Intestinal Dysbiosis and Autoimmune Pancreatitis

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

Abstract

Autoimmune pancreatitis (AIP) is a chronic fibro-inflammatory disorder of the pancreas. Recent clinicopathological analysis revealed that most cases of AIP are pancreatic manifestations of systemic IgG4-related disease (IgG4-RD), a newly established disease characterized by enhanced IgG4 antibody responses and the involvement of multiple organs. Although the immuno-pathogenesis of AIP and IgG4-RD has been poorly defined, we recently showed that activation of plasmacytoid dendritic cells (pDCs) with the ability to produce large amounts of IFN-α and IL-33 mediates chronic fibro-inflammatory responses in experimental and human AIP. Moreover, M2 macrophages producing a large amount of IL-33 play pathogenic roles in the development of human IgG4-RD. Interestingly, recent studies including ours provide evidence that compositional alterations of gut microbiota are associated with the development of human AIP and IgG4-RD. In addition, intestinal dysbiosis plays pathological roles in the development of chronic pancreatic inflammation as dysbiosis mediates the activation of pDCs producing IFN-α and IL-33, thereby causing experimental AIP. In this Mini Review, we focus on compositional alterations of gut microbiota in AIP and IgG4-RD to clarify the mechanisms by which intestinal dysbiosis contributes to the development of these disorders.

Keywords: IgG4-related disease; autoimmune pancreatitis; dysbiosis; intestinal microbiota; plasmacytoid dendritic cells.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Yoshikawa, Watanabe, Kamata, Hara, Minaga and Kudo.

Figures

Figure 1
Figure 1
Intestinal dysbiosis and autoimmune pancreatitis. Intestinal dysbiosis activates plasmacytoid dendritic cells (pDCs) which produce IFN-α and IL-33. Klebsiella pneumoniae and microbe-associated molecular patterns (MAMPs) activate pancreatic pDCs to produce IFN-α and IL-33. Recognition of MAMPs by toll-like receptor 7 (TLR7) and exposure to short-chain fatty acids (SCFAs) and bile acids may lead to IL-33 production by M2 macrophages. Accumulation of pDCs and M2 macrophages in the pancreas causes infiltration of immune cells including IgG4-expressing plasmacytes, B cells, and T cells, destruction of acinar architecture, and fibrosis.

References

    1. Levy M, Kolodziejczyk AA, Thaiss CA, Elinav E. Dysbiosis and the immune system. Nat Rev Immunol (2017) 17:219–32. 10.1038/nri.2017.7
    1. Skelly AN, Sato Y, Kearney S, Honda K. Mining the microbiota for microbial and metabolite-based immunotherapies. Nat Rev Immunol (2019) 19:305–23. 10.1038/s41577-019-0144-5
    1. Lynch SV, Pedersen O. The Human Intestinal Microbiome in Health and Disease. N Engl J Med (2016) 375:2369–79. 10.1056/NEJMra1600266
    1. Honjo H, Watanabe T, Arai Y, Kamata K, Minaga K, Komeda Y, et al. . ATG16L1 negatively regulates RICK/RIP2-mediated innate immune responses. Int Immunol (2021) 33:91–105. 10.1093/intimm/dxaa062
    1. Watanabe T, Minaga K, Kamata K, Sakurai T, Komeda Y, Nagai T, et al. . RICK/RIP2 is a NOD2-independent nodal point of gut inflammation. Int Immunol (2019) 31:669–83. 10.1093/intimm/dxz045
    1. Adolph TE, Mayr L, Grabherr F, Schwarzler J, Tilg H. Pancreas-Microbiota Cross Talk in Health and Disease. Annu Rev Nutr (2019) 39:249–66. 10.1146/annurev-nutr-082018-124306
    1. Akshintala VS, Talukdar R, Singh VK, Goggins M. The Gut Microbiome in Pancreatic Disease. Clin Gastroenterol Hepatol (2019) 17:290–5. 10.1016/j.cgh.2018.08.045
    1. Thomas RM, Jobin C. Microbiota in pancreatic health and disease: the next frontier in microbiome research. Nat Rev Gastroenterol Hepatol (2020) 17:53–64. 10.1038/s41575-019-0242-7
    1. Watanabe T, Kudo M, Strober W. Immunopathogenesis of pancreatitis. Mucosal Immunol (2017) 10:283–98. 10.1038/mi.2016.101
    1. Tsuji Y, Watanabe T, Kudo M, Arai H, Strober W, Chiba T. Sensing of Commensal Organisms by the Intracellular Sensor NOD1 Mediates Experimental Pancreatitis. Immunity (2012) 37:326–38. 10.1016/j.immuni.2012.05.024
    1. Kamisawa T, Chari ST, Lerch MM, Kim MH, Gress TM, Shimosegawa T. Recent advances in autoimmune pancreatitis: type 1 and type 2. Gut (2013) 62:1373–80. 10.1136/gutjnl-2012-304224
    1. Watanabe T, Minaga K, Kamata K, Kudo M, Strober W. Mechanistic Insights into Autoimmune Pancreatitis and IgG4-Related Disease. Trends Immunol (2018) 39:874–89. 10.1016/j.it.2018.09.005
    1. Kamisawa T, Zen Y, Pillai S, Stone JH. IgG4-related disease. Lancet (2015) 385:1460–71. 10.1016/S0140-6736(14)60720-0
    1. Stone JH, Zen Y, Deshpande V. IgG4-related disease. N Engl J Med (2012) 366:539–51. 10.1056/NEJMra1104650
    1. Shiokawa M, Kodama Y, Sekiguchi K, Kuwada T, Tomono T, Kuriyama K, et al. . Laminin 511 is a target antigen in autoimmune pancreatitis. Sci Trans Med (2018) 10:eaaq0997. 10.1126/scitranslmed.aaq0997
    1. Perugino CA, AlSalem SB, Mattoo H, Della-Torre E, Mahajan V, Ganesh G, et al. . Identification of galectin-3 as an autoantigen in patients with IgG4-related disease. J Allergy Clin Immunol (2019) 143:736–45.e6. 10.1016/j.jaci.2018.05.011
    1. Hubers LM, Vos H, Schuurman AR, Erken R, Oude Elferink RP, Burgering B, et al. . Annexin A11 is targeted by IgG4 and IgG1 autoantibodies in IgG4-related disease. Gut (2018) 67:728–35. 10.1136/gutjnl-2017-314548
    1. Shiokawa M, Kodama Y, Kuriyama K, Yoshimura K, Tomono T, Morita T, et al. . Pathogenicity of IgG in patients with IgG4-related disease. Gut (2016) 65:1322–32. 10.1136/gutjnl-2015-310336
    1. Aalberse RC, Stapel SO, Schuurman J, Rispens T. Immunoglobulin G4: an odd antibody. Clin Exp Allergy (2009) 39:469–77. 10.1111/j.1365-2222.2009.03207.x
    1. Bach JF. The hygiene hypothesis in autoimmunity: the role of pathogens and commensals. Nat Rev Immunol (2018) 18:105–20. 10.1038/nri.2017.111
    1. Kamata K, Watanabe T, Minaga K, Hara A, Yoshikawa T, Okamoto A, et al. . Intestinal dysbiosis mediates experimental autoimmune pancreatitis via activation of plasmacytoid dendritic cells. Int Immunol (2019) 31:795–809. 10.1093/intimm/dxz050
    1. Kamata K, Watanabe T, Minaga K, Hara A, Sekai I, Otsuka Y, et al. . Gut microbiome alterations in type 1 autoimmune pancreatitis after induction of remission by prednisolone. Clin Exp Immunol (2020) 202:308–20. 10.1111/cei.13509
    1. Takeda K, Akira S. Toll-like receptors in innate immunity. Int Immunol (2005) 17:1–14. 10.1093/intimm/dxh186
    1. Strober W, Murray PJ, Kitani A, Watanabe T. Signalling pathways and molecular interactions of NOD1 and NOD2. Nat Rev Immunol (2006) 6:9–20. 10.1038/nri1747
    1. Ishiguro N, Moriyama M, Furusho K, Furukawa S, Shibata T, Murakami Y, et al. . Activated M2 Macrophages Contribute to the Pathogenesis of IgG4-Related Disease via Toll-like Receptor 7/Interleukin-33 Signaling. Arthritis Rheumatol (2020) 72:166–78. 10.1002/art.41052
    1. Fukui Y, Uchida K, Sakaguchi Y, Fukui T, Nishio A, Shikata N, et al. . Possible involvement of Toll-like receptor 7 in the development of type 1 autoimmune pancreatitis. J Gastroenterol (2015) 50:435–44. 10.1007/s00535-014-0977-4
    1. Furukawa S, Moriyama M, Miyake K, Nakashima H, Tanaka A, Maehara T, 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. 10.1038/srep42413
    1. Arai Y, Yamashita K, Kuriyama K, Shiokawa M, Kodama Y, Sakurai T, 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. 10.4049/jimmunol.1500971
    1. Watanabe T, Yamashita K, Arai Y, Minaga K, Kamata K, Nagai T, 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. 10.4049/jimmunol.1700060
    1. Kamata K, Watanabe T, Minaga K, Strober W, Kudo M. Autoimmune Pancreatitis Mouse Model. Curr Protoc Immunol (2018) 120:15 31 1–15 31 8. 10.1002/cpim.41
    1. Swiecki M, Colonna M. The multifaceted biology of plasmacytoid dendritic cells. Nat Rev Immunol (2015) 15:471–85. 10.1038/nri3865
    1. Ganguly D. Do Type I Interferons Link Systemic Autoimmunities and Metabolic Syndrome in a Pathogenetic Continuum? Trends Immunol (2018) 39:28–43. 10.1016/j.it.2017.07.001
    1. Watanabe T, Sadakane Y, Yagama N, Sakurai T, Ezoe H, Kudo M, 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. 10.1038/mi.2015.144
    1. Minaga K, Watanabe T, Arai Y, Shiokawa M, Hara A, Yoshikawa T, et al. . Activation of interferon regulatory factor 7 in plasmacytoid dendritic cells promotes experimental autoimmune pancreatitis. J Gastroenterol (2020) 55:565–76. 10.1007/s00535-020-01662-2
    1. Minaga K, Watanabe T, Hara A, Kamata K, Omoto S, Nakai A, et al. . Identification of serum IFN-alpha and IL-33 as novel biomarkers for type 1 autoimmune pancreatitis and IgG4-related disease. Sci Rep (2020) 10:14879. 10.1038/s41598-020-71848-4
    1. Hamada S, Masamune A, Nabeshima T, Shimosegawa T. Differences in Gut Microbiota Profiles between Autoimmune Pancreatitis and Chronic Pancreatitis. Tohoku J Exp Med (2018) 244:113–7. 10.1620/tjem.244.113
    1. Yamaki K, Ohta M, Nakashima I, Noda A, Asai J, Kato N. Microbial adjuvant and autoimmunity. IV. Production of lesions in the exocrine pancreas of mice by repeated injection of syngeneic pancreatic extract together with the capsular polysaccharide of Klebsiella pneumoniae. Microbiol Immunol (1980) 24:945–56. 10.1111/j.1348-0421.1980.tb02900.x
    1. Contractor N, Louten J, Kim L, Biron CA, Kelsall BL. Cutting edge: Peyer’s patch plasmacytoid dendritic cells (pDCs) produce low levels of type I interferons: possible role for IL-10, TGFbeta, and prostaglandin E2 in conditioning a unique mucosal pDC phenotype. J Immunol (2007) 179:2690–4. 10.4049/jimmunol.179.5.2690
    1. Haruta I, Yanagisawa N, Kawamura S, Furukawa T, Shimizu K, Kato H, et al. . A mouse model of autoimmune pancreatitis with salivary gland involvement triggered by innate immunity via persistent exposure to avirulent bacteria. Lab Invest (2010) 90:1757–69. 10.1038/labinvest.2010.153
    1. Cayrol C, Girard JP. IL-33: an alarmin cytokine with crucial roles in innate immunity, inflammation and allergy. Curr Opin Immunol (2014) 31C:31–7. 10.1016/j.coi.2014.09.004
    1. Conrad C, Gregorio J, Wang YH, Ito T, Meller S, Hanabuchi S, et al. . Plasmacytoid dendritic cells promote immunosuppression in ovarian cancer via ICOS costimulation of Foxp3(+) T-regulatory cells. Cancer Res (2012) 72:5240–9. 10.1158/0008-5472.CAN-12-2271
    1. Watanabe T, Yamashita K, Fujikawa S, Sakurai T, Kudo M, Shiokawa M, et al. . Activation of Toll-like Receptors and NOD-like Receptors Is Involved in Enhanced IgG4 Responses in Autoimmune Pancreatitis. Arthritis Rheumatism (2012) 64:914–24. 10.1002/art.33386
    1. Garrett WS. Immune recognition of microbial metabolites. Nat Rev Immunol (2020) 20:91–2. 10.1038/s41577-019-0252-2
    1. Ji J, Shu D, Zheng M, Wang J, Luo C, Wang Y, et al. . Microbial metabolite butyrate facilitates M2 macrophage polarization and function. Sci Rep (2016) 6:24838. 10.1038/srep24838
    1. Biagioli M, Carino A, Cipriani S, Francisci D, Marchiano S, Scarpelli P, et al. . The Bile Acid Receptor GPBAR1 Regulates the M1/M2 Phenotype of Intestinal Macrophages and Activation of GPBAR1 Rescues Mice from Murine Colitis. J Immunol (2017) 199:718–33. 10.4049/jimmunol.1700183
    1. Vavassori P, Mencarelli A, Renga B, Distrutti E, Fiorucci S. The bile acid receptor FXR is a modulator of intestinal innate immunity. J Immunol (2009) 183:6251–61. 10.4049/jimmunol.0803978
    1. Arpaia N, Campbell C, Fan X, Dikiy S, van der Veeken J, deRoos P, et al. . Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature (2013) 504:451–5. 10.1038/nature12726

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