 3

Regulatory roles of ginseng on inflammatory caspases (A) The indicated ginseng preparations (total saponins, ginseng mixtures, ginsenoside, and red ginseng) suppress caspase-1, and consequently, caspase-1–induced inflammatory responses are inhibited. (B) The ginseng extract (EMGE) and ginsenoside (Rh2) promote the apoptotic function of caspase-4, which induces apoptosis. (C) The indicated ginseng preparations (total saponins, ginseng extract, ginseng mixture, and ginsenosides) suppress caspase-12, which plays a proinflammatory role, and consequently, caspase-12–induced inflammatory responses are inhibited (left). Although ginseng total saponins, PTS, promotes caspase-12, which plays an anti-inflammatory role and induces anti-inflammatory responses. TSPN, total saponins of Panax notoginseng; SPJ, total saponins of Japanese ginseng, Panax japonicas; SMS, Saengmaeksan; IGS, Igongsan; Cs Via, Chikusetsu saponin Iva; CK, compound K, RGE, Korean Red Ginseng extract; KRG, extract of Korean Red Ginseng; EMGE, enzyme-modified ginseng extract; PQS, total saponins of Panax quinquefolium; WEG, water extract of Panax ginseng; AS IV, Astragaloside IV; Cs V, Chikusetsu saponin V; PTS, total protopanaxatriol (PPT) saponins of Panax notoginseng.