title: Autoimmune disease-associated variants of extracellular endoplasmic reticulum aminopeptidase 1 induce altered innate immune responses by human immune cells.
abstract: Endoplasmic reticulum aminopeptidase 1 (ERAP1) gene polymorphisms have been linked to several autoimmune diseases; however, the molecular mechanisms underlying these associations are not well understood. Recently, we demonstrated that ERAP1 regulates key aspects of the innate immune response. Previous studies show ERAP1 to be endoplasmic reticulum-localized and secreted during inflammation. Herein, we investigate the possible roles that ERAP1 polymorphic variants may have in modulating the innate immune responses of human peripheral blood mononuclear cells (hPBMCs) using two experimental methods: extracellular exposure of hPBMCs to ERAP1 variants and adenovirus (Ad)-based ERAP1 expression. We found that exposure of hPBMCs to ERAP1 variant proteins as well as ERAP1 overexpression by Ad5 vectors increased inflammatory cytokine and chemokine production, and enhanced immune cell activation. Investigating the molecular mechanisms behind these responses revealed that ERAP1 is able to activate innate immunity via multiple pathways, including the NLRP3 (NOD-like receptor, pyrin domain-containing 3) inflammasome. Importantly, these responses varied if autoimmune disease-associated variants of ERAP1 were examined in the assay systems. Unexpectedly, blocking ERAP1 cellular internalization augmented IL-1β production. To our knowledge, this is the first report identifying ERAP1 as being involved in modulating innate responses of human immune cells, a finding that may explain why ERAP1 has been genetically associated with several autoimmune diseases.
authors.affiliation: Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, Mich., USA.
authors.forename: Yasser A
authors.initials: YA
authors.lastname: Aldhamen
authors.forename: Yuliya
authors.initials: Y
authors.lastname: Pepelyayeva
authors.forename: David P W
authors.initials: DP
authors.lastname: Rastall
authors.forename: Sergey S
authors.initials: SS
authors.lastname: Seregin
authors.forename: Efthalia
authors.initials: E
authors.lastname: Zervoudi
authors.forename: Despoina
authors.initials: D
authors.lastname: Koumantou
authors.forename: Charles F
authors.initials: CF
authors.lastname: Aylsworth
authors.forename: Dionisia
authors.initials: D
authors.lastname: Quiroga
authors.forename: Sarah
authors.initials: S
authors.lastname: Godbehere
authors.forename: Dimitris
authors.initials: D
authors.lastname: Georgiadis
authors.forename: Efstratios
authors.initials: E
authors.lastname: Stratikos
authors.forename: Andrea
authors.initials: A
authors.lastname: Amalfitano
mesh_terms: D000256:Adenoviridae; D000626:Aminopeptidases / Q000235:genetics / Q000276:immunology*; D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D006801:Humans; D007113:Immunity, Innate; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000276:immunology* / Q000473:pathology; D051379:Mice; D015778:Minor Histocompatibility Antigens; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D014161:Transduction, Genetic
chemical_list: D002352:Carrier Proteins; C508585:IL1B protein, human; C587672:IL1B protein, mouse; D053583:Interleukin-1beta; D015778:Minor Histocompatibility Antigens; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C492716:Nlrp3 protein, mouse; D000626:Aminopeptidases; C464841:ERAP1 protein, human; C509944:ERAP1 protein, mouse