title: Relevance of the mouse model as a therapeutic approach for neutrophil proteinase 3-associated human diseases.
abstract: Proteinase 3 (PR3) is one of the four elastase-related serine proteinases stored in the azurophilic granules of neutrophils. Although it participates in the pro- and anti-inflammatory responses to infection and inflammation it also retains specific functions that make it different from neutrophil elastase in spite of their close structural resemblance. PR3 is involved in the immune response to infection and is the major autoantigen in granulomatosis with polyangiitis (GPA, formerly Wegener disease), an autoimmune systemic vasculitis with granulomas. Thus, PR3 appears to be a relevant therapeutic target in a variety of inflammatory human diseases. Animal models are required for the testing of new drugs that target PR3 specifically but differences between human and rodent neutrophil PR3 expression and substrate specificity have greatly impaired progress in this direction. This may explain that, to date, there is no spontaneous model of vasculitis associated with anti-PR3 antibodies. In this review, we will focus on the structural and functional differences between human and murine PR3, and how these differences may be by-passed in order to develop a relevant animal model.
authors.affiliation: "Centre d'Etudes des Pathologies Respiratoires", INSERM U-1100/EA-6305 37032, Université François Rabelais, 37032 Tours, France. Electronic address: brice.korkmaz@inserm.fr.
authors.forename: Brice
authors.initials: B
authors.lastname: Korkmaz
authors.forename: Dieter E
authors.initials: DE
authors.lastname: Jenne
authors.forename: Francis
authors.initials: F
authors.lastname: Gauthier
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D053146:Myeloblastin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009504:Neutrophils / Q000378:metabolism; D011487:Protein Conformation
chemical_list: D053146:Myeloblastin
keywords: ANCA; Abz; CG; COPD; EDDnp; FRET; GPA; In vivo animal model; LPS; MPO; N-(2,4-dinitrophenyl)ethylenediamine; NET; NSPs; Neutrophil; P21; Proteinase 3 (myeloblastin); Structure function; antineutrophil cytoplasm auto-antibodies; cathepsin G; chronic obstructive pulmonary disease; cyclin-dependent kinase inhibitor-1; fluorescence resonance energy transfer; granulomatosis polyangiitis; hNE; hPR3; human neutrophil elastase; human proteinase 3; lipopolysaccharide; mPR3; mouse proteinase 3; myeloperoxidase; neutral serine proteinases; neutrophil extracellular traps; ortho-aminobenzoic acid; α1-proteinase inhibitor; αl-PI