Endoplasmic Reticulum Aminopeptidase-1 Functions Regulate Key Aspects of the Innate Immune Response

Yasser A. Aldhamen, Sergey S. Seregin, David P W Rastall, Charles F. Aylsworth, Yuliya Pepelyayeva, Christopher J. Busuito, Sarah Godbehere-Roosa, Sung Jin Kim, Andrea Amalfitano

Research output: Contribution to journalArticle

14 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere69539
JournalPLoS One
Volume8
Issue number7
DOIs
StatePublished - Jul 24 2013
Externally publishedYes

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Aminopeptidases
aminopeptidases
Innate Immunity
Endoplasmic Reticulum
endoplasmic reticulum
Natural Killer Cells
Interleukin-12
Pathogens
natural killer cells
Antigen Presentation
pathogens
mice
Natural Killer T-Cells
Genome-Wide Association Study
Chemical activation
Autoimmune Diseases
innate immunity
Hepatocytes
Immune System
Trimming

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Aldhamen, Y. A., Seregin, S. S., Rastall, D. P. W., Aylsworth, C. F., Pepelyayeva, Y., Busuito, C. J., ... Amalfitano, A. (2013). Endoplasmic Reticulum Aminopeptidase-1 Functions Regulate Key Aspects of the Innate Immune Response. PLoS One, 8(7), [e69539]. https://doi.org/10.1371/journal.pone.0069539

Endoplasmic Reticulum Aminopeptidase-1 Functions Regulate Key Aspects of the Innate Immune Response. / Aldhamen, Yasser A.; Seregin, Sergey S.; Rastall, David P W; Aylsworth, Charles F.; Pepelyayeva, Yuliya; Busuito, Christopher J.; Godbehere-Roosa, Sarah; Kim, Sung Jin; Amalfitano, Andrea.

In: PLoS One, Vol. 8, No. 7, e69539, 24.07.2013.

Research output: Contribution to journalArticle

Aldhamen, YA, Seregin, SS, Rastall, DPW, Aylsworth, CF, Pepelyayeva, Y, Busuito, CJ, Godbehere-Roosa, S, Kim, SJ & Amalfitano, A 2013, 'Endoplasmic Reticulum Aminopeptidase-1 Functions Regulate Key Aspects of the Innate Immune Response', PLoS One, vol. 8, no. 7, e69539. https://doi.org/10.1371/journal.pone.0069539
Aldhamen YA, Seregin SS, Rastall DPW, Aylsworth CF, Pepelyayeva Y, Busuito CJ et al. Endoplasmic Reticulum Aminopeptidase-1 Functions Regulate Key Aspects of the Innate Immune Response. PLoS One. 2013 Jul 24;8(7). e69539. https://doi.org/10.1371/journal.pone.0069539
Aldhamen, Yasser A. ; Seregin, Sergey S. ; Rastall, David P W ; Aylsworth, Charles F. ; Pepelyayeva, Yuliya ; Busuito, Christopher J. ; Godbehere-Roosa, Sarah ; Kim, Sung Jin ; Amalfitano, Andrea. / Endoplasmic Reticulum Aminopeptidase-1 Functions Regulate Key Aspects of the Innate Immune Response. In: PLoS One. 2013 ; Vol. 8, No. 7.
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