title: PCSK9 is a critical regulator of the innate immune response and septic shock outcome.
abstract: A decrease in the activity of proprotein convertase subtilisin/kexin type 9 (PCSK9) increases the amount of low-density lipoprotein (LDL) receptors on liver cells and, therefore, LDL clearance. The clearance of lipids from pathogens is related to endogenous lipid clearance; thus, PCSK9 may also regulate removal of pathogen lipids such as lipopolysaccharide (LPS). Compared to controls, Pcsk9 knockout mice displayed decreases in inflammatory cytokine production and in other physiological responses to LPS. In human liver cells, PCSK9 inhibited LPS uptake, a necessary step in systemic clearance and detoxification. Pharmacological inhibition of PCSK9 improved survival and inflammation in murine polymicrobial peritonitis. Human PCSK9 loss-of-function genetic variants were associated with improved survival in septic shock patients and a decrease in inflammatory cytokine response both in septic shock patients and in healthy volunteers after LPS administration. The PCSK9 effect was abrogated in LDL receptor (LDLR) knockout mice and in humans who are homozygous for an LDLR variant that is resistant to PCSK9. Together, our results show that reduced PCSK9 function is associated with increased pathogen lipid clearance via the LDLR, a decreased inflammatory response, and improved septic shock outcome.
authors.affiliation: Centre for Heart Lung Innovation, University of British Columbia, Vancouver V6Z 1Y6, Canada. keith.walley@hli.ubc.ca.
authors.forename: Keith R
authors.initials: KR
authors.lastname: Walley
authors.affiliation: Centre for Heart Lung Innovation, University of British Columbia, Vancouver V6Z 1Y6, Canada.
authors.forename: Katherine R
authors.initials: KR
authors.lastname: Thain
authors.affiliation: Centre for Heart Lung Innovation, University of British Columbia, Vancouver V6Z 1Y6, Canada.
authors.forename: James A
authors.initials: JA
authors.lastname: Russell
authors.affiliation: Cardiovascular Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Muredach P
authors.initials: MP
authors.lastname: Reilly
authors.affiliation: Pulmonary, Allergy, and Critical Care Division, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. Center for Translational Lung Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Nuala J
authors.initials: NJ
authors.lastname: Meyer
authors.affiliation: Cardiovascular Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Jane F
authors.initials: JF
authors.lastname: Ferguson
authors.affiliation: Pulmonary, Allergy, and Critical Care Division, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. Center for Translational Lung Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Christie
authors.affiliation: Department of Emergency and Critical Care Medicine, Chiba University Graduate School of Medicine, Chiba 260-8677, Japan.
authors.forename: Taka-aki
authors.initials: TA
authors.lastname: Nakada
authors.affiliation: Centre for Heart Lung Innovation, University of British Columbia, Vancouver V6Z 1Y6, Canada.
authors.forename: Chris D
authors.initials: CD
authors.lastname: Fjell
authors.affiliation: Centre for Heart Lung Innovation, University of British Columbia, Vancouver V6Z 1Y6, Canada.
authors.forename: Simone A
authors.initials: SA
authors.lastname: Thair
authors.affiliation: Centre for Heart Lung Innovation, University of British Columbia, Vancouver V6Z 1Y6, Canada.
authors.forename: Mihai S
authors.initials: MS
authors.lastname: Cirstea
authors.affiliation: Centre for Heart Lung Innovation, University of British Columbia, Vancouver V6Z 1Y6, Canada.
authors.forename: John H
authors.initials: JH
authors.lastname: Boyd
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D014644:Genetic Variation; D056945:Hep G2 Cells; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012772:Shock, Septic / Q000276:immunology* / Q000378:metabolism*
chemical_list: D008070:Lipopolysaccharides; C472125:PCSK9 protein, human; C472126:Pcsk9 protein, mouse; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases