Neutrophil Cell Death Mechanisms in Inflammation

Neutrophils are essential first responders in innate immunity, eliminating pathogens and orchestrating inflammatory reactions. Their short lifespan and programmed demise are critical for balancing host defence with tissue integrity. Apoptosis provides an immunologically silent route for neutrophil clearance and promotes resolution by enabling phagocytic removal without provoking further inflammation. In contrast, necroptosis and pyroptosis form lytic programmes driven by receptor‐interacting kinases and inflammasome activation, respectively, releasing intracellular contents that amplify cytokine storms and vascular injury. NETosis, the expulsion of decondensed chromatin loaded with antimicrobial proteins, traps microbes but can also instigate thrombosis and autoimmunity if unchecked. Emerging evidence for ferroptosis, an iron‐dependent lipid peroxidation pathway, and autophagy‐associated death highlights additional layers of regulation under oxidative stress. Crosstalk among caspases, RIP kinases, gasdermins and reactive oxygen species dictates the choice of death modality. Dysregulation of these pathways underlies chronic inflammatory diseases, sepsis and cancer progression, emphasising the need to modulate neutrophil fate therapeutically to control infection while preventing collateral tissue damage.

Research from Nature Portfolio

Recent studies have identified mRNA acetylation as a pivotal regulator of neutrophil pyroptosis in sepsis, demonstrating that acetyltransferase‐mediated stabilisation of ULK1 transcripts restrains STING-driven inflammasome activation and reduces lung injury, thereby improving survival in experimental models. In addition, integrative transcriptomic and network analyses have delineated key long non-coding RNAs and protein-coding genes that govern spontaneous neutrophil apoptosis. Hub molecules such as NFκB1 and BIRC3, together with correlated lncRNAs, have been pinpointed as modulators of apoptosis timing, offering new molecular targets for enhancing resolution of inflammation.

Neutrophil Cell Death Mechanisms in Inflammation publication trend

The graph below shows the total number of articles in neutrophil cell death mechanisms in inflammation across all publications each year (not limited to Nature Index journals).

Technical terms

Apoptosis: Programmed cell death characterised by cell shrinkage, membrane blebbing and phagocytic clearance without provoking inflammation.

Necroptosis: A regulated necrotic process dependent on RIPK1/RIPK3 kinases and MLKL, resulting in membrane rupture and inflammatory mediator release.

Pyroptosis: Inflammasome-driven cell death programme mediated by gasdermin pores, leading to rapid lysis and secretion of interleukins.

NETosis: A unique form of death whereby neutrophils eject decondensed chromatin and granule proteins to form extracellular traps against pathogens.

Ferroptosis: Iron-dependent cell death caused by lipid peroxidation and failure of glutathione-dependent antioxidant systems.

Inflammasome: Multiprotein cytosolic complex that activates inflammatory caspases and processes cytokines such as interleukin-1β.

References

1. Dying to Defend: Neutrophil Death Pathways and their Implications in Immunity. Advanced Science (2023).
2. NAT10 regulates neutrophil pyroptosis in sepsis via acetylating ULK1 RNA and activating STING pathway. Communications Biology (2022).
3. Identification of key protein-coding genes and lncRNAs in spontaneous neutrophil apoptosis. Scientific Reports (2019).
4. Dysregulation of neutrophil death in sepsis. Frontiers in Immunology (2022).
5. Pharmacological Induction of Granulocyte Cell Death As Therapeutic Strategy. The Annual Review of Pharmacology and Toxicology (2022).
6. The role of neutrophil death in chronic inflammation and cancer. Cell Death Discovery (2020).
7. NETosis – Does It Really Represent Nature’s “Suicide Bomber”?. Frontiers in Immunology (2016).