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Aryl hydrocarbon receptor activation drives polymorphonuclear myeloid-derived suppressor cell response and efficiently attenuates experimental Sjögren’s syndrome

Abstract

Myeloid-derived suppressor cells (MDSCs) comprise heterogeneous myeloid cell populations with immunosuppressive capacity that contribute to immune regulation and tolerance induction. We previously reported impaired MDSC function in patients with primary Sjögren’s syndrome (pSS) and mice with experimental SS (ESS). However, the molecular mechanisms underlying MDSC dysfunction remain largely unclear. In this study, we first found that aryl hydrocarbon receptor (AhR) was highly expressed by human and murine polymorphonuclear MDSCs (PMN-MDSCs). Indole-3-propionic acid (IPA), a natural AhR ligand produced from dietary tryptophan, significantly promoted PMN-MDSC differentiation and suppressive function on CD4+ T cells. In contrast, feeding a tryptophan-free diet resulted in a decreased PMN-MDSC response, a phenotype that could be reversed by IPA supplementation. The functional importance of PMN-MDSCs was demonstrated in ESS mice by using a cell-depletion approach. Notably, AhR expression was reduced in PMN-MDSCs during ESS development, while AhR antagonism resulted in exacerbated ESS pathology and dysregulated T effector cells, which could be phenocopied by a tryptophan-free diet. Interferon regulatory factor 4 (IRF4), a repressive transcription factor, was upregulated in PMN-MDSCs during ESS progression. Chromatin immunoprecipitation analysis revealed that IRF4 could bind to the promoter region of AhR, while IRF4 deficiency markedly enhanced AhR-mediated PMN-MDSC responses. Furthermore, dietary supplementation with IPA markedly ameliorated salivary glandular pathology in ESS mice with restored MDSC immunosuppressive function. Together, our results identify a novel function of AhR in modulating the PMN-MDSC response and demonstrate the therapeutic potential of targeting AhR for the treatment of pSS.

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References

  1. Nagaraj S, Youn JI, Gabrilovich DI. Reciprocal relationship between myeloid-derived suppressor cells and T cells. J Immunol. 2013;191:17–23.

    Article  CAS  PubMed  Google Scholar 

  2. Knier B, Hiltensperger M, Sie C, Aly L, Lepennetier G, Engleitner T, et al. Myeloid-derived suppressor cells control B cell accumulation in the central nervous system during autoimmunity. Nat Immunol. 2018;19:1341–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Alshetaiwi H, Pervolarakis N, McIntyre LL, Ma D, Nguyen Q, Rath JA, et al. Defining the emergence of myeloid-derived suppressor cells in breast cancer using single-cell transcriptomics. Sci Immunol. 2020;5:5341.

    Article  Google Scholar 

  4. Otsuji M, Kimura Y, Aoe T, Okamoto Y, Saito T. Oxidative stress by tumor-derived macrophages suppresses the expression of CD3 zeta chain of T-cell receptor complex and antigen-specific T-cell responses. Proc Natl Acad Sci USA. 1996;93:13119–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Flores-Toro JA, Luo D, Gopinath A, Sarkisian MR, Campbell JJ, Charo IF, et al. CCR2 inhibition reduces tumor myeloid cells and unmasks a checkpoint inhibitor effect to slow progression of resistant murine gliomas. Proc Natl Acad Sci USA. 2020;117:1129–38.

    Article  CAS  PubMed  Google Scholar 

  6. Park MJ, Lee SH, Kim EK, Lee EJ, Park SH, Kwok SK, et al. Myeloid-derived suppressor cells induce the expansion of regulatory B cells and ameliorate autoimmunity in the sanroque mouse model of systemic lupus erythematosus. Arthritis Rheumatol. 2016;68:2717–27.

    Article  CAS  PubMed  Google Scholar 

  7. Nocturne G, Mariette X. Advances in understanding the pathogenesis of primary Sjogren’s syndrome. Nat Rev Rheumatol. 2013;9:544–56.

    Article  CAS  PubMed  Google Scholar 

  8. Fu W, Liu X, Lin X, Feng H, Sun L, Li S, et al. Deficiency in T follicular regulatory cells promotes autoimmunity. J Exp Med. 2018;215:815–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Lin X, Rui K, Deng J, Tian J, Wang X, Wang S, et al. Th17 cells play a critical role in the development of experimental Sjogren’s syndrome. Ann Rheum Dis. 2015;74:1302–10.

    Article  CAS  PubMed  Google Scholar 

  10. Psianou K, Panagoulias I, Papanastasiou AD, de Lastic AL, Rodi M, Spantidea PI, et al. Clinical and immunological parameters of Sjogren’s syndrome. Autoimmun Rev. 2018;17:1053–64.

