A biomaterial implant model demonstrates that immature neutrophils drive immunopathology following acute injury.

Individuals with underlying chronic inflammatory conditions are prone to increased morbidity when posed with an additional inflammatory challenge such as an injury or infection. Numerous components of the immune system including immature neutrophils are thought to contribute to the increased morbidity, but ascribing causation remains challenging due to lack of preclinical models to test the contribution of individual components. Herein, we address this challenge by developing and using a mouse model of biomaterial (chitosan-microspheres) implantation, which results in a specific and pronounced expansion of circulating immature neutrophils that exhibit dysregulated effector functions as determined by single cell RNA sequencing and ex vivo functional assays. Next, in this chitosan-implant model, we pose a second inflammatory challenge involving acute lung injury and demonstrate that the immature neutrophils drive an increase in lung immunopathology. Blocking the migration of these immature neutrophils through the administration of therapeutic antibodies or their function using specific small molecule inhibitors, profoundly lowers the immunopathology caused by the inflammatory challenge. Together, these studies demonstrate the utility of a biomaterial-implant model to establish a causal link between immature neutrophils and increased immunopathology and provides insights into new therapeutic strategies for treating individuals with chronic inflammatory ailments.