Macrophage peroxisomes guide alveolar regeneration and limit SARS-CoV-2 tissue sequelae
Xiaoqin Wei,
Wei Qian,
Harish Narasimhan,
Ting Chan,
Xue Liu,
Mohd Arish,
Samuel Young,
Chaofan Li,
In Su Cheon,..., and
Jie Sun +20 authors
Authors Info & Affiliations
Science 7 Mar 2025 Vol 387, Issue 6738
Editor’s summary:
Peroxisomes are small, membrane-bound structures within cells that play a crucial role in synthesizing and breaking down fat. Wei et al. found that that severe COVID-19 can disrupt peroxisomes in macrophages, an immune cell type specialized in engulfing cellular debris and pathogens. This disruption led to impaired lung repair, prolonged inflammation, and chronic fibrosis (see the Perspective by Sariol and Perlman). In mouse models, enhancing peroxisome function using an FDA-approved drug improved lung healing and reduced long-term damage after viral infection. Thus, targeting peroxisomes could offer a promising therapeutic strategy for addressing acute and chronic complications caused by respiratory viruses. —Stella M. Hurtley
Structured Abstract
INTRODUCTION
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes both acute manifestations and long-term complications. These post acute sequelae (PASC) of SARS-CoV-2 infection or Long Covid have affected more than 60 million individuals worldwide. Similar chronic sequelae have also been observed after other respiratory viral infections, including influenza. Despite advances in antiviral and anti-inflammatory therapies, we lack effective interventions that target tissue regeneration and recovery after severe viral injury to minimize the development of chronic host conditions. Following alveolar damage, the emergence of epithelial progenitors—including transitional progenitor cells highly expressing cytokeratin 8 (KRT8)—is a hallmark of the lung repair process. However, dysregulated persistence of these cells can lead to pathological tissue remodeling and fibrosis, characteristics of post viral chronic lung sequelae. The immunological mechanisms regulating the development and persistence of dysplastic KRT8 cells after infection are not fully understood.
RATIONALE
Macrophages are critical in antiviral immunity, lung inflammation, and tissue repair after viral infection. Peroxisomes, cellular organelles involved in lipid metabolism and cellular redox balance, are often overlooked compared with other organelles such as mitochondria. Working in mouse models of infection, we examined the dynamic changes of macrophage peroxisome compartment in vivo after respiratory viral infection including SARS-CoV-2. We also investigated how peroxisomes regulate macrophage inflammatory and repair function in the lung after viral injury in vivo. Furthermore, we evaluated whether pharmacologically enhancing peroxisome biogenesis could serve as a pro-repair therapeutic approach to mitigate acute and chronic host conditions following infection.
Results
Severe COVID-19 significantly remodeled the peroxisome compartment, reducing the number of peroxisomes in mouse lung macrophages, as revealed by bioinformatic and immunofluorescence analyses. We found that increased interferon signaling, especially IFNγ signaling, inhibited peroxisome biogenesis and promoted peroxisome degradation through pexophagy (autophagy of peroxisomes) in macrophages. Mouse models with selective depletion of macrophage peroxisomes demonstrated that peroxisomes were essential for resolving inflammation and promoting alveolar regeneration after severe viral injury. Mechanistically, peroxisomes exhibited cell type–specific modulation of lipid metabolism, enhancing mitochondrial health and supporting macrophage repair programs for the self-renewal of alveolar type 2 (AT2) cells. Macrophage peroxisome dysfunction, however, led to increased inflammasome activation and excessive IL-1β release by means of the Gasdermin D pore. Persistent IL-1β production subsequently caused the accumulation of dysplastic KRT8 transitional epithelial progenitors in the lung, driving chronic tissue pathology and fibrotic remodeling following acute SARS-CoV-2 infection. Chronic peroxisome impairment was observed in the lungs from human patients with PASC pulmonary fibrosis and relevant mouse models. Notably, in our mouse models, pharmacological enhancement of peroxisome biogenesis using sodium 4-phenylbutyrate (4-PBA) restored peroxisome function in macrophages, mitigated lung inflammation and fibrosis, and enhanced alveolar regeneration after viral infection.
CONCLUSION
This study suggests that severe respiratory viral infections can reduce peroxisome biogenesis and promote peroxisome degradation in response to raised interferon levels. Our findings reveal that peroxisomes act as essential regulators of macrophage-mediated lung inflammation resolution and tissue regeneration following viral injury. Thus, peroxisomal dysfunction in macrophages contributes to the development of severe acute morbidity and chronic tissue sequelae post-COVID-19. Targeting peroxisome biogenesis or enhancing peroxisomal metabolic function represents a promising therapeutic approach for mitigating the long-term consequences of respiratory viral infections, with potential for improving health outcomes for patients with PASC.
