Neutrophil Apoptosis and Inflammation Resolution

Neutrophil apoptosis is a pivotal mechanism in innate immunity, serving to limit tissue damage and promote the restoration of homeostasis once a threat has been neutralised. Following their rapid recruitment to sites of infection or injury, neutrophils deploy cytotoxic mediators and microbial killing mechanisms. To prevent excessive inflammation and collateral tissue injury, these effector cells undergo programmed cell death and are subsequently cleared by macrophages and other phagocytes. This clearance process, known as efferocytosis, triggers anti-inflammatory and pro-resolving pathways, including the release of specialised lipid mediators, which orchestrate tissue repair and the cessation of leukocyte recruitment. Dysregulation of neutrophil apoptosis contributes to chronic inflammatory diseases such as rheumatoid arthritis, chronic obstructive pulmonary disease and sepsis. An intricate network of intracellular signalling pathways, involving members of the Bcl-2 family, caspases, kinases and transcription factors, integrates survival and pro-apoptotic cues from cytokines, extracellular matrix ligands and pathogen-associated stimuli. Understanding these checkpoints has opened avenues for therapeutic strategies aimed at modulating neutrophil lifespan to enhance resolution and mitigate inflammatory pathology.

Research from Nature Portfolio

Recent studies have shown that cyclin-dependent kinase 9 (CDK9) is a critical regulator of neutrophil survival and that its inhibition promotes apoptosis in vivo. Genetic knockdown and pharmacological blockade of CDK9 in a vertebrate model led to accelerated reduction of neutrophil numbers at sites of injury, demonstrating a conserved role for CDK9 in controlling the timing of resolution. This work highlights CDK9 as a promising target to fine-tune the inflammatory response. In parallel, investigations into engineered nanoparticles revealed distinct neutrophil subpopulations with variable susceptibility to apoptosis. Exposure to silver nanoparticles triggered enhanced transit of mature neutrophils through late apoptosis without eliciting necrosis, suggesting that modulation of neutrophil heterogeneity can be harnessed to clear cells non-inflammatorily and avoid tissue damage.

Neutrophil Apoptosis and Inflammation Resolution publication trend

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

Technical terms

Neutrophil apoptosis: Programmed cell death of neutrophils, essential for terminating inflammation.

Efferocytosis: Phagocytic clearance of apoptotic cells by macrophages, triggering anti-inflammatory signals.

Pro-resolving mediators: Bioactive lipids, such as lipoxins and resolvins, that promote the resolution of inflammation.

Cyclin-dependent kinase 9 (CDK9): A kinase involved in transcriptional regulation whose inhibition induces neutrophil apoptosis.

Neutrophil heterogeneity: The existence of distinct neutrophil subpopulations differing in maturity, activation state and lifespan.

References

1. Targeting Neutrophils for Promoting the Resolution of Inflammation. Frontiers in Immunology (2022).
2. Genetic and pharmacological inhibition of CDK9 drives neutrophil apoptosis to resolve inflammation in zebrafish in vivo. Scientific Reports (2016).
3. Silver nanoparticles promote the emergence of heterogeneic human neutrophil sub-populations. Scientific Reports (2018).
4. Influence of Microbes on Neutrophil Life and Death. Frontiers in Cellular and Infection Microbiology (2017).
5. Modulation of Neutrophil Apoptosis and the Resolution of Inflammation through β2 Integrins. Frontiers in Immunology (2013).