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Activation of interferon regulatory factor 7 in plasmacytoid dendritic cells promotes experimental autoimmune pancreatitis

  • Original Article—Liver, Pancreas, and Biliary Tract
  • Published:
Journal of Gastroenterology Aims and scope Submit manuscript

Abstract

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

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

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

These findings suggest that the IRF7-IFN-I-IL-33 axis activated in pDCs drives pathogenic innate immune responses associated with type 1 AIP.

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Abbreviations

Ab:

Antibody

Ag:

Antigen

AIP:

Autoimmune pancreatitis

BDCA2:

Blood dendritic cell antigen 2

CP:

Chronic pancreatitis

ELISA:

Enzyme-linked immunosorbent assay

H&E:

Hematoxylin and eosin

IFN-I:

Type I IFN

IgG4-RD:

IgG4-related disease

IP:

Intraperitoneal

IRF:

Interferon regulatory factor

IV:

Intravenous

MSU:

Monosodium urate

NET:

Neutrophil extracellular trap

PC:

Pancreatic cancer

pDC:

Plasmacytoid dendritic cell

PDCA:

pDC antigen

pIRF3:

Phospho-IRF3

pIRF7:

Phospho-IRF7

PMNC:

Pancreatic mononuclear cell

poly(I:C):

Polyinosinic–polycytidylic acid

SLE:

Systemic lupus erythematosus

TF:

Transcription factor

TLR:

Toll-like receptor

References

  1. Swiecki M, Colonna M. The multifaceted biology of plasmacytoid dendritic cells. Nat Rev Immunol. 2015;15:471–85.

    Article  CAS  Google Scholar 

  2. Gilliet M, Cao W, Liu YJ. Plasmacytoid dendritic cells: sensing nucleic acids in viral infection and autoimmune diseases. Nat Rev Immunol. 2008;8:594–606.

    Article  CAS  Google Scholar 

  3. Honda K, Takaoka A, Taniguchi T. Type I interferon [corrected] gene induction by the interferon regulatory factor family of transcription factors. Immunity. 2006;25:349–60.

    Article  CAS  Google Scholar 

  4. Wang Y, Swiecki M, McCartney SA, et al. dsRNA sensors and plasmacytoid dendritic cells in host defense and autoimmunity. Immunol Rev. 2011;243:74–90.

    Article  CAS  Google Scholar 

  5. Ganguly D. Do type I interferons link systemic autoimmunities and metabolic syndrome in a pathogenetic continuum? Trends Immunol. 2018;39:28–43.

    Article  CAS  Google Scholar 

  6. Watanabe T, Minaga K, Kamata K, et al. Mechanistic insights into autoimmune pancreatitis and IgG4-related disease. Trends Immunol. 2018;39:874–89.

    Article  CAS  Google Scholar 

  7. Garcia-Romo GS, Caielli S, Vega B, et al. Netting neutrophils are major inducers of type I IFN production in pediatric systemic lupus erythematosus. Sci Transl Med. 2011;3:73ra20.

  8. Lande R, Ganguly D, Facchinetti V, et al. Neutrophils activate plasmacytoid dendritic cells by releasing self-DNA-peptide complexes in systemic lupus erythematosus. Sci Transl Med. 2011;3:73ra19.

  9. Furie R, Khamashta M, Merrill JT, et al. Anifrolumab, an anti-interferon-alpha receptor monoclonal antibody, in moderate-to-severe systemic lupus erythematosus. Arthritis Rheumatol. 2017;69:376–86.

    Article  CAS  Google Scholar 

  10. Khamashta M, Merrill JT, Werth VP, et al. Sifalimumab, an anti-interferon-alpha monoclonal antibody, in moderate to severe systemic lupus erythematosus: a randomised, double-blind, placebo-controlled study. Ann Rheum Dis. 2016;75:1909–16.

    Article  CAS  Google Scholar 

  11. Stone JH, Zen Y, Deshpande V. IgG4-related disease. N Engl J Med. 2012;366:539–51.

    Article  CAS  Google Scholar 

  12. Kamisawa T, Zen Y, Pillai S, et al. IgG4-related disease. Lancet. 2015;385:1460–71.

    Article  CAS  Google Scholar 

  13. Shimosegawa T, Chari ST, Frulloni L, et al. International consensus diagnostic criteria for autoimmune pancreatitis: guidelines of the International Association of Pancreatology. Pancreas. 2011;40:352–8.

    Article  Google Scholar 

  14. Okazaki K, Uchida K, Koyabu M, et al. Recent advances in the concept and diagnosis of autoimmune pancreatitis and IgG4-related disease. J Gastroenterol. 2011;46:277–88.

    Article  CAS  Google Scholar 

  15. Kawa S, Okazaki K, Kamisawa T, Working members of Research Committee for Intractable Pancreatic D, et al. Japanese consensus guidelines for management of autoimmune pancreatitis: II. Extrapancreatic lesions, differential diagnosis. J Gastroenterol. 2010;45:355–69.

  16. Arai Y, Yamashita K, Kuriyama K, et al. Plasmacytoid dendritic cell activation and IFN-alpha production are prominent features of murine autoimmune pancreatitis and human IgG4-related autoimmune pancreatitis. J Immunol. 2015;195:3033–44.

