Characterizing the diabetes-induced pathological changes of the mouse lung by single-cell RNA sequencing.

Pulmonary disorders are exacerbated by high blood sugar, leading to a disordered immune defense and increased susceptibility to infection. Type 2 diabetes mellitus (T2D) is characterized by insulin resistance and inadequate insulin production. Mechanisms leading to pulmonary alternation due to T2D are not clear. The advancements in single-cell RNA sequencing aid in characterizing the effects of T2D on lungs and its altered mechanisms. Our results first revealed that in late-stage diabetic mice, the number of immune cells in the lungs significantly increased, with these immune cells predominantly being immature polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). At the early stages of diabetes, alveolar cell type I and type II (AT I & II) exhibited a mesenchymal phenotype and showed reduced expression of several key cytokines essential for maintaining lung immunity, including Cxcl15, Cxcl14, and Il34. Additionally, the antigen-presenting cell function of AT II, resulting from the downregulation of several MHC type II proteins, was markedly diminished in diabetic mice. Moreover, decreased expressions of interferon-related genes Ifnar1 and Ifnar2, along with impaired Sftpd expression, compromised lung immunity impairment in diabetic mice. These pathogenic changes contributed to the increased susceptibility and severity of respiratory syncytial virus and tuberculosis in the lung of diabetes. In addition to alveolar cells, pulmonary capillary endothelial cells also exhibited an immature transition phenotype, with a significant increase in angiogenic capacity. Our findings provided a comprehensive exploration of lung pathology under the influence of diabetes and explained the multiple factors impacting lung immunity in diabetic conditions.