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Endoplasmic reticulum aminopeptidase-1 functions regulate key aspects of the innate immune response.

Aldhamen YA, Seregin SS, Rastall DP, Aylsworth CF, Pepelyayeva Y, Busuito CJ, Godbehere-Roosa S, Kim S, Amalfitano A - PLoS ONE (2013)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, Michigan, United States of America.

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.

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ERAP1-KO mice exhibit dramatically enhanced capabilities to respond to rEA and release pro-inflammatory cytokines.C57BL/6 WT and ERAP1-KO mice were either mock (PBS) injected or intraperitoneally injected with 100 ng/mouse of rEA protein. n = 4 for all groups of mice. Plasma samples were collected at 6 hpi and were analyzed using a multiplexed bead array based quantitative system. Bars represent mean ± SEM. Statistical analysis was completed using two-tailed homoscedastic Student’s t-tests; *, ** - indicate values, statistically different between WT_rEA and ERAP1-KO_rEA groups, p<0.05, p<0.001, respectively.
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pone-0069539-g006: ERAP1-KO mice exhibit dramatically enhanced capabilities to respond to rEA and release pro-inflammatory cytokines.C57BL/6 WT and ERAP1-KO mice were either mock (PBS) injected or intraperitoneally injected with 100 ng/mouse of rEA protein. n = 4 for all groups of mice. Plasma samples were collected at 6 hpi and were analyzed using a multiplexed bead array based quantitative system. Bars represent mean ± SEM. Statistical analysis was completed using two-tailed homoscedastic Student’s t-tests; *, ** - indicate values, statistically different between WT_rEA and ERAP1-KO_rEA groups, p<0.05, p<0.001, respectively.

Mentions: We next assessed reactive cytokine and chemokine responses of ERAP1-KO mice as compared to WT mice. We first confirmed that baseline cytokine and chemokine levels were not significantly different between WT mock and ERAP1-KO mock mice (data not shown). We recently demonstrated that, administration of the TLR11/12 agonist rEA induces systemic cytokine and chemokine releases in WT mice [18]. In this study we not only again confirmed the pro-inflammatory cytokine and chemokine inductions by rEA in C57BL/6 WT mice, but we also found that ERAP1-KO mice exhibited dramatically higher production levels of several pro-inflammatory cytokines and chemokines in response to exposure to rEA, with 3–4 fold increased levels of IL12p40, IL12p70 and MCP1, and significantly increased production levels of IL1α, IL2, IL5, IL6, IL9, IL10, IL13, GCSF, GMCSF, IFNγ, MIP1α, MIP1β, RANTES and TNFα as compared to WT mice (Figure 6). Not all of the cytokines induced by rEA were modulated by ERAP1 such as IL1β and EOTAXIN.


Endoplasmic reticulum aminopeptidase-1 functions regulate key aspects of the innate immune response.

Aldhamen YA, Seregin SS, Rastall DP, Aylsworth CF, Pepelyayeva Y, Busuito CJ, Godbehere-Roosa S, Kim S, Amalfitano A - PLoS ONE (2013)

ERAP1-KO mice exhibit dramatically enhanced capabilities to respond to rEA and release pro-inflammatory cytokines.C57BL/6 WT and ERAP1-KO mice were either mock (PBS) injected or intraperitoneally injected with 100 ng/mouse of rEA protein. n = 4 for all groups of mice. Plasma samples were collected at 6 hpi and were analyzed using a multiplexed bead array based quantitative system. Bars represent mean ± SEM. Statistical analysis was completed using two-tailed homoscedastic Student’s t-tests; *, ** - indicate values, statistically different between WT_rEA and ERAP1-KO_rEA groups, p<0.05, p<0.001, respectively.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3722114&req=5

pone-0069539-g006: ERAP1-KO mice exhibit dramatically enhanced capabilities to respond to rEA and release pro-inflammatory cytokines.C57BL/6 WT and ERAP1-KO mice were either mock (PBS) injected or intraperitoneally injected with 100 ng/mouse of rEA protein. n = 4 for all groups of mice. Plasma samples were collected at 6 hpi and were analyzed using a multiplexed bead array based quantitative system. Bars represent mean ± SEM. Statistical analysis was completed using two-tailed homoscedastic Student’s t-tests; *, ** - indicate values, statistically different between WT_rEA and ERAP1-KO_rEA groups, p<0.05, p<0.001, respectively.
Mentions: We next assessed reactive cytokine and chemokine responses of ERAP1-KO mice as compared to WT mice. We first confirmed that baseline cytokine and chemokine levels were not significantly different between WT mock and ERAP1-KO mock mice (data not shown). We recently demonstrated that, administration of the TLR11/12 agonist rEA induces systemic cytokine and chemokine releases in WT mice [18]. In this study we not only again confirmed the pro-inflammatory cytokine and chemokine inductions by rEA in C57BL/6 WT mice, but we also found that ERAP1-KO mice exhibited dramatically higher production levels of several pro-inflammatory cytokines and chemokines in response to exposure to rEA, with 3–4 fold increased levels of IL12p40, IL12p70 and MCP1, and significantly increased production levels of IL1α, IL2, IL5, IL6, IL9, IL10, IL13, GCSF, GMCSF, IFNγ, MIP1α, MIP1β, RANTES and TNFα as compared to WT mice (Figure 6). Not all of the cytokines induced by rEA were modulated by ERAP1 such as IL1β and EOTAXIN.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, Michigan, United States of America.

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.

Show MeSH
Related in: MedlinePlus