Neutrophils in toxicology: a forgotten field.

Neutrophils are the most abundant leukocytes in humans and essential for innate immune responses despite a short lifespan in the bloodstream. A complex and tightly regulated production of neutrophils is required to maintain host defense. This process involves intricate signaling between the bone marrow, blood, and tissue clearance. Deficiency or excessive neutrophil infiltration impairs host defenses. Historically, neutrophils were viewed as initial effectors in innate immune responses. Recent discoveries have expanded our understanding of neutrophil biology, identifying multiple activation states and subsets. These subsets may switch phenotypes based on the composition of the microenvironment and might exhibit reverse migratory behavior, moving from inflamed tissues back into the bloodstream. This versatility poses neutrophils as key players in (1) signaling for host defenses, (2) trained immunity, (3) tissue repair, and (4) cancer biology. Disturbances in neutrophil production, responsiveness, apoptosis, and cell removal significantly affect inflammatory diseases and cancer progression. Environmental factors may directly affect the immune system and trigger the onset of many diseases; however, the precise mechanisms underlying the impact of xenobiotics on neutrophil production and functions remain unclear. This review aimed to summarize the current knowledge on neutrophil ontogeny, plasticity, and roles in inflammation, tissue repair, and cancer, emphasizing their susceptibility to different sources of xenobiotic exposures.