Roles of neutrophil granule proteins in orchestrating inflammation and immunity

Neutrophil granulocytes form the first line of host defense against invading pathogens and tissue injury. They are rapidly recruited from the blood to the affected sites, where they deploy an impressive arsenal of effectors to eliminate invading microbes and damaged cells. This capacity is endowed in part by readily mobilizable proteins acquired during granulopoiesis and stored in multiple types of cytosolic granules with each granule type containing a unique cargo. Once released, granule proteins contribute to killing bacteria within the phagosome or the extracellular milieu, but are also capable of inflicting collateral tissue damage. Neutrophil‐driven inflammation underlies many common diseases. Research over the last decade has documented neutrophil heterogeneity and functional versatility far beyond their antimicrobial function. Emerging evidence indicates that neutrophils utilize granule proteins to interact with innate and adaptive immune cells and orchestrate the inflammatory response. Granule proteins have been identified as important modulators of neutrophil trafficking, reverse transendothelial migration, phagocytosis, neutrophil life span, neutrophil extracellular trap formation, efferocytosis, cytokine activity, and autoimmunity. Hence, defining their roles within the inflammatory locus is critical for minimizing damage to the neighboring tissue and return to homeostasis. Here, we provide an overview of recent advances in the regulation of degranulation, granule protein functions, and signaling in modulating neutrophil‐mediated immunity. We also discuss how targeting granule proteins and/or signaling could be harnessed for therapeutic benefits.