Alveolar epithelial cells mitigate neutrophilic inflammation in lung injury through regulating mitochondrial fatty acid oxidation

Kuei Pin Chung; Chih Ning Cheng; Yi Jung Chen; Chia Lang Hsu; Yen Lin Huang; Min Shu Hsieh; Han Chun Kuo; Ya Ting Lin; Yi Hsiu Juan; Kiichi Nakahira; Yen Fu Chen; Wei Lun Liu; Sheng Yuan Ruan; Jung Yien Chien; Maria Plataki; Suzanne M. Cloonan; Peter Carmeliet; Augustine M.K. Choi; Ching Hua Kuo; Chong Jen Yu

doi:10.1038/s41467-024-51683-1

Alveolar epithelial cells mitigate neutrophilic inflammation in lung injury through regulating mitochondrial fatty acid oxidation

Kuei Pin Chung^*, Chih Ning Cheng, Yi Jung Chen, Chia Lang Hsu, Yen Lin Huang, Min Shu Hsieh, Han Chun Kuo, Ya Ting Lin, Yi Hsiu Juan, Kiichi Nakahira, Yen Fu Chen, Wei Lun Liu, Sheng Yuan Ruan, Jung Yien Chien, Maria Plataki, Suzanne M. Cloonan, Peter Carmeliet, Augustine M.K. Choi, Ching Hua Kuo^*, Chong Jen Yu^*

^*Corresponding author for this work

Research output: Contribution to journal › Journal Article › peer-review

19 Scopus citations

Abstract

Type 2 alveolar epithelial (AT2) cells of the lung are fundamental in regulating alveolar inflammation in response to injury. Impaired mitochondrial long-chain fatty acid β-oxidation (mtLCFAO) in AT2 cells is assumed to aggravate alveolar inflammation in acute lung injury (ALI), yet the importance of mtLCFAO to AT2 cell function needs to be defined. Here we show that expression of carnitine palmitoyltransferase 1a (CPT1a), a mtLCFAO rate limiting enzyme, in AT2 cells is significantly decreased in acute respiratory distress syndrome (ARDS). In mice, Cpt1a deletion in AT2 cells impairs mtLCFAO without reducing ATP production and alters surfactant phospholipid abundance in the alveoli. Impairing mtLCFAO in AT2 cells via deleting either Cpt1a or Acadl (acyl-CoA dehydrogenase long chain) restricts alveolar inflammation in ALI by hindering the production of the neutrophilic chemokine CXCL2 from AT2 cells. This study thus highlights mtLCFAO as immunometabolism to injury in AT2 cells and suggests impaired mtLCFAO in AT2 cells as an anti-inflammatory response in ARDS.

Original language	English
Article number	7241
Pages (from-to)	7241
Journal	Nature Communications
Volume	15
Issue number	1
DOIs	https://doi.org/10.1038/s41467-024-51683-1
State	Published - 22 08 2024
Externally published	Yes

Bibliographical note

Keywords

Animals
Carnitine O-Palmitoyltransferase/metabolism
Mitochondria/metabolism
Oxidation-Reduction
Alveolar Epithelial Cells/metabolism
Fatty Acids/metabolism
Acute Lung Injury/metabolism
Mice
Respiratory Distress Syndrome/metabolism
Male
Humans
Chemokine CXCL2/metabolism
Mice, Inbred C57BL
Neutrophils/immunology
Mice, Knockout
Acyl-CoA Dehydrogenase, Long-Chain/metabolism
Inflammation/metabolism
Pulmonary Alveoli/metabolism
Adenosine Triphosphate/metabolism
Pneumonia/metabolism

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-024-51683-1

Cite this

Chung, K. P., Cheng, C. N., Chen, Y. J., Hsu, C. L., Huang, Y. L., Hsieh, M. S., Kuo, H. C., Lin, Y. T., Juan, Y. H., Nakahira, K., Chen, Y. F., Liu, W. L., Ruan, S. Y., Chien, J. Y., Plataki, M., Cloonan, S. M., Carmeliet, P., Choi, A. M. K., Kuo, C. H., & Yu, C. J. (2024). Alveolar epithelial cells mitigate neutrophilic inflammation in lung injury through regulating mitochondrial fatty acid oxidation. Nature Communications, 15(1), 7241. Article 7241. https://doi.org/10.1038/s41467-024-51683-1

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title = "Alveolar epithelial cells mitigate neutrophilic inflammation in lung injury through regulating mitochondrial fatty acid oxidation",

abstract = "Type 2 alveolar epithelial (AT2) cells of the lung are fundamental in regulating alveolar inflammation in response to injury. Impaired mitochondrial long-chain fatty acid β-oxidation (mtLCFAO) in AT2 cells is assumed to aggravate alveolar inflammation in acute lung injury (ALI), yet the importance of mtLCFAO to AT2 cell function needs to be defined. Here we show that expression of carnitine palmitoyltransferase 1a (CPT1a), a mtLCFAO rate limiting enzyme, in AT2 cells is significantly decreased in acute respiratory distress syndrome (ARDS). In mice, Cpt1a deletion in AT2 cells impairs mtLCFAO without reducing ATP production and alters surfactant phospholipid abundance in the alveoli. Impairing mtLCFAO in AT2 cells via deleting either Cpt1a or Acadl (acyl-CoA dehydrogenase long chain) restricts alveolar inflammation in ALI by hindering the production of the neutrophilic chemokine CXCL2 from AT2 cells. This study thus highlights mtLCFAO as immunometabolism to injury in AT2 cells and suggests impaired mtLCFAO in AT2 cells as an anti-inflammatory response in ARDS.",

keywords = "Animals, Carnitine O-Palmitoyltransferase/metabolism, Mitochondria/metabolism, Oxidation-Reduction, Alveolar Epithelial Cells/metabolism, Fatty Acids/metabolism, Acute Lung Injury/metabolism, Mice, Respiratory Distress Syndrome/metabolism, Male, Humans, Chemokine CXCL2/metabolism, Mice, Inbred C57BL, Neutrophils/immunology, Mice, Knockout, Acyl-CoA Dehydrogenase, Long-Chain/metabolism, Inflammation/metabolism, Pulmonary Alveoli/metabolism, Adenosine Triphosphate/metabolism, Pneumonia/metabolism",

author = "Chung, \{Kuei Pin\} and Cheng, \{Chih Ning\} and Chen, \{Yi Jung\} and Hsu, \{Chia Lang\} and Huang, \{Yen Lin\} and Hsieh, \{Min Shu\} and Kuo, \{Han Chun\} and Lin, \{Ya Ting\} and Juan, \{Yi Hsiu\} and Kiichi Nakahira and Chen, \{Yen Fu\} and Liu, \{Wei Lun\} and Ruan, \{Sheng Yuan\} and Chien, \{Jung Yien\} and Maria Plataki and Cloonan, \{Suzanne M.\} and Peter Carmeliet and Choi, \{Augustine M.K.\} and Kuo, \{Ching Hua\} and Yu, \{Chong Jen\}",

note = "{\textcopyright} 2024. The Author(s).",

year = "2024",

month = aug,

day = "22",

doi = "10.1038/s41467-024-51683-1",

language = "英语",

volume = "15",

pages = "7241",

journal = "Nature Communications",

issn = "2041-1723",

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number = "1",

}

Chung, KP, Cheng, CN, Chen, YJ, Hsu, CL, Huang, YL, Hsieh, MS, Kuo, HC, Lin, YT, Juan, YH, Nakahira, K, Chen, YF, Liu, WL, Ruan, SY, Chien, JY, Plataki, M, Cloonan, SM, Carmeliet, P, Choi, AMK, Kuo, CH & Yu, CJ 2024, 'Alveolar epithelial cells mitigate neutrophilic inflammation in lung injury through regulating mitochondrial fatty acid oxidation', Nature Communications, vol. 15, no. 1, 7241, pp. 7241. https://doi.org/10.1038/s41467-024-51683-1

TY - JOUR

T1 - Alveolar epithelial cells mitigate neutrophilic inflammation in lung injury through regulating mitochondrial fatty acid oxidation

AU - Chung, Kuei Pin

AU - Cheng, Chih Ning

AU - Chen, Yi Jung

AU - Hsu, Chia Lang

AU - Huang, Yen Lin

AU - Hsieh, Min Shu

AU - Kuo, Han Chun

AU - Lin, Ya Ting

AU - Juan, Yi Hsiu

AU - Nakahira, Kiichi

AU - Chen, Yen Fu

AU - Liu, Wei Lun

AU - Ruan, Sheng Yuan

AU - Chien, Jung Yien

AU - Plataki, Maria

AU - Cloonan, Suzanne M.

AU - Carmeliet, Peter

AU - Choi, Augustine M.K.

AU - Kuo, Ching Hua

AU - Yu, Chong Jen

PY - 2024/8/22

Y1 - 2024/8/22

N2 - Type 2 alveolar epithelial (AT2) cells of the lung are fundamental in regulating alveolar inflammation in response to injury. Impaired mitochondrial long-chain fatty acid β-oxidation (mtLCFAO) in AT2 cells is assumed to aggravate alveolar inflammation in acute lung injury (ALI), yet the importance of mtLCFAO to AT2 cell function needs to be defined. Here we show that expression of carnitine palmitoyltransferase 1a (CPT1a), a mtLCFAO rate limiting enzyme, in AT2 cells is significantly decreased in acute respiratory distress syndrome (ARDS). In mice, Cpt1a deletion in AT2 cells impairs mtLCFAO without reducing ATP production and alters surfactant phospholipid abundance in the alveoli. Impairing mtLCFAO in AT2 cells via deleting either Cpt1a or Acadl (acyl-CoA dehydrogenase long chain) restricts alveolar inflammation in ALI by hindering the production of the neutrophilic chemokine CXCL2 from AT2 cells. This study thus highlights mtLCFAO as immunometabolism to injury in AT2 cells and suggests impaired mtLCFAO in AT2 cells as an anti-inflammatory response in ARDS.

AB - Type 2 alveolar epithelial (AT2) cells of the lung are fundamental in regulating alveolar inflammation in response to injury. Impaired mitochondrial long-chain fatty acid β-oxidation (mtLCFAO) in AT2 cells is assumed to aggravate alveolar inflammation in acute lung injury (ALI), yet the importance of mtLCFAO to AT2 cell function needs to be defined. Here we show that expression of carnitine palmitoyltransferase 1a (CPT1a), a mtLCFAO rate limiting enzyme, in AT2 cells is significantly decreased in acute respiratory distress syndrome (ARDS). In mice, Cpt1a deletion in AT2 cells impairs mtLCFAO without reducing ATP production and alters surfactant phospholipid abundance in the alveoli. Impairing mtLCFAO in AT2 cells via deleting either Cpt1a or Acadl (acyl-CoA dehydrogenase long chain) restricts alveolar inflammation in ALI by hindering the production of the neutrophilic chemokine CXCL2 from AT2 cells. This study thus highlights mtLCFAO as immunometabolism to injury in AT2 cells and suggests impaired mtLCFAO in AT2 cells as an anti-inflammatory response in ARDS.

KW - Animals

KW - Carnitine O-Palmitoyltransferase/metabolism

KW - Mitochondria/metabolism

KW - Oxidation-Reduction

KW - Alveolar Epithelial Cells/metabolism

KW - Fatty Acids/metabolism

KW - Acute Lung Injury/metabolism

KW - Mice

KW - Respiratory Distress Syndrome/metabolism

KW - Male

KW - Humans

KW - Chemokine CXCL2/metabolism

KW - Mice, Inbred C57BL

KW - Neutrophils/immunology

KW - Mice, Knockout

KW - Acyl-CoA Dehydrogenase, Long-Chain/metabolism

KW - Inflammation/metabolism

KW - Pulmonary Alveoli/metabolism

KW - Adenosine Triphosphate/metabolism

KW - Pneumonia/metabolism

UR - https://www.scopus.com/pages/publications/85201795703

U2 - 10.1038/s41467-024-51683-1

DO - 10.1038/s41467-024-51683-1

M3 - 文章

C2 - 39174557

AN - SCOPUS:85201795703

SN - 2041-1723

VL - 15

SP - 7241

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 7241

ER -

Alveolar epithelial cells mitigate neutrophilic inflammation in lung injury through regulating mitochondrial fatty acid oxidation

Abstract

Bibliographical note

Keywords

UN SDGs

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