Chronic Inflammation Induced Immature Neutrophils Drive Immunopathology During Subsequent Inflammatory Events

Individuals with underlying chronic inflammatory conditions are prone to increased morbidity when posed with an additional inflammatory challenge such as an injury or infection, but why this occurs remains unclear. Herein, we address this question in mouse models by demonstrating that chronic inflammation results in a pronounced expansion of circulating immature neutrophils that exhibit dysregulated effector functions as determined by single cell RNA sequencing and ex vivo functional assays. We show that these immature neutrophils are associated with and contribute to increased immunopathology in response to a new inflammatory challenge. Blocking the migration or function of these immature neutrophils through the administration of therapeutic antibodies or small molecules, profoundly lowers the immunopathology caused by the inflammatory challenge. Together, these studies establish a causal link between immature neutrophils and increased immunopathology, while also providing insights into new therapeutic strategies for treating individuals with chronic inflammatory ailments.