    Article  CAS  PubMed  Google Scholar 

  11. Xiao F, Lin X, Tian J, Wang X, Chen Q, Rui K, et al. Proteasome inhibition suppresses Th17 cell generation and ameliorates autoimmune development in experimental Sjogren’s syndrome. Cell Mol Immunol. 2017;14:924–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Lin X, Wang X, Xiao F, Ma K, Liu L, Wang X, et al. IL-10-producing regulatory B cells restrain the T follicular helper cell response in primary Sjogren’s syndrome. Cell Mol Immunol. 2019;16:921–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Guggino G, Lin X, Rizzo A, Xiao F, Saieva L, Raimondo S, et al. Interleukin-25 axis is involved in the pathogenesis of human primary and experimental murine Sjogren’s syndrome. Arthritis Rheumatol. 2018;70:1265–75.

    Article  CAS  PubMed  Google Scholar 

  14. Tian J, Rui K, Hong Y, Wang X, Xiao F, Lin X, et al. Increased GITRL impairs the function of myeloid-derived suppressor cells and exacerbates primary Sjogren syndrome. J Immunol. 2019;202:1693–703.

    Article  CAS  PubMed  Google Scholar 

  15. Kumar V, Cheng P, Condamine T, Mony S, Languino LR, McCaffrey JC, et al. CD45 phosphatase inhibits STAT3 transcription factor activity in myeloid cells and promotes tumor-associated macrophage differentiation. Immunity. 2016;44:303–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Ainsua-Enrich E, Hatipoglu I, Kadel S, Turner S, Paul J, Singh S, et al. IRF4-dependent dendritic cells regulate CD8(+) T-cell differentiation and memory responses in influenza infection. Mucosal Immunol. 2019;12:1025–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Chistiakov DA, Myasoedova VA, Revin VV, Orekhov AN, Bobryshev YV. The impact of interferon-regulatory factors to macrophage differentiation and polarization into M1 and M2. Immunobiology. 2018;223:101–11.

    Article  CAS  PubMed  Google Scholar 

  18. Nam S, Kang K, Cha JS, Kim JW, Lee HG, Kim Y, et al. Interferon regulatory factor 4 (IRF4) controls myeloid-derived suppressor cell (MDSC) differentiation and function. J Leukoc Biol. 2016;100:1273–84.

    Article  CAS  PubMed  Google Scholar 

  19. Goudot C, Coillard A, Villani AC, Gueguen P, Cros A, Sarkizova S, et al. Aryl hydrocarbon receptor controls monocyte differentiation into dendritic cells versus macrophages. Immunity. 2017;47:582–96.e586.

    Article  CAS  PubMed  Google Scholar 

  20. Giani Tagliabue S, Faber SC, Motta S, Denison MS, Bonati L. Modeling the binding of diverse ligands within the Ah receptor ligand binding domain. Sci Rep. 2019;9:10693.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Rothhammer V, Mascanfroni ID, Bunse L, Takenaka MC, Kenison JE, Mayo L, et al. Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and central nervous system inflammation via the aryl hydrocarbon receptor. Nat Med. 2016;22:586–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Hyland NP, Cavanaugh CR, Hornby PJ. Emerging effects of tryptophan pathway metabolites and intestinal microbiota on metabolism and intestinal function. Amino Acids. 2022;54:57–70.

    Article  CAS  PubMed  Google Scholar 

  23. Coligan JE, Bierer BE, Margulies DH, Shevach EM, Strober W, Solito S, et al. Methods to measure MDSC immune suppressive activity in vitro and in vivo. Curr Protoc Immunol. 2019;124:e61.

    Article  Google Scholar 

  24. Tian J, Ma J, Ma K, Guo H, Baidoo SE, Zhang Y, et al. beta-Glucan enhances antitumor immune responses by regulating differentiation and function of monocytic myeloid-derived suppressor cells. Eur J Immunol. 2013;43:1220–30.

    Article  CAS  PubMed  Google Scholar 

  25. Veglia F, Perego M, Gabrilovich D. Myeloid-derived suppressor cells coming of age. Nat Immunol. 2018;19:108–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Krishnan S, Ding Y, Saedi N, Choi M, Sridharan GV, Sherr DH, et al. Gut microbiota-derived tryptophan metabolites modulate inflammatory response in hepatocytes and macrophages. Cell Rep. 2018;23:1099–111.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Ouyang X, Zhang R, Yang J, Li Q, Qin L, Zhu C, et al. Transcription factor IRF8 directs a silencing programme for TH17 cell differentiation. Nat Commun. 2011;2:314.

    Article  PubMed  Google Scholar 

  28. Wada T, Sunaga H, Ohkawara R, Shimba S. Aryl hydrocarbon receptor modulates NADPH oxidase activity via direct transcriptional regulation of p40phox expression. Mol Pharm. 2013;83:1133–40.

    Article  CAS  Google Scholar 

  29. Fang S, Cheng Y, Deng F, Zhang B. RNF34 ablation promotes cerebrovascular remodeling and hypertension by increasing NADPH-derived ROS generation. Neurobiol Dis. 2021;156:105396.

    Article  CAS  PubMed  Google Scholar 

  30. Danaceau JP, Anderson GM, McMahon WM, Crouch DJ. A liquid chromatographic-tandem mass spectrometric method for the analysis of serotonin and related indