Pyruvate dehydrogenase kinase supports macrophage NLRP3 inflammasome activation during acute inflammation
Summary Activating macrophage NLRP3 inflammasome can promote excessive inflammation, leading to severe cell and tissue damage and organ dysfunction. Here, we show that pharmacological or genetic inhibition of pyruvate dehydrogenase kinase (PDHK) significantly attenuates NLRP3 inflammasome activation in murine and human macrophages. PDHK inhibition lowers caspase-1 cleavage and IL-1β secretion in septic mice. PDHK inhibition reverses NLRP3 inflammasome-induced metabolic defect and enhances autophagic flux. Moreover, PDHK inhibition favors mitochondrial fusion over fission, attenuates mitochondrial ROS production, and preserves cristae ultrastructure. Unexpectedly, the suppressive effect of PDHK inhibition on the NLRP3 inflammasome is independent of pyruvate metabolism, pyruvate dehydrogenase, autophagy, or ROS production. In conclusion, our study suggests a non-canonical role for PDHK in supporting mitochondrial dysfunction and NLRP3 inflammasome activation during acute inflammation, independent of its canonical role as a pyruvate dehydrogenase regulator..
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Preprint| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
bioRxiv.org - (2022) vom: 02. Sept. Zur Gesamtaufnahme - year:2022 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Meyers, Allison K. [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| doi: |
10.1101/2021.10.02.462869 |
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| PPN (Katalog-ID): |
XBI037108689 |
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| 245 | 1 | 0 | |a Pyruvate dehydrogenase kinase supports macrophage NLRP3 inflammasome activation during acute inflammation |
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| 520 | |a Summary Activating macrophage NLRP3 inflammasome can promote excessive inflammation, leading to severe cell and tissue damage and organ dysfunction. Here, we show that pharmacological or genetic inhibition of pyruvate dehydrogenase kinase (PDHK) significantly attenuates NLRP3 inflammasome activation in murine and human macrophages. PDHK inhibition lowers caspase-1 cleavage and IL-1β secretion in septic mice. PDHK inhibition reverses NLRP3 inflammasome-induced metabolic defect and enhances autophagic flux. Moreover, PDHK inhibition favors mitochondrial fusion over fission, attenuates mitochondrial ROS production, and preserves cristae ultrastructure. Unexpectedly, the suppressive effect of PDHK inhibition on the NLRP3 inflammasome is independent of pyruvate metabolism, pyruvate dehydrogenase, autophagy, or ROS production. In conclusion, our study suggests a non-canonical role for PDHK in supporting mitochondrial dysfunction and NLRP3 inflammasome activation during acute inflammation, independent of its canonical role as a pyruvate dehydrogenase regulator. | ||
| 650 | 4 | |a Biology |7 (dpeaa)DE-84 | |
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| 700 | 1 | |a Wang, Zhan |e verfasserin |4 aut | |
| 700 | 1 | |a Han, Wenzheng |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Qingxia |e verfasserin |4 aut | |
| 700 | 1 | |a Zabalawi, Manal |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Qianyi |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Juan |e verfasserin |4 aut | |
| 700 | 1 | |a Manne, Rajesh K |e verfasserin |4 aut | |
| 700 | 1 | |a Lorenzo, Felipe |e verfasserin |4 aut | |
| 700 | 1 | |a Quinn, Matthew A. |e verfasserin |4 aut | |
| 700 | 1 | |a Song, Qianqian |e verfasserin |4 aut | |
| 700 | 1 | |a Fan, Daping |e verfasserin |4 aut | |
| 700 | 1 | |a Lin, Hui-Kuan |e verfasserin |4 aut | |
| 700 | 1 | |a Furdui, Cristina M. |e verfasserin |4 aut | |
| 700 | 1 | |a Locasale, Jason W. |e verfasserin |4 aut | |
| 700 | 1 | |a McCall, Charles E. |e verfasserin |4 aut | |
| 700 | 1 | |a Zhu, Xuewei |e verfasserin |4 aut | |
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