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Journal Article Research Support, Non-U.S. Gov't Ppublish 19 citations

PubMed: 36448837 DOI: 10.1128/iai.00465-22

PRKCA Promotes Mitophagy through the miR-15a-5p/PDK4 Axis to Relieve Sepsis-Induced Acute Lung Injury.

Infect Immun 91(1):e0046522

Authors: Qiu-Jiao Zhu, Jian Wang, Ying Li, Zhen-Jiang Bai, Xu-Bei Guo, Tao Pan

Affiliations

  • Intensive Care Unit, Children's Hospital of Soochow University, Suzhou, Jiangsu Province, People's Republic of China.
  • Department of Pediatric Surgery, Children's Hospital of Soochow University, Suzhou, Jiangsu Province, People's Republic of China.
  • Department of Neonatology, Children's Hospital of Soochow University, Suzhou, Jiangsu Province, People's Republic of China.

Abstract

Acute lung injury (ALI) caused by sepsis is a common respiratory critical illness with high morbidity and mortality. Protein kinase C-alpha (PRKCA) plays a protective role in sepsis-induced ALI. However, the detailed molecular mechanism of PRKCA in ALI caused by sepsis is unclear. Animal and cell models of sepsis were established by cecal ligation and puncture (CLP)-surgery and lipopolysaccharide (LPS)/interferon-gamma (IFN-γ) treatment, respectively. Lentivirus transfection was used to overexpress PRKCA. H&E staining and lung injury in CLP-surgery mice were evaluated. Gene expression was evaluated using qPCR and Western blotting. The expression of TNF-α, IL-1β, and IL-6 was examined using qPCR and ELISA. The expression of LC3 and TOM20 was evaluated using immunofluorescence assays. Cell apoptosis was assessed using a flow cytometry assay. The bond between miR-15a-5p and PDK4 was confirmed by dual-luciferase reporter gene and RNA immunoprecipitation assays. and in vitro, PRKCA overexpression reduced lung injury to prompt mitophagy and inhibit the inflammatory response, ROS production, and cell apoptosis. miR-15a-5p was highly expressed in macrophages treated with LPS/IFN-γ and was negatively mediated by PRKCA. The overexpression of miR-15a-5p reduced the effects of PRKCA upregulation in macrophages. miR-15a-5p could restrain mitophagy in LPS/IFN-γ-treated macrophages by directly targeting PDK4. Furthermore, PDK4 knockdown reversed the inhibition of cell apoptosis and inflammatory factor release caused by miR-15a-5p silencing. The PRKCA/miR-15a-5p/PDK4 axis alleviated ALI caused by sepsis by promoting mitophagy and repressing anti-inflammatory response.

MeSH

Sepsis, Immunity, Infections, Apoptosis, Macrophages, Cells, Acute Lung Injury, Respiratory Distress Syndrome, Protein Kinase C-Alpha, Mitophagy

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