Activation of interferon regulatory factor 7 in plasmacytoid dendritic cells promotes experimental autoimmune pancreatitis.
Autoimmune pancreatitis
IRF7
Plasmacytoid dendritic cells
Journal
Journal of gastroenterology
ISSN: 1435-5922
Titre abrégé: J Gastroenterol
Pays: Japan
ID NLM: 9430794
Informations de publication
Date de publication:
May 2020
May 2020
Historique:
received:
06
08
2019
accepted:
05
01
2020
pubmed:
22
1
2020
medline:
14
10
2021
entrez:
22
1
2020
Statut:
ppublish
Résumé
Excessive type I IFN (IFN-I) production by plasmacytoid dendritic cells (pDCs) promotes autoimmunity. Recently, we reported that a prominent feature of both experimental autoimmune pancreatitis (AIP) and human type 1 AIP is pDC activation followed by enhanced production of IFN-I and IL-33. However, the roles played by interferon regulatory factor 7 (IRF7), a critical transcription factor for IFN-I production in pDCs, in these disorders have not been clarified. Whole and nuclear extracts were isolated from pancreatic mononuclear cells (PMNCs) from MRL/MpJ mice exhibiting AIP. Expression of phospho-IRF7 and nuclear translocation of IRF7 was examined in these extracts by immunoblotting. Pancreatic expression of IRF7 was assessed by immunofluorescence analysis in experimental AIP. Nuclear translocation of IRF7 upon exposure to neutrophil extracellular traps (NETs) was assessed in peripheral blood pDCs from type 1 AIP patients. Pancreatic IRF7 expression was examined in surgically operated specimens from type 1 AIP patients. IRF7 activation was induced in pancreatic pDCs in experimental AIP. siRNA-mediated knockdown of IRF7 expression prevented AIP development, which was accompanied by a marked reduction in both pancreatic accumulation of pDCs and production of IFN-α and IL-33. Notably, in peripheral blood pDCs isolated from patients with type 1 AIP, nuclear translocation of IRF7 was enhanced as compared with the translocation in pDCs from healthy controls. Furthermore, IRF7-expressing pDCs were detected in the pancreas of patients with type 1 AIP. These findings suggest that the IRF7-IFN-I-IL-33 axis activated in pDCs drives pathogenic innate immune responses associated with type 1 AIP.
Sections du résumé
BACKGROUND
BACKGROUND
Excessive type I IFN (IFN-I) production by plasmacytoid dendritic cells (pDCs) promotes autoimmunity. Recently, we reported that a prominent feature of both experimental autoimmune pancreatitis (AIP) and human type 1 AIP is pDC activation followed by enhanced production of IFN-I and IL-33. However, the roles played by interferon regulatory factor 7 (IRF7), a critical transcription factor for IFN-I production in pDCs, in these disorders have not been clarified.
METHODS
METHODS
Whole and nuclear extracts were isolated from pancreatic mononuclear cells (PMNCs) from MRL/MpJ mice exhibiting AIP. Expression of phospho-IRF7 and nuclear translocation of IRF7 was examined in these extracts by immunoblotting. Pancreatic expression of IRF7 was assessed by immunofluorescence analysis in experimental AIP. Nuclear translocation of IRF7 upon exposure to neutrophil extracellular traps (NETs) was assessed in peripheral blood pDCs from type 1 AIP patients. Pancreatic IRF7 expression was examined in surgically operated specimens from type 1 AIP patients.
RESULTS
RESULTS
IRF7 activation was induced in pancreatic pDCs in experimental AIP. siRNA-mediated knockdown of IRF7 expression prevented AIP development, which was accompanied by a marked reduction in both pancreatic accumulation of pDCs and production of IFN-α and IL-33. Notably, in peripheral blood pDCs isolated from patients with type 1 AIP, nuclear translocation of IRF7 was enhanced as compared with the translocation in pDCs from healthy controls. Furthermore, IRF7-expressing pDCs were detected in the pancreas of patients with type 1 AIP.
CONCLUSIONS
CONCLUSIONS
These findings suggest that the IRF7-IFN-I-IL-33 axis activated in pDCs drives pathogenic innate immune responses associated with type 1 AIP.
Identifiants
pubmed: 31960143
doi: 10.1007/s00535-020-01662-2
pii: 10.1007/s00535-020-01662-2
doi:
Substances chimiques
Interferon Regulatory Factor-7
0
Interferon Type I
0
Interferon-alpha
0
Interleukin-33
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
565-576Subventions
Organisme : Japan Society for the Promotion of Science
ID : 19K08455
Organisme : Japan Society for the Promotion of Science
ID : 19K17506
Références
Arthritis Rheumatol. 2017 Feb;69(2):376-386
pubmed: 28130918
J Clin Invest. 2010 May;120(5):1645-62
pubmed: 20389019
Sci Transl Med. 2011 Mar 9;3(73):73ra20
pubmed: 21389264
Gut. 2018 Apr;67(4):728-735
pubmed: 28765476
Nat Rev Immunol. 2008 Aug;8(8):594-606
pubmed: 18641647
J Allergy Clin Immunol. 2019 Feb;143(2):736-745.e6
pubmed: 29852256
Trends Immunol. 2018 Jan;39(1):28-43
pubmed: 28826817
Eur J Immunol. 2014 Jul;44(7):2153-64
pubmed: 24777946
Sci Transl Med. 2016 Apr 27;8(336):336ra59
pubmed: 27122612
Ann Rheum Dis. 2014 Jun;73(6):1259-63
pubmed: 24385203
J Immunol. 2017 May 15;198(10):3886-3896
pubmed: 28373582
N Engl J Med. 2012 Feb 9;366(6):539-51
pubmed: 22316447
Lancet. 2015 Apr 11;385(9976):1460-71
pubmed: 25481618
Trends Immunol. 2018 Nov;39(11):874-889
pubmed: 30401468
Nat Rev Immunol. 2015 Aug;15(8):471-85
pubmed: 26160613
J Immunol. 2015 Oct 1;195(7):3033-44
pubmed: 26297761
Sci Transl Med. 2018 Aug 8;10(453):
pubmed: 30089633
Sci Transl Med. 2011 Mar 9;3(73):73ra19
pubmed: 21389263
Pancreas. 2011 Apr;40(3):352-8
pubmed: 21412117
Immunity. 2006 Sep;25(3):349-60
pubmed: 16979567
J Gastroenterol. 2010 Apr;45(4):355-69
pubmed: 20127119
Am J Gastroenterol. 2019 Jun;114(6):1002-1003
pubmed: 31058651
Mucosal Immunol. 2016 Sep;9(5):1234-49
pubmed: 26813347
Ann Rheum Dis. 2016 Nov;75(11):1909-1916
pubmed: 27009916
Sci Rep. 2017 Feb 13;7:42413
pubmed: 28205524
Immunity. 2012 Aug 24;37(2):326-38
pubmed: 22902233
Int Immunol. 2019 Nov 8;31(12):795-809
pubmed: 31287532
J Immunol. 2012 Sep 15;189(6):2689-95
pubmed: 22956760
Immunol Rev. 2011 Sep;243(1):74-90
pubmed: 21884168
J Gastroenterol. 2011 Mar;46(3):277-88
pubmed: 21452084