Macrophage peroxisomes guide alveolar regeneration and limit SARS-CoV-2 tissue sequelae
Peroxisomes are vital but often overlooked metabolic organelles. We found that excessive interferon signaling remodeled macrophage peroxisomes. This loss of peroxisomes impaired inflammation resolution and lung repair during severe respiratory viral infections. Peroxisomes were found to modulate lipid metabolism and mitochondrial health in a macrophage type-specific manner and enhanced alveolar macrophage-mediated tissue repair and alveolar regeneration after viral infection. Peroxisomes also prevented excessive macrophage inflammasome activation and IL-1β release, limiting accumulation of KRT8<sup>high</sup> dysplastic epithelial progenitors following viral injury. Pharmacologically enhancing peroxisome biogenesis mitigated both acute symptoms and post-acute sequelae of COVID-19 (PASC) in animal models. Thus, macrophage peroxisome dysfunction contributes to chronic lung pathology and fibrosis after severe acute respiratory syndrome coronavirus 2 infection.
Authors
- Tanyalak Parimon (ORCID: https://orcid.org/0000-0002-4790-0730)
- Jie Sun (ORCID: https://orcid.org/0000-0002-2347-4511)
- Yinshan Fang (ORCID: https://orcid.org/0000-0001-9249-4498)
- Young S. Hahn (ORCID: https://orcid.org/0000-0002-2698-9844)
- Mark H. Kaplan (ORCID: https://orcid.org/0000-0002-2923-8245)
- Anja C. Roden (ORCID: https://orcid.org/0000-0001-8948-4758)
- Robert Vassallo (ORCID: https://orcid.org/0000-0003-2328-0255)
- Sarah E. Ewald (ORCID: https://orcid.org/0000-0002-5327-7578)
- Yun M. Shim (ORCID: https://orcid.org/0000-0002-3780-3371)
- In Su Cheon (ORCID: https://orcid.org/0000-0001-5160-7783)
- Qing Yu (ORCID: https://orcid.org/0000-0002-6459-072X)
- Mou Yi
- Lindsay Somerville (ORCID: https://orcid.org/0000-0001-7052-0640)
- Gislane de Almeida Santos (ORCID: https://orcid.org/0000-0002-9605-2061)
- Xiaoqin Wei (ORCID: https://orcid.org/0000-0001-6210-7899)
- Jianwen Que (ORCID: https://orcid.org/0000-0002-6540-6701)
- Harish Narasimhan (ORCID: https://orcid.org/0000-0002-3376-8257)
- Dianhua Jiang (ORCID: https://orcid.org/0000-0002-4508-3829)
- Mohd Arish (ORCID: https://orcid.org/0000-0003-4933-5808)
- Timothy N. J. Bullock (ORCID: https://orcid.org/0000-0001-6141-3261)
- Anne I. Sperling (ORCID: https://orcid.org/0000-0002-4265-9212)
- Xue Liu (ORCID: https://orcid.org/0000-0002-2104-9335)
- Chaofan Li (ORCID: https://orcid.org/0000-0002-5426-1498)
- Peter Chen (ORCID: https://orcid.org/0000-0002-5330-1718)
- Xiaoyu Zhao (ORCID: https://orcid.org/0000-0001-5095-7212)
- Wei Qian (ORCID: https://orcid.org/0009-0000-3843-6510)
- Scott Young (ORCID: https://orcid.org/0009-0008-9124-9827)
- T. K. Chan
- Eric V. Yeatts
- Olivia J. Spear
Institutions
- Cedars-Sinai Medical Center (US)
- Carter Center (US)
- Columbia University Irving Medical Center (US)
- Lung Institute (US)
- Mayo Clinic in Arizona (US)
- University of Virginia (US)
- Indiana University – Purdue University Indianapolis (US)
Publication Details
- Journal
- Science
- Published
- 2025-03-06
- DOI
- https://doi.org/10.1126/science.adq2509
- Citations
- 36
- Primary Topic
- Respiratory Support and Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 54.66