title: Endoplasmic reticulum aminopeptidase-1 functions regulate key aspects of the innate immune response.
abstract: Endoplasmic reticulum aminopeptidase-1 (ERAP1) is a multifunctional, ubiquitously expressed enzyme whose peptide-trimming role during antigen processing for presentation by MHC I molecules is well established, however, a role for ERAP1 in modulating global innate immune responses has not been described to date. Here we demonstrate that, relative to wild type mice, mice lacking ERAP1 exhibit exaggerated innate immune responses early during pathogen recognition, as characterized by increased activation of splenic and hepatic NK and NKT cells and enhanced production of pro-inflammatory cytokines such as IL12 and MCP1. Our data also revealed that ERAP1 is playing a critical role in NK cell development and function. We observed higher frequencies of terminally matured NK cells, as well as higher frequencies of licensed NK cells (expressing the Ly49C and Ly49I receptors) in ERAP1-KO mice, results that positively correlated with an enhanced NK activation and IFNγ production by ERAP1-KO mice challenged with pro-inflammatory stimuli. Furthermore, during pathogen recognition, ERAP1 regulates IL12 production by CD11c(+) DCs specifically, with increases in IL12 production positively correlated with an increased phagocytic activity of splenic DCs and macrophages. Collectively, our results demonstrate a previously unrecognized, more central role for the ERAP1 protein in modulating several aspects of both the development of the innate immune system, and its responses during the initial stages of pathogen recognition. Such a role may explain why ERAP1 has been implicated by GWAS in the pathogenesis of autoimmune diseases that may be precipitated by aberrant responses to pathogen encounters.
authors.affiliation: Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, Michigan, United States of America.
authors.forename: Yasser A
authors.initials: YA
authors.lastname: Aldhamen
authors.forename: Sergey S
authors.initials: SS
authors.lastname: Seregin
authors.forename: David P W
authors.initials: DP
authors.lastname: Rastall
authors.forename: Charles F
authors.initials: CF
authors.lastname: Aylsworth
authors.forename: Yuliya
authors.initials: Y
authors.lastname: Pepelyayeva
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Busuito
authors.forename: Sarah
authors.initials: S
authors.lastname: Godbehere-Roosa
authors.forename: Sungjin
authors.initials: S
authors.lastname: Kim
authors.forename: Andrea
authors.initials: A
authors.lastname: Amalfitano
mesh_terms: D000626:Aminopeptidases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D007113:Immunity, Innate / Q000235:genetics / Q000502:physiology*; D018664:Interleukin-12 / Q000378:metabolism; D007694:Killer Cells, Natural / Q000378:metabolism; D008099:Liver / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015778:Minor Histocompatibility Antigens; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000166:cytology
chemical_list: D015778:Minor Histocompatibility Antigens; D018664:Interleukin-12; D000626:Aminopeptidases; C509944:ERAP1 protein, mouse
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