C1q/tumour necrosis factor-related protein-9 aggravates lipopolysaccharide-induced inflammation via promoting NLRP3 inflammasome activation.

Abstract

The NLRP3 inflammasome plays a vital role in inflammation by increasing the maturation of interleukin-1β (IL-1β) and promoting pyroptosis. Given that C1q/tumour necrosis factor-related protein-9 (CTRP9) has been shown to be involved in diverse inflammatory diseases, we sought to assess the underlying impact of CTRP9 on NLRP3 inflammasome activation. In vitro, macrophages isolated from murine peritonea were stimulated with exogenous CTRP9, followed by lipopolysaccharide (LPS) and adenosine 5'-triphosphate (ATP). We demonstrated that CTRP9 markedly augmented the activation of the NLRP3 inflammasome, as shown by increased mature IL-1β secretion, triggering ASC speck formation and promoting pyroptosis. Mechanistically, CTRP9 increased the levels of NADPH oxidase 2 (NOX2)-derived reactive oxygen species (ROS). Suppressing ROS with N-acetylcysteine (NAC) or interfering with NOX2 by small interfering RNA weakened the promoting effect of CTRP9 on the NLRP3 inflammasome. Furthermore, NLRP3 inflammasome activation, pyroptosis and secretion of mature IL-1β were significantly decreased in macrophages from CTRP9-KO mice compared to those from WT mice with the same treatment. In vivo, we established a sepsis model by intraperitoneal injection of LPS into WT and CTRP9-KO mice. CTRP9 knockout improved the survival rates of the septic mice and attenuated NLRP3 inflammasome-mediated inflammation. In conclusion, our study indicates that CTRP9 aggravates LPS-induced inflammation by promoting NLRP3 inflammasome activation via the NOX2/ROS pathway. CTRP9 could be a promising target for NLRP3 inflammasome-driven inflammatory diseases.

• Authors: Dan Xu, Xin Zhou, Jiying Chen, Na Li, Shiyan Ruan, Anju Zuo, Shengyun Lei, Linxi Li, Yuan Guo
• Journal: International immunopharmacology (Int Immunopharmacol) Vol. 104 Pg. 108513 (Mar 2022) ISSN: 1878-1705 [Electronic] Netherlands
• PMID: 35008006 (Publication Type: Journal Article)
• Copyright: Copyright © 2022 Elsevier B.V. All rights reserved.

Chemical References

• Adiponectin
• CTRP9 protein, mouse
• Glycoproteins
• IL1B protein, mouse
• Inflammasomes
• Interleukin-1beta
• Lipopolysaccharides
• NLR Family, Pyrin Domain-Containing 3 Protein
• Nlrp3 protein, mouse
• Reactive Oxygen Species
• Cybb protein, mouse
• NADPH Oxidase 2

Topics

• Adiponectin (genetics, immunology)
• Animals
• Female
• Glycoproteins (genetics, immunology)
• Inflammasomes (genetics, immunology)
• Inflammation (chemically induced, genetics, immunology)
• Interleukin-1beta (blood, genetics, immunology)
• Lipopolysaccharides
• Macrophages, Peritoneal (immunology)
• Mice, Inbred C57BL
• Mice, Knockout
• NADPH Oxidase 2 (genetics, immunology)
• NLR Family, Pyrin Domain-Containing 3 Protein (genetics, immunology)
• Pyroptosis
• Reactive Oxygen Species (immunology)
• Mice