Glucagon-like Peptide-1 Receptor Agonist Prevents Pulmonary Fibrosis Following Acute COVID-19 Infection Associated with Type 2 Diabetes

Post-acute sequelae of COVID-19 (PASC) poses a major health burden after SARS-CoV-2 infection. Although type 2 diabetes (T2D) is associated with PASC, the mechanism of T2D-mediated PASC in the lung remains elusive. Here, we found that people with T2D (PWT2D) exhibited significantly upregulated fibrosis-related genes in monocytes, which positively correlated with pulmonary fibrosis-related biomarkers up to 3 months after acute SARS-CoV-2 infection. Using db/db mice to model human T2D, we found consistently that SARS-CoV-2 infection resulted in upregulation of fibrosis-related genes in lung macrophages and persistent pulmonary fibrosis. Moreover, the macrophage-depletion demonstrated that pro-inflammatory macrophages in db/db mice were determinants for inducing pulmonary fibrosis post-infection. Importantly, the anti-T2D glucagon-like peptide-1 receptor agonist (GLP1-RA) reprogramed macrophage responses to SARS-CoV-2 by normalizing fibrosis-related genes, significantly reducing the pulmonary fibrosis in a glucose-independent manner. These findings demonstrated that SARS-CoV-2-induced proinflammatory macrophages are detrimental factors in T2D-mediated PASC, which can be prevented by GLP1-RA. IMPORTANCE:Some COVID-19 patients develop pulmonary post-acute sequelae of COVID-19 (PASC) with clinical symptoms lasting for years. Critically, the incidence of pulmonary PASC in PWT2D is four times higher than that in those without T2D. However, the immune mechanisms underlying pulmonary PASC in PWT2D remain poorly understood. Our findings demonstrate that SARS-CoV-2-induced proinflammatory macrophages are key drivers of PASC-associated pulmonary fibrosis. We further provide in vivo evidence that glucagon-like peptide-1 receptor agonists (GLP1-RAs) can reprogram pulmonary macrophages to prevent SARS-CoV-2-induced PASC in a T2D mouse model, with important implications for therapy in PWT2D.