Reprogrammed Neutrophil Pool in Type 2 Diabetes Exacerbates Acute Lung Injury that is Reversed by Neutrophil Elastase Inhibition
Year: 2026
Type: other
Abstract: Individuals with type 2 diabetes (T2D) are at a higher risk of morbidity associated with inflammatory injury, however, the cellular basis of this vulnerability is unclear. To define the cellular changes in T2D, we performed single-cell RNA sequencing and detailed phenotypic and functional analysis of immune cells in a longitudinally screened human cohort. This analysis showed that among the circulating immune cells, neutrophils are the most transcriptionally altered in T2D, and that the diabetic neutrophil pool is reprogrammed toward an immature, less differentiated state and displays a divergent functional profile, combining heightened extracellular output, including increased NET formation, with impaired phagocytosis, with the magnitude of these changes scaling with glycemic burden. Together, this data reconciles longstanding but opposing views of diabetic neutrophils as either suppressed or hyperinflammatory. Next, using a leptin receptor knockout (db/db) mouse model, we demonstrate that mice with diabetes also recapitulate the altered neutrophil state. Importantly, upon a second inflammatory insult, these mice develop exacerbated acute lung injury, impaired lung mechanics, and increased mortality. Pharmacological inhibition of neutrophil elastase with sivelestat rescues the injury. These findings define a diabetes-conditioned neutrophil state that drives amplified lung injury and identify neutrophil elastase as a tractable therapeutic target.
Source: Figshare
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7167679166