The long shadow of a short life: How neutrophils confer trained immunity.

Abstract

Neutrophils, traditionally viewed as short-lived, terminally differentiated innate immune cells with no capacity for immunological memory, have recently been recognized as key players in trained immunity. This concept challenges the classical dichotomy between innate and adaptive immunity by demonstrating that prior microbial or inflammatory stimuli can induce long-lasting functional reprogramming of innate immune cells. This review provides a comprehensive overview of neutrophil-trained immunity, covering the central role of the bone marrow niche in storing innate immune memory, the epigenetic and metabolic mechanisms that underpin training, the diverse triggers (microbial ligands, vaccines, and endogenous sterile inducers), and the resulting functional consequences in neutrophils. Crucially, this response operates on a dose-dependent polarity: low-dose priming induces protective memory, whereas chronic or excessive inflammatory stimuli trigger neutrophil exhaustion and persistent tissue injury. We argue that the classical paradigm of autoantibody-driven tissue damage in autoimmune conditions is fundamentally anchored by "maladaptive trained immunity" established at the central hematopoietic level. Finally, this review discusses new strategies for the preparation of trained immunity-based vaccines and adjuvants, enhancement of immunity in immunocompromised patients, and clinical treatment to inhibit chronic inflammation, while also highlighting research gaps regarding the durability of neutrophil-trained immunity, the potential for de-training, and the interplay between trained immunity and other immune components, thereby revealing the significant implications and research prospects of neutrophil-trained immunity.