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. This article describes recent studies defining the in vivo importance of neutrophil serine proteases in the intracellular and extracellular killing of microorganisms, as well as in the regulation of non-infectious inflammatory processes, such as the modulation of active cytokine concentrations. 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.