title: Disruption of proprotein convertase 1/3 (PC1/3) expression in mice causes innate immune defects and uncontrolled cytokine secretion.
abstract: The proprotein convertase 1/3 is expressed in the regulated secretory pathway of neural and endocrine cells. Its major function is in the post-translational processing and activation of precursor proteins. The PC1/3 knock-out (KO) mouse model has allowed us to elucidate its physiological functions in studies focused primarily on neuroendocrine tissues. However, PC1/3 is also expressed in cells of the immune system, mainly in macrophages. The present study explores the effects of innate immune challenge in the PC1/3 KO mouse. PC1/3 KO mice have an enlarged spleen with marked disorganization of the marginal zone and red pulp. Immunohistochemical studies using various markers demonstrate a depletion of dendritic cells in PC1/3 KO spleens. When challenged with lipopolysaccharide, PC1/3 KO mice are more susceptible to septic shock than wild-type controls or other PC KO mice, such as PC2 and PC7 null mice. Plasma levels of proinflammatory cytokines (IL-6, IL-1β, and TNF-α) were very significantly elevated in PC1/3 KO mice, consistent with a hypercytokinemia, i.e. indicative of a major systemic uncontrolled inflammatory response or cytokine storm. Peritoneal macrophages isolated from PC1/3 KO mice also demonstrate elevated cytokine secretion when treated with LPS. Electron micrographs show morphological features indicating a prolonged activation of these cells following LPS stimulation. We also present evidence that the proinflammatory T(h)1 pathway is dominant in the PC1/3 KO mouse model. We conclude that aside from its important role in neuroendocrine functions PC1/3 also has an important role in the regulation of the innate immune system, most likely through the regulation of cytokine secretion in macrophages.
authors.affiliation: Institut de pharmacologie de Sherbrooke, Université de Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada.
authors.forename: Sarah
authors.initials: S
authors.lastname: Refaie
authors.forename: Sandra
authors.initials: S
authors.lastname: Gagnon
authors.forename: Hugo
authors.initials: H
authors.lastname: Gagnon
authors.forename: Roxane
authors.initials: R
authors.lastname: Desjardins
authors.forename: François
authors.initials: F
authors.lastname: D'Anjou
authors.forename: Pedro
authors.initials: P
authors.lastname: D'Orléans-Juste
authors.forename: Xiaorong
authors.initials: X
authors.lastname: Zhu
authors.forename: Donald F
authors.initials: DF
authors.lastname: Steiner
authors.forename: Nabil G
authors.initials: NG
authors.lastname: Seidah
authors.forename: Claude
authors.initials: C
authors.lastname: Lazure
authors.forename: Michel
authors.initials: M
authors.lastname: Salzet
authors.forename: Robert
authors.initials: R
authors.lastname: Day
mesh_terms: D000818:Animals; D016207:Cytokines / Q000276:immunology* / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D007154:Immune System Diseases / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D007113:Immunity, Innate; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000276:immunology* / Q000378:metabolism / Q000648:ultrastructure; D051379:Mice; D018345:Mice, Knockout; D045664:Proprotein Convertase 1 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D018417:Th1 Cells / Q000201:enzymology / Q000378:metabolism
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; D045664:Proprotein Convertase 1