    Article  CAS  Google Scholar 

  17. Watanabe T, Yamashita K, Arai Y, et al. Chronic fibro-inflammatory responses in autoimmune pancreatitis depend on IFN-alpha and IL-33 produced by plasmacytoid dendritic cells. J Immunol. 2017;198:3886–96.

    Article  CAS  Google Scholar 

  18. Kamata K, Watanabe T, Minaga K, et al. Autoimmune pancreatitis mouse model. Curr Protoc Immunol. 2018;120:15 31 1–15 31 8.

  19. Puthia M, Ambite I, Cafaro C, et al. IRF7 inhibition prevents destructive innate immunity-A target for nonantibiotic therapy of bacterial infections. Sci Transl Med. 2016;8:336ra59.

  20. Watanabe T, Asano N, Fichtner-Feigl S, et al. NOD1 contributes to mouse host defense against Helicobacter pylori via induction of type I IFN and activation of the ISGF3 signaling pathway. J Clin Invest. 2010;120:1645–62.

    Article  CAS  Google Scholar 

  21. Tsuji Y, Watanabe T, Kudo M, et al. Sensing of commensal organisms by the intracellular sensor NOD1 mediates experimental pancreatitis. Immunity. 2012;37:326–38.

    Article  CAS  Google Scholar 

  22. Watanabe T, Sadakane Y, Yagama N, et al. Nucleotide-binding oligomerization domain 1 acts in concert with the cholecystokinin receptor agonist, cerulein, to induce IL-33-dependent chronic pancreatitis. Mucosal Immunol. 2016;9:1234–49.

    Article  CAS  Google Scholar 

  23. The Japan Pancreas Society. Japanese clinical diagnostic criteria for autoimmune pancreatitis, 2018 (Proposal) revision of japanese clinical diagnostic criteria for autoimmune pancreatitis, 2011. Suizo. 2018;33:902–13.

    Article  Google Scholar 

  24. Sun L, Zhu Z, Cheng N, et al. Serum amyloid A induces interleukin-33 expression through an IRF7-dependent pathway. Eur J Immunol. 2014;44:2153–64.

    Article  CAS  Google Scholar 

  25. Kamata K, Watanabe T, Minaga K, et al. Intestinal dysbiosis mediates experimental autoimmune pancreatitis via activation of plasmacytoid dendritic cells. Int Immunol. 2019;31:795–809.

    Article  Google Scholar 

  26. Kaplan MJ, Radic M. Neutrophil extracellular traps: double-edged swords of innate immunity. J Immunol. 2012;189:2689–95.

    Article  CAS  Google Scholar 

  27. Shiokawa M, Kodama Y, Sekiguchi K, et al. Laminin 511 is a target antigen in autoimmune pancreatitis. Sci Transl Med. 2018;10:eaaq0997.

  28. Hubers LM, Vos H, Schuurman AR, et al. Annexin A11 is targeted by IgG4 and IgG1 autoantibodies in IgG4-related disease. Gut. 2018;67:728–35.

    CAS  PubMed  Google Scholar 

  29. Perugino CA, AlSalem SB, Mattoo H, et al. Identification of galectin-3 as an autoantigen in patients with IgG4-related disease. J Allergy Clin Immunol. 2019;143(736–45):e6.

    Google Scholar 

  30. Furukawa S, Moriyama M, Miyake K, et al. Interleukin-33 produced by M2 macrophages and other immune cells contributes to Th2 immune reaction of IgG4-related disease. Sci Rep. 2017;7:42413.

    Article  CAS  Google Scholar 

  31. Awada A, Nicaise C, Ena S, et al. Potential involvement of the IL-33-ST2 axis in the pathogenesis of primary Sjogren's syndrome. Ann Rheum Dis. 2014;73:1259–63.

    Article  CAS  Google Scholar 

  32. Minaga K, Watanabe T, Kamata K, et al. The IFN-alpha-IL-33 Axis as Possible Biomarkers in IgG4-Related Disease. Am J Gastroenterol. 2019;114:1002–3.

    Article  Google Scholar 

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Acknowledgements

This work was supported by Grants-in-Aid for Scientific Research (19K08455, 19K17506) from Japan Society for the Promotion of Science, Takeda Science Foundation, Smoking Research Foundation, Yakult Bio-Science Foundation, SENSHIN Medical Research Foundation, and Japan Agency for Medical Research and Development (AMED) for Research on Intractable Diseases.

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Authors and Affiliations

  1. Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan

    Kosuke Minaga, Tomohiro Watanabe, Akane Hara, Tomoe Yoshikawa, Ken Kamata & Masatoshi Kudo

  2. Department of Hematology and Oncology, Kyoto University Graduate School of Medicine, Kyoto, Japan

    Yasuyuki Arai & Kouhei Yamashita

  3. Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan

    Masahiro Shiokawa

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  1. Kosuke Minaga
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  2. Tomohiro Watanabe
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  3. Yasuyuki Arai
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Correspondence to Tomohiro Watanabe.

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Minaga, K., Watanabe, T., Arai, Y. et al. Activation of interferon regulatory factor 7 in plasmacytoid dendritic cells promotes experimental autoimmune pancreatitis. J Gastroenterol 55, 565–576 (2020). https://doi.org/10.1007/s00535-020-01662-2

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  • DOI: https://doi.org/10.1007/s00535-020-01662-2

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