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  • Review Article
  • Published:

Neutrophil serine proteases: specific regulators of inflammation

Key Points

  • The neutrophil serine proteases cathepsin G, neutrophil elastase and proteinase 3 are structurally related enzymes that are stored in their active form in the azurophil granules of neutrophils.

  • They are synthesized during the pro-myelocytic stage of neutrophil differentiation as inactive zymogens that require proteolytic processing at the amino terminus to become active. The enzyme responsible for activation of the neutrophil serine proteases is the cysteine protease dipeptidyl peptidase I (DPPI; also known as cathepsin C).

  • Loss-of-function mutations in the gene encoding DPPI in humans result in only residual neutrophil serine protease activity. These patients have Papillon–Lefèvre Syndrome, which is a rare autosomal recessive disorder characterized by severe periodontitis and thickened skin on the hands and feet.

  • Neutrophil serine proteases are involved in the non-oxidative mechanism of bacterial killing. They cleave the outer membrane protein of Gram-negative bacteria and degrade virulence factors of several species of enterobacteria.

  • Neutrophil serine proteases can also convert chemokines to more potent chemoattractants by limited proteolysis of their amino terminus.

  • Proteinase 3 can process pro-tumour-necrosis factor to a biologically active soluble form and directly activate pro-interleukin-1β, thereby potentially increasing the inflammatory response.

  • Cathepsin G modulates neutrophil effector functions through an indirect interaction with surface integrins that results in increased chemokine release.

  • Interaction of neutrophil serine proteases with proteinase-activated receptors, Toll-like receptors and formyl peptide receptor leads to increased production of chemokines and pro-inflammatory cytokines. This induces chemotaxis and recruitment of leukocytes and provides more evidence of a role for these proteases in the inflammatory process that extends beyond their degradative activity.

Abstract

Neutrophils are essential for host defence against invading pathogens. They engulf and degrade microorganisms using an array of weapons that include reactive oxygen species, antimicrobial peptides, and proteases such as cathepsin G, neutrophil elastase and proteinase 3. As discussed in this Review, the generation of mice deficient in these proteases has established a role for these enzymes as intracellular microbicidal agents. However, I focus mainly on emerging data indicating that, after release, these proteases also contribute to the extracellular killing of microorganisms, and regulate non-infectious inflammatory processes by activating specific receptors and modulating the levels of cytokines.

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Figure 1: Neutrophil granule content.
Figure 2: Biology of neutrophil serine proteases.
Figure 3: Intracellular and extracellular bacterial killing.
Figure 4: Neutrophil serine proteases in inflammation.

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Acknowledgements

The author thanks T. Ley, D. Link, and S. Raptis for their insightful comments. This work was supported by a grant from the National Institutes of Health, USA and the Sandler Program for Asthma Research.

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DATABASES

OMIM

chronic granulomatous disease

cyclic neutropaenia

Papillon–Lefèvre syndrome

severe congenital neutropaenia

Wegener's granulomatosis

FURTHER INFORMATION

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Glossary

NADPH oxidase

An enzyme system that consists of multiple cytosolic and membrane-bound subunits. The complex is assembled in activated neutrophils mainly on the phagolysosomal membrane. NADPH oxidase uses electrons from NADPH to reduce molecular oxygen to form superoxide anions. Superoxide anions are enzymatically converted to hydrogen peroxide, which is converted by myeloperoxidase to hypochloric acid, a highly toxic and microbicidal agent.

Defensins

Small (2–6–kDa) cationic microbicidal peptides that participate in innate immunity. Their tertiary structures are stabilized by intradisulphide bridges and clusters of positively charged amino acids, which resemble those found in chemokines. Several defensins have chemotactic activity for leukocytes.

Serine proteases

A family of 30–35–kDa enzymes that contain a serine residue in the active site. Serine proteases are synthesized as inactive pre-pro-enzymes with a leader sequence of 18–26 amino-acid residues that is cleaved, leaving a pro-enzyme that constitutes a pro-dipeptide and the mature active protease. Activation of the protease requires the removal of the pro-dipeptide sequence by the cysteine protease dipeptidyl peptidase I.

Bullous pemphigoid

An autoimmune disorder characterized by deposition of autoantibodies directed against components of the basement-membrane zone at the dermal–epidermal junction, leading to inflammation and blister formation.

Beige mice

A spontaneous mutation in the Lyst gene, which encodes lysosomal trafficking regulator and is the mouse orthologue of the human CHS1 gene (the gene that is mutated in individuals with Chediak-Higashi syndrome), that results in hypopigmentation and the accumulation of giant lysosomes in neutrophils, cytotoxic lymphocytes, mast cells and melanosomes. Because of the altered granule formation, beige mice have reduced levels of neutrophil serine proteases.

Pro-myelocytic stage

A stage of neutrophil development when the cell transitions from myeloblast to myelocyte. At this stage, the cell contains only azurophil granules.

Zymogen

The inactive precursor of a protease. The zymogen contains an amino-terminal pro-domain that keeps the protease in an inactive state. The removal of the pro-domain by another protease or by autoproteolysis leads to a conformational change that exposes the active site.

Serpin family

Serpins are a family of serine-protease inhibitors that share a high degree of structural homology. The inhibitory specificity of serpins is defined by a single P1 amino acid at the reactive centre loop (RCL). The serpin–protease interaction leads to the cleavage of this P1 residue in the RCL, a reaction that traps the enzyme and distorts the catalytic site. Non-inhibitory forms of serpins might function in processes such as blood coagulation, tumorigenesis and hormone transport.

Respiratory burst

The process by which molecular oxygen is reduced by the NADPH oxidase system to produce reactive oxygen species.

Cathelicidin

Cationic microbicidal peptides found in myeloperoxidase-negative granules of neutrophils that share a highly conserved 'cathelin' 12 kDa pro-sequence at the amino terminus, followed by diversified mature sequences at the carboxy terminus. Activation of most cathelicidin precursors requires proteolytic cleavage to release the C-terminal domain, which has microbicidal activities.

Collagen-induced arthritis

A mouse model of polyarticular arthritis that closely resembles rheumatoid arthritis in humans. The disease is induced by immunizing mice with bovine type II collagen.

Subcutaneous air pouch model

Air pouches formed by subcutaneous injection of air in the back of a mouse provide a suitable and easily accessible space to investigate inflammatory responses induced by various stimuli such as yeast zymosan particles and immune complexes.

Proteinase-activated receptor family

(PAR family). A family of G-protein-coupled receptors that carry their own ligands tethered at the amino terminus. Following proteolytic cleavage of the N terminus, the exposed ligand autoactivates the receptor. The four known PARs are expressed widely by various cell types. PAR1, PAR3 and PAR4 are activated mainly by thrombin, whereas PAR2 is activated by trypsin, tryptase and factor Xa.

G-protein-coupled receptors

(GPCRs). Receptors that are composed of seven membrane-spanning helical segments, which are connected by extracellular and intracellular loops. These receptors associate with G-proteins, which are a family of trimeric intracellular signalling proteins with common β- and γ-chains, and one of several α-chains. The α-chain determines the nature of the signal that is transmitted from a ligand-occupied GPCR to downstream effector systems.

Formyl peptide receptor

This receptor was originally defined as the high affinity, G-protein-coupled receptor for the bacterial chemotactic peptide N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP). Binding of fMLP to the receptor induces neutrophil and monocyte chemotaxis.

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Pham, C. Neutrophil serine proteases: specific regulators of inflammation. Nat Rev Immunol 6, 541–550 (2006). https://doi.org/10.1038/nri1841

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