1. Extracellular citrate serves as a DAMP to activate macrophages and promote LPS-induced lung injury in mice
- Author
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Wen-Jing Zhong, Cheng Zu, Hui-Ling Jiang, Jia-Hao Tao, Jia-Xi Duan, Jin-Tong Yang, Ping Chen, Xin-Xin Guan, Yu-Biao Liu, Hui-Hui Yang, Chen-Yu Zhang, and Yong Zhou
- Subjects
Damp ,Lipopolysaccharides ,Male ,Lipopolysaccharide ,Immunology ,Inflammation ,Lung injury ,Citric Acid ,chemistry.chemical_compound ,Mice ,Random Allocation ,Adenosine Triphosphate ,NLR Family, Pyrin Domain-Containing 3 Protein ,Extracellular ,medicine ,Immunology and Allergy ,Alarmins ,Animals ,Pharmacology ,chemistry.chemical_classification ,Reactive oxygen species ,Macrophages ,Inflammasome ,Lung Injury ,Macrophage Activation ,In vitro ,Cell biology ,Mice, Inbred C57BL ,chemistry ,Gene Expression Regulation ,Cytokines ,medicine.symptom ,medicine.drug - Abstract
Citrate has a prominent role as a substrate in cellular energy metabolism. Recently, citrate has been shown to drive inflammation. However, the role of citrate in lipopolysaccharide (LPS)-induced acute lung injury (ALI) remains unclear. Here, we aimed to clarify whether extracellular citrate aggravated the LPS-induced ALI and the potential mechanism. Our findings demonstrated that extracellular citrate aggravated the pathological lung injury induced by LPS in mice, characterized by up-regulation of pro-inflammatory factors and over-activation of NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome in the lungs. In vitro, we found that citrate treatment significantly augmented the expression of NLRP3 and pro-IL-1β and enhanced the translocation of NF-κB/p65 into the nucleus. Furthermore, extracellular citrate plus adenosine-triphosphate (ATP) significantly increased the production of reactive oxygen species (ROS) in primary murine macrophages. Inhibiting the production of ROS with a ROS scavenger N-acetyl-L-cysteine (NAC) attenuated the activation of NLRP3 inflammasome. Altogether, we conclude that extracellular citrate may serve as a damage-associated molecular pattern (DAMP) and aggravates LPS-induced ALI by activating the NLRP3 inflammasome.
- Published
- 2021