Inflammation is one of the most important host defense mechanisms in mammals and is also required for wound healing. However, uncontrolled inflammation is harmful to health. Precise control of the inflammatory response is important for limiting pathogenic infections without causing host damage. Unlike traditional proinflammatory cytokines, IL-1ß and IL-18 production are regulated by post-translational modification catalyzed by protease caspase-1, which is regulated by a group of cytoplasmic multiprotein complexes called inflammasomes. Several inflammasomes have been described, including NLR-containing NLRP1-, NLRP3-, NLRP6-, NLRP7-, NLRP12-, NLRC4-inflammasome and PYHIN-containing AIM2- and IFI16-inflammasome. The most extensively studied and characterized inflammasome is the NLRP3, ASC and pro-caspase-1 containing NLRP3 inflammasome. This is because it recognizes and responses to a broad range of medically relevant stimulus, including pathogenic infection and diverse sterile host-derived or environmental danger signals to promote inflammatory disease development.
Activation of the NLRP3 inflammasome leads to caspase-1 dependent maturation and release of proinflammatory cytokines IL-1ß and IL-18. It also promotes Gasdermin D dependent pyroptotic cell death. The two-step activation of the NLRP3 inflammasome involves a priming stage and an activation stage, the former transcriptionally controlling the expression of NLRP3 and proIL-1ß and the latter controlling the activation of caspase-1. Although the NLRP3 inflammasome is essential for the host defense during infections, dysregulation of the NLRP3 inflammasome is associated with a number of inflammatory conditions such as metabolic disorders, type II diabetes, cardiovascular diseases, neurodegenerative diseases, inflammatory bowel disease, chronic kidney diseases and cancers. The current therapeutic strategies for NLRP3-associated complications are based on the non-steroidal anti-inflammatory drugs, which are not satisfactory and cause significant side effects. Therefore, the development of specific, small-molecular inhibitors of the NLRP3 inflammasome is a therapeutic option to counteract dysregulated NLRP3-associated diseases. Currently, several direct or indirect inhibitors of the NLRP3 inflammasome have been reported. The direct NLRP3 inflammasome inhibitors MCC950, CY-09, OLT1177 and 3, 4-methylenedioxy-b-nitrostyrene that block NLRP3 ATPase activity and the indirect NLRP3 inflammasome inhibitors Glyburide and ß-hydroxybutyrate that block K+ efflux.
Current research should focus on the development of safe, cost-effective NLRP3 inflammasome inhibitors which have improved pharmacokinetic properties. A deeper insight into the NLRP3 inflammasome regulation will help in developing targeted and beneficial therapeutics in the future. This Research Topic, welcomes Original Research and Review articles in the field, with a focus on, but not limited to:
• The molecular and mechanistic basis for the NLRP3 inflammasome activation
• NLRP3 inflammasome-associated pathogenesis
• NLRP3 inflammasome inhibitor development
• NLRP3 inflammasome-specific therapeutics
Dr Hua, Dr Chen and Dr Chernikov have patents related to the treatment and diagnosis of inflammatory disorders. The other Topic Editors declare no potential conflicts of interest with relation to the topic theme.
Inflammation is one of the most important host defense mechanisms in mammals and is also required for wound healing. However, uncontrolled inflammation is harmful to health. Precise control of the inflammatory response is important for limiting pathogenic infections without causing host damage. Unlike traditional proinflammatory cytokines, IL-1ß and IL-18 production are regulated by post-translational modification catalyzed by protease caspase-1, which is regulated by a group of cytoplasmic multiprotein complexes called inflammasomes. Several inflammasomes have been described, including NLR-containing NLRP1-, NLRP3-, NLRP6-, NLRP7-, NLRP12-, NLRC4-inflammasome and PYHIN-containing AIM2- and IFI16-inflammasome. The most extensively studied and characterized inflammasome is the NLRP3, ASC and pro-caspase-1 containing NLRP3 inflammasome. This is because it recognizes and responses to a broad range of medically relevant stimulus, including pathogenic infection and diverse sterile host-derived or environmental danger signals to promote inflammatory disease development.
Activation of the NLRP3 inflammasome leads to caspase-1 dependent maturation and release of proinflammatory cytokines IL-1ß and IL-18. It also promotes Gasdermin D dependent pyroptotic cell death. The two-step activation of the NLRP3 inflammasome involves a priming stage and an activation stage, the former transcriptionally controlling the expression of NLRP3 and proIL-1ß and the latter controlling the activation of caspase-1. Although the NLRP3 inflammasome is essential for the host defense during infections, dysregulation of the NLRP3 inflammasome is associated with a number of inflammatory conditions such as metabolic disorders, type II diabetes, cardiovascular diseases, neurodegenerative diseases, inflammatory bowel disease, chronic kidney diseases and cancers. The current therapeutic strategies for NLRP3-associated complications are based on the non-steroidal anti-inflammatory drugs, which are not satisfactory and cause significant side effects. Therefore, the development of specific, small-molecular inhibitors of the NLRP3 inflammasome is a therapeutic option to counteract dysregulated NLRP3-associated diseases. Currently, several direct or indirect inhibitors of the NLRP3 inflammasome have been reported. The direct NLRP3 inflammasome inhibitors MCC950, CY-09, OLT1177 and 3, 4-methylenedioxy-b-nitrostyrene that block NLRP3 ATPase activity and the indirect NLRP3 inflammasome inhibitors Glyburide and ß-hydroxybutyrate that block K+ efflux.
Current research should focus on the development of safe, cost-effective NLRP3 inflammasome inhibitors which have improved pharmacokinetic properties. A deeper insight into the NLRP3 inflammasome regulation will help in developing targeted and beneficial therapeutics in the future. This Research Topic, welcomes Original Research and Review articles in the field, with a focus on, but not limited to:
• The molecular and mechanistic basis for the NLRP3 inflammasome activation
• NLRP3 inflammasome-associated pathogenesis
• NLRP3 inflammasome inhibitor development
• NLRP3 inflammasome-specific therapeutics
Dr Hua, Dr Chen and Dr Chernikov have patents related to the treatment and diagnosis of inflammatory disorders. The other Topic Editors declare no potential conflicts of interest with relation to the topic theme.