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Long-chain acyl-CoA synthetase 4-mediated mitochondrial fatty acid metabolism and dendritic cell antigen presentation

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Abstract

Objective

This study aims to investigate the role of Acyl-CoA synthetase 4 (ACSL4) in mediating mitochondrial fatty acid metabolism and dendritic cell (DC) antigen presentation in the immune response associated with asthma.

Methods

RNA sequencing was employed to identify key genes associated with mitochondrial function and fatty acid metabolism in DCs. ELISA was employed to assess the levels of fatty acid metabolism in DCs. Mitochondrial morphology was evaluated using laser confocal microscopy, structured illumination microscopy, and transmission electron microscopy. Flow cytometry and immunofluorescence were utilized to detect changes in mitochondrial superoxide generation in DCs, followed by immunofluorescence co-localization analysis of ACSL4 and the mitochondrial marker protein COXIV. Subsequently, pathological changes and immune responses in mouse lung tissue were observed. ELISA was conducted to measure the levels of fatty acid metabolism in lung tissue DCs. qRT-PCR and western blotting were employed to respectively assess the expression levels of mitochondrial-associated genes (ATP5F1A, VDAC1, COXIV, TFAM, iNOS) and proteins (ATP5F1A, VDAC1, COXIV, TOMM20, iNOS) in lung tissue DCs. Flow cytometry was utilized to analyze changes in the expression of surface antigens presented by DCs in lung tissue, specifically the MHCII molecule and the co-stimulatory molecules CD80/86.

Results

The sequencing results reveal that ACSL4 is a crucial gene regulating mitochondrial function and fatty acid metabolism in DCs. Inhibiting ACSL4 reduces the levels of fatty acid oxidases in DCs, increases arachidonic acid levels, and decreases A-CoA synthesis. Simultaneously, ACSL4 inhibition leads to an increase in mitochondrial superoxide production (MitoSOX) in DCs, causing mitochondrial rupture, vacuolization, and sparse mitochondrial cristae. In mice, ACSL4 inhibition exacerbates pulmonary pathological changes and immune responses, reducing the fatty acid metabolism levels within lung tissue DCs and the expression of mitochondria-associated genes and proteins. This inhibition induces an increase in the expression of MHCII antigen presentation molecules and co-stimulatory molecules CD80/86 in DCs.

Conclusions

The research findings indicate that ACSL4-mediated mitochondrial fatty acid metabolism and dendritic cell antigen presentation play a crucial regulatory role in the immune response of asthma. This discovery holds promise for enhancing our understanding of the mechanisms underlying asthma pathogenesis and potentially identifying novel targets for its prevention and treatment.

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Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

AA:

Arachidonic acid

ACSL4:

Acyl-CoA synthetase 4

A-CoA:

Acyl-coenzyme A

BALF:

Bronchoalveolar lavage fluid

DC:

Dendritic cell

DEGs:

Differentially expressed genes

FAO:

Fatty acid oxidases

GO:

Gene ontology

IACUC:

Institutional animal care and use committee

KEGG:

Kyoto encyclopedia of genes and genomes

MAM:

Mitochondria-associated membrane

MHCII:

Major histocompatibility complex class II

MOC:

Mander's overlap coefficient

PCC:

Pearson’s correlation coefficient

PUFA:

Polyunsaturated fatty acids

qRT-PCR:

Quantitative real-time PCR

SEM:

Standard error of the mean

SPF:

Specific pathogen-free

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Acknowledgements

This study was supported by the Scientific Natural Science Foundation of Chongqing (cstc2020jcyj-msxmX0615), Youth Project of Scientific and Technological Research of Chongqing Municipal Education Commission (KJQN202200411), Chongqing Municipal Health Commission—Joint Scientific Research Project (2023QNXM015) and China Postdoctoral Science Foundation (2021MD703923) and the Graduate Student Research and Innovation Project of Chongqing Municipality (No.CYB22211).

Funding

Scientific Natural Science Foundation of Chongqing, cstc2020jcyj-msxmX0615, Youth Project of Scientific and Technological Research of Chongqing Municipal Education Commission, KJQN202200411, Chongqing Municipal Health Commission—Joint Scientific Research Project, 2023QNXM015, China Postdoctoral Science Foundation, 2021MD703923, Graduate Student Research and Innovation Project of Chongqing Municipality, CYB222111.

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Authors and Affiliations

  1. Department of Respiratory Medicine, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children’s Hospital of Chongqing Medical University, No. 136, Zhongshan 2 Road, Yuzhong Dis, Chongqing, 400014, People’s Republic of China

    Yan Li, Wenlong Fu, JinYing Xiang, Yinying Ren, Yuehan Li, Mi Zhou, Zhengxiu Luo, Enmei Liu, Zhou Fu & Fengxia Ding

  2. Department of Cardiothoracic Surgery, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children’s Hospital of Chongqing Medical University, No. 136, Zhongshan 2 Road, Yuzhong Dis, Chongqing, 400014, People’s Republic of China

    Bo Liu

  3. Chongqing Key Laboratory of Pediatrics, Chongqing Engineering Research Center of Stem Cell Therapy, Chongqing Medical University, Chongqing, People’s Republic of China

    Yan Li, Wenlong Fu, JinYing Xiang, Yinying Ren, Yuehan Li, Mi Zhou, Zhengxiu Luo, Enmei Liu, Zhou Fu, Bo Liu & Fengxia Ding

  4. Bristol Medical School, University of Bristol, Bristol, UK

    Jinyue Yu

  5. Great Ormond Street Institute of Child Health, University College London, London, UK

    Jinyue Yu

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  1. Yan Li
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Contributions

YL, EML, ZXL, ZF, BL and FXD were responsible for the overall conception and design of the study. YL performed most of the experiments and the data analysis, collected the data, and wrote the manuscript. YL, WLF, JYY, BL and FXD revising the manuscript. JYX, YYR, YHL and MZ contributed to the sample collection. All authors reviewed, edited and approved the manuscript.

Corresponding authors

Correspondence to Bo Liu or Fengxia Ding.

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The authors declare that they have no competing interests.

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The study received approval from the Ethics Committee of the Children's Hospital of Chongqing Medical University (Approval No. 2022-004).

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Li, Y., Fu, W., Xiang, J. et al. Long-chain acyl-CoA synthetase 4-mediated mitochondrial fatty acid metabolism and dendritic cell antigen presentation. Inflamm. Res. 73, 819–839 (2024). https://doi.org/10.1007/s00011-024-01868-7

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