Extracellular citrate serves as a DAMP to activate macrophages and promote LPS-induced lung injury in mice

  • Int Immunopharmacol. 2021 Dec;101(Pt B):108372. doi: 10.1016/j.intimp.2021.108372.
Jia-Xi Duan  1 ,  Hui-Ling Jiang  2 ,  Xin-Xin Guan  2 ,  Chen-Yu Zhang  2 ,  Wen-Jing Zhong  2 ,  Cheng Zu  2 ,  Jia-Hao Tao  2 ,  Jin-Tong Yang  2 ,  Yu-Biao Liu  2 ,  Yong Zhou  2 ,  Ping Chen  1 ,  Hui-Hui Yang  3
Affiliations
  • 1. Department of Pulmonary and Critical Care Medicine, the Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China; Research Unit of Respiratory Disease, Central South University, Changsha, Hunan 410011, China; Hunan Diagnosis and Treatment Center of Respiratory Disease, Central South University, Changsha, Hunan 410011, China.
  • 2. Department of Physiology, School of Basic Medical Science, Central South University, Changsha, Hunan 410078, China.
  • 3. Department of Physiology, School of Basic Medical Science, Central South University, Changsha, Hunan 410078, China. Electronic address: [email protected].
PMID: 34810128 DOI: 10.1016/j.intimp.2021.108372
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.

Keywords
Acute lung injury; DAMPs; Extracellular citrate; Macrophages; NLRP3 inflammasome.
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