GLP-1 receptor agonist prevents pulmonary fibrosis after COVID-19 in type 2 diabetes by reprogramming macrophages.

The Post-acute sequelae of COVID-19 (PASC), particularly pulmonary fibrosis, represents a significant long-term health burden following SARS-CoV-2 infection. Patients with type 2 diabetes (T2D) face a four times higher incidence of pulmonary PASC compared to non-diabetic individuals, yet the underlying immune mechanisms remain poorly understood. Current standard-of-care primarily focuses on symptomatic relief, lacking targeted interventions for T2D-mediated PASC. This gap highlights the need to explore existing therapeutics like glucagon-like peptide-1 receptor agonists (GLP-1RAs), known for their cardiometabolic benefits, for their potential in mitigating post-viral fibrotic complications.

Researchers first analyzed human data, observing T2D patients post-acute SARS-CoV-2 infection for 3 months, correlating fibrosis-related gene expression in monocytes with pulmonary fibrosis biomarkers. To model human T2D, they utilized db/db mice, infecting them with SARS-CoV-2. A macrophage depletion experiment was conducted to confirm the role of pro-inflammatory macrophages. Finally, GLP1-RA was administered to SARS-CoV-2-infected db/db mice to assess its impact on macrophage responses and pulmonary fibrosis. Primary endpoints included expression of fibrosis-related genes via qPCR and assessment of persistent pulmonary fibrosis.

In T2D patients, fibrosis-related genes in monocytes were significantly upregulated and positively correlated with pulmonary fibrosis biomarkers up to 3 months post-infection. > Mirroring human observations, SARS-CoV-2 infection in db/db mice led to upregulation of fibrosis-related genes in lung macrophages and persistent pulmonary fibrosis. Macrophage depletion experiments confirmed that pro-inflammatory macrophages in db/db mice were determinants for inducing post-infection pulmonary fibrosis. Crucially, GLP1-RA treatment reprogrammed macrophage responses to SARS-CoV-2, normalizing fibrosis-related genes and significantly reducing pulmonary fibrosis in a glucose-independent manner. These findings underscore the detrimental role of SARS-CoV-2-induced pro-inflammatory macrophages in T2D-mediated PASC.