Advertisement

Digestive Diseases and Sciences

, Volume 63, Issue 12, pp 3307–3316 | Cite as

Activation of PD-1 Protects Intestinal Immune Defense Through IL-10/miR-155 Pathway After Intestinal Ischemia Reperfusion

  • Xu-Yu Zhang
  • Su Guan
  • Hu-Fei Zhang
  • Rui-Yun Li
  • Zi-Meng LiuEmail author
Original Article
  • 220 Downloads

Abstract

Background

To date, mechanisms of intestinal immunoglobulin (Ig) dysfunction following intestinal ischemia/reperfusion (I/R) remain unclear. Programmed death 1 (PD-1) is associated with immune responses of lymphocytes.

Aim

We aimed to verify the hypothesis that activation of PD-1 may improve intestinal immune dysfunction by regulating IL-10/miR-155 production after intestinal IR injury.

Methods

Intestinal I/R injury was induced in mice by clamping the superior mesenteric artery for 1 h followed by 2-h reperfusion. PD-L1 fusion Ig, anti-interleukin (IL)-10 monoclonal antibody (mAb), and microRNA (miR)-155 agomir were administered. PD-1 expression, IL-10 mRNA, and protein expression in Peyer’s patches (PP) CD4+ cells were measured. MiR-155 levels, tumor necrosis factor (TNF)-α and IL-1β concentration, and activation-induced cytidine deaminase (AID), a key enzyme for intestinal immune antibodies, in PP tissues were measured, respectively. Importantly, the production and cecal bacteria-binding capacity of IgA and IgM were detected.

Results

Intestinal I/R led to decreased PD-1 expression, imbalanced production, and impaired bacteria-binding capacity of IgA and IgM. Activating PD-1 by PD-L1 Ig facilitated IL-10 synthesis, then decreased miR-155 levels, and subsequently promoted AID expression and reduced TNF-α, IL-1β concentration. Upregulation of AID improved the disruptions of intestinal immune barrier caused by IgA and IgM dysfunction. Anti-IL-10 mAb and miR-155 agomir abolished the protective effects of PD-L1 Ig on the intestinal immune defense.

Conclusion

Activation of PD-1 with PD-L1 Ig relieves intestinal immune defensive injury through IL-10/miR-155 pathway following intestinal I/R attack. PD-1, IL-10, and miR-155 may be potential targets for the damages of intestinal barrier and immunity.

Keywords

Intestinal mucosa Reperfusion injury Programmed cell death 1 receptor microRNA Interleukin-10 

Notes

Acknowledgments

The authors thank Jie Li (Laboratory Animal Center, Sun Yat-sen University) for her help in animal experiments.

Funding

The present study was supported by Grants from the Natural Science Foundation of Guangdong Province, China (Grant 2017A030313572 to Xu-Yu Zhang) and grants from the National Natural Science Foundation of China (Grant 81701874 to Zi-meng Liu).

Compliance with ethical standards

Conflicts of Interest

The authors declare that they have no conflict of interest.

Supplementary material

10620_2018_5282_MOESM1_ESM.docx (838 kb)
Supplementary material 1 (DOCX 837 kb)

References

  1. 1.
    Mallick IH, Yang W, Winslet MC, et al. Ischemia-reperfusion injury of the intestine and protective strategies against injury. Dig Dis Sci. 2004;49:1359–1377.  https://doi.org/10.1023/B:DDAS.0000042232.98927.91.CrossRefPubMedGoogle Scholar
  2. 2.
    Zhang XY, Liu ZM, Wen SH, et al. Dexmedetomidine administration before, but not after, ischemia attenuates intestinal injury induced by intestinal ischemia-reperfusion in rats. Anesthesiology. 2012;116:1035–1046.CrossRefGoogle Scholar
  3. 3.
    Fukatsu K, Sakamoto S, Hara E, et al. Gut ischemia-reperfusion affects gut mucosal immunity: a possible mechanism for infectious complications after severe surgical insults. Crit Care Med. 2006;34:182–187.CrossRefGoogle Scholar
  4. 4.
    Wang F, Li Q, Wang C, et al. Dynamic alteration of the colonic microbiota in intestinal ischemia-reperfusion injury. PLoS ONE. 2012;7:e42027.CrossRefGoogle Scholar
  5. 5.
    MacFie J, O’Boyle C, Mitchell CJ, et al. Gut origin of sepsis: a prospective study investigating associations between bacterial translocation, gastric microflora, and septic morbidity. Gut. 1999;45:223–228.CrossRefGoogle Scholar
  6. 6.
    Deitch EA. Gut-origin sepsis: evolution of a concept. Surgeon. 2012;10:350–356.CrossRefGoogle Scholar
  7. 7.
    Pabst O. New concepts in the generation and functions of IgA. Nat Rev Immunol. 2012;12:821–832.CrossRefGoogle Scholar
  8. 8.
    Li H, Wu GH, Chen J. Effect of glucagon-like peptide 2 on the intestinal mucosal immunity and correlative cytokines in mice with gut ischemia/reperfusion injury. Zhonghua Wei Chang Wai Ke Za Zhi. 2006;9:67–70.PubMedGoogle Scholar
  9. 9.
    Zhang XY, Liu ZM, Zhang HF, et al. TGF-β1 improves mucosal IgA dysfunction and dysbiosis following intestinal ischaemia-reperfusion in mice. J Cell Mol Med. 2016;20:1014–1023.CrossRefGoogle Scholar
  10. 10.
    Lenaerts K, Ceulemans LJ, Hundscheid IH, et al. New insights in intestinal ischemia-reperfusion injury: implications for intestinal transplantation. Curr Opin Organ Transplant. 2013;18:298–303.CrossRefGoogle Scholar
  11. 11.
    Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. Immunol Rev. 2010;236:219–242.CrossRefGoogle Scholar
  12. 12.
    Brown KE, Freeman GJ, Wherry EJ, et al. Role of PD-1 in regulating acute infections. Curr Opin Immunol. 2010;22:397–401.CrossRefGoogle Scholar
  13. 13.
    Esch KJ, Juelsgaard R, Martinez PA, et al. Programmed death 1-mediated T cell exhaustion during visceral leishmaniasis impairs phagocyte function. J Immunol. 2013;191:5542–5550.CrossRefGoogle Scholar
  14. 14.
    Kawamoto S, Tran TH, Maruya M, et al. The inhibitory receptor PD-1 regulates IgA selection and bacterial composition in the gut. Science. 2012;336:485–489.CrossRefGoogle Scholar
  15. 15.
    Zhang XY, Liu ZM, Zhang HF, et al. Decreased PD-1/PD-L1 expression is associated with the reduction in mucosal immunoglobulin A in mice with intestinal ischemia reperfusion. Dig Dis Sci. 2015;60:2662–2669.  https://doi.org/10.1007/s10620-015-3684-y.CrossRefPubMedGoogle Scholar
  16. 16.
    Jankovic D, Kugler DG, Sher A. IL-10 production by CD4 + effector T cells: a mechanism for self-regulation. Mucosal Immunol. 2010;3:239–246.CrossRefGoogle Scholar
  17. 17.
    Fairfax KA, Gantier MP, Mackay F, et al. IL-10 regulates Aicda expression through miR-155. J Leukoc Biol. 2015;97:71–78.CrossRefGoogle Scholar
  18. 18.
    Liao W, Zheng H, Wu S, et al. The systemic activation of programmed death 1-PD L1 axis protects systemic lupus erythematosus model from nephritis. Am J Nephrol. 2017;46:371–379.CrossRefGoogle Scholar
  19. 19.
    Chen WJ, Hu XF, Yan M, et al. Human umbilical vein endothelial cells promote the inhibitory activation of CD4(+)CD25(+)Foxp3(+) regulatory T cells via PD-L1. Atherosclerosis. 2016;244:108–112.CrossRefGoogle Scholar
  20. 20.
    Zhang XY, Chen X, Zhang HF, et al. Propofol does not reduce pyroptosis of enterocytes and intestinal epithelial injury after lipopolysaccharide challenge. Dig Dis Sci. 2018;63:81–91.  https://doi.org/10.1007/s10620-017-4801-x.CrossRefPubMedGoogle Scholar
  21. 21.
    Proietti M, Cornacchione V, RezzonicoJost T, et al. ATP-gated ionotropic P2X7 receptor controls follicular T helper cell numbers in Peyer’s patches to promote host-microbiota mutualism. Immunity. 2014;41:789–801.CrossRefGoogle Scholar
  22. 22.
    Turner JR. Intestinal mucosal barrier function in health and disease. Nat Rev Immunol. 2009;9:799–809.CrossRefGoogle Scholar
  23. 23.
    Zan H, Casali P. Regulation of Aicda expression and AID activity. Autoimmunity. 2013;46:83–101.CrossRefGoogle Scholar
  24. 24.
    Fagarasan S, Muramatsu M, Suzuki K, et al. Critical roles of activation-induced cytidine deaminase in the homeostasis of gut flora. Science. 2002;298:1424–1427.CrossRefGoogle Scholar
  25. 25.
    Ji H, Shen X, Gao F, et al. Programmed death-1/B7-H1 negative costimulation protects mouse liver against ischemia and reperfusion injury. Hepatology. 2010;52:1380–1389.CrossRefGoogle Scholar
  26. 26.
    Jaworska K, Ratajczak J, Huang L, et al. Both PD-1 ligands protect the kidney from ischemia reperfusion injury. J Immunol. 2015;194:325–333.CrossRefGoogle Scholar
  27. 27.
    Roussey JA, Viglianti SP, Teitz-Tennenbaum S, et al. Anti-PD-1 antibody treatment promotes clearance of persistent cryptococcal lung infection in mice. J Immunol. 2017;199:3535–3546.CrossRefGoogle Scholar
  28. 28.
    Zhang Y, Du W, Chen Z, Xiang C. Upregulation of PD-L1 by SPP1 mediates macrophage polarization and facilitates immune escape in lung adenocarcinoma. Exp Cell Res. 2017;359:449–457.CrossRefGoogle Scholar
  29. 29.
    Manukyan MC, Alvernaz CH, Poynter JA, et al. Interleukin-10 protects the ischemic heart from reperfusion injury via the STAT3 pathway. Surgery. 2011;150:231–239.CrossRefGoogle Scholar
  30. 30.
    Wan X, Huang WJ, Chen W, et al. IL-10 deficiency increases renal ischemia-reperfusion injury. Nephron Exp Nephrol. 2014;128:37–45.CrossRefGoogle Scholar
  31. 31.
    Fouda AY, Pillai B, Dhandapani KM, et al. Role of interleukin-10 in the neuroprotective effect of the angiotensin type 2 receptor agonist, compound 21, after ischemia/reperfusion injury. Eur J Pharmacol. 2017;799:128–134.CrossRefGoogle Scholar
  32. 32.
    Basso K, Schneider C, Shen Q, et al. BCL6 positively regulates AID and germinal center gene expression via repression of miR-155. J Exp Med. 2012;209:2455–2465.CrossRefGoogle Scholar
  33. 33.
    Eisenhardt SU, Weiss JB, Smolka C, et al. MicroRNA-155 aggravates ischemia-reperfusion injury by modulation of inflammatory cell recruitment and the respiratory oxidative burst. Basic Res Cardiol. 2015;110:32.CrossRefGoogle Scholar
  34. 34.
    Pena-Philippides JC, Caballero-Garrido E, Lordkipanidze T, Roitbak T. In vivo inhibition of miR-155 significantly alters post-stroke inflammatory response. J Neuroinflammation. 2016;13:287.CrossRefGoogle Scholar
  35. 35.
    Li Y, Ma D, Wang Z, Yang J. MicroRNA-155 deficiency in Kupffer cells ameliorates liver ischemia-reperfusion injury in mice. Transplantation. 2017;101:1600–1608.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Anesthesiology, The First Affiliated HospitalSun Yat-sen UniversityGuangzhouChina
  2. 2.School of Biology and Biological EngineeringSouth China University of TechnologyGuangzhouChina
  3. 3.Surgical Intensive Care Unit, The First Affiliated HospitalSun Yat-sen UniversityGuangzhouChina

Personalised recommendations