Neutrophil Signaling and Activation Mechanisms

Neutrophils are frontline effector cells of the innate immune system that detect and respond to pathogens or tissue injury through a coordinated sequence of receptor-mediated events, intracellular signal transduction and effector functions. Surface receptors—including G-protein-coupled chemokine receptors, Fc receptors, β2-integrins and pattern-recognition receptors—sense chemotactic gradients, immune complexes and microbial ligands. Ligand binding triggers cascades of protein kinases and phosphatases, cytoskeletal rearrangement, calcium fluxes and transcriptional adaptations. These events culminate in directed migration, phagocytosis, degranulation, generation of reactive oxygen species via the NADPH oxidase complex, and the formation of neutrophil extracellular traps. Tight regulatory circuits, involving both positive and negative nodes, prevent excessive tissue damage. Dysregulated neutrophil activation underpins a range of inflammatory and autoimmune pathologies, while targeted modulation of signalling pathways offers therapeutic promise in infection, chronic inflammation and autoimmunity.

Research from Nature Portfolio

Recent studies have illuminated how gain-of-function mutations in a Src-family tyrosine kinase profoundly alter neutrophil adhesion and transendothelial migration, leading to small-vessel vasculitis and organ fibrosis in infancy. Constitutive kinase activity elevates expression of adhesion molecules on both endothelium and neutrophils, while pharmacological kinase inhibition restores vascular integrity and resolves fibrotic lesions, highlighting a druggable axis in autoinflammatory disease. Foundational work has revealed that the adaptor protein CARD9 orchestrates divergent neutrophil outputs in sterile inflammation, coupling immune-complex stimulation via Src-family kinases and Syk to pro-inflammatory cytokine and chemokine release, yet sparing lipid mediator production. Complementary functional-genomics screens have defined transcriptional, metabolic and ubiquitin-cycling regulators of the phagocyte oxidative burst, identifying nodal factors that fine-tune reactive oxygen species generation and bacterial clearance.

Neutrophil Signaling and Activation Mechanisms publication trend

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

Technical terms

β2-integrins: Cell-surface heterodimeric adhesion receptors that mediate firm neutrophil attachment to endothelium and extracellular matrix.

Neutrophil extracellular traps (NETs): Meshworks of decondensed chromatin decorated with granular proteins that immobilise and kill microbes.

Reactive oxygen species (ROS): Chemically reactive molecules generated by the NADPH oxidase complex, central to microbial killing and redox signalling.

Tyrosine kinase: An enzyme that phosphorylates tyrosine residues on substrate proteins to propagate intracellular signalling cascades.

Dipeptidyl peptidase-1 (DPP-1): A protease responsible for activating neutrophil serine proteases during neutrophil maturation.

CARD9: An intracellular scaffold protein that couples upstream receptor signals to nuclear factor kappa-B activation, driving cytokine gene expression.

SHP1: A protein tyrosine phosphatase that dephosphorylates signalling intermediates, serving as a negative regulator of neutrophil activation.

References

1. Neutrophil cell surface receptors and their intracellular signal transduction pathways. International Immunopharmacology (2013).
2. Constitutively active Lyn kinase causes a cutaneous small vessel vasculitis and liver fibrosis syndrome. Nature Communications (2023).
3. Neutrophil-specific deletion of the CARD9 gene expression regulator suppresses autoantibody-induced inflammation in vivo. Nature Communications (2016).
4. Functional genomics identifies negative regulatory nodes controlling phagocyte oxidative burst. Nature Communications (2015).
5. Balancing immune response: SHP1 controls neutrophil activation in inflamed lungs. Journal of Clinical Investigation (2024).
6. Brensocatib (an oral, reversible inhibitor of dipeptidyl peptidase-1) attenuates disease progression in two animal models of rheumatoid arthritis. Frontiers in Immunology (2023).
7. Targeting Neutrophil β2-Integrins: A Review of Relevant Resources, Tools, and Methods. Biomolecules (2023).