2. Academic Validation
  3. Apolipoprotein C3 (ApoC3) facilitates NLRP3 mediated pyroptosis of macrophages through mitochondrial damage by accelerating of the interaction between SCIMP and SYK pathway in acute lung injury

Apolipoprotein C3 (ApoC3) facilitates NLRP3 mediated pyroptosis of macrophages through mitochondrial damage by accelerating of the interaction between SCIMP and SYK pathway in acute lung injury

  • Int Immunopharmacol. 2024 Jan 16:128:111537. doi: 10.1016/j.intimp.2024.111537.
Zhichen Pu 1,  Wenhui Wang 2,  Haitang Xie 3,  Wusan Wang 4
Affiliations

Affiliations

  • 1 Drug Clinical Evaluation, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui 241001, China; Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution, Wannan Medical College, Wuhu 241001, China; State Key Laboratory of Natural Medicines, Key Lab of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Tongjiaxiang 24, Nanjing 210009, China.
  • 2 Drug Clinical Evaluation, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui 241001, China.
  • 3 Drug Clinical Evaluation, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui 241001, China. Electronic address: [email protected].
  • 4 Department of Pharmacology, Wannan Medical College, Wuhu, Anhui 241001, China. Electronic address: [email protected].
PMID: 38232538 DOI: 10.1016/j.intimp.2024.111537
Abstract

Respiratory failure caused by severe acute lung injury (ALI) is the main cause of mortality in patients with COVID-19.This study aimed to investigate the effects and underlying biological mechanism of Apolipoprotein C3 (ApoC3) in ALI. To establish an in vivo model, C57BL/6 mice were exposed by lipopolysaccharide (LPS). For the in vitro model, murine bone marrow-derived macrophages (BMDMs) or RAW264.7 cells were stimulated with LPS + adenosine triphosphate (ATP). Serum levels of ApoC3 were found to be upregulated in patients with COVID-19 or pneumonia-induced ALI. Inhibition of ApoC3 reduced lung injury in an ALI model, while overexpression of ApoC3 promoted lung injury. ApoC3 induced mitochondrial damage-mediated Pyroptosis in ALI through the activation of the NOD-like receptorprotein 3 (NLRP3) inflammasome. ApoC3 recombinant protein significantly increased SCIMP expression in the lung tissue of mice models with ALI. ApoC3 also facilitated the interaction between the SLP adapter and CSK-interacting membrane protein (SCIMP) protein and Spleen tyrosine kinase (Syk) protein in the ALI model. Moreover, ApoC3 accelerated calcium-dependent Reactive Oxygen Species (ROS) production in the ALI model. The effects of ApoC3 on Pyroptosis were mitigated by the use of a Pyroptosis Inhibitor or an ROS inhibitor in the ALI model. Furthermore, ApoC3 activated the expression of Syk, which in turn induced NLRP3 inflammasome-regulated Pyroptosis in the ALI model. METTL3 was found to mediate the m6A mRNA expression of ApoC3. Overall, our study highlights the crucial role of ApoC3 in promoting macrophage Pyroptosis in ALI through calcium-dependent ROS production and NLRP3 inflammasome activation via the SCIMP-SYK pathway, providing a potential therapeutic strategy for ALI and other inflammatory diseases.

Keywords

Acute lung injury; ApoC3; COVID-19; Mitochondrial damage; Pyroptosis.

Figures
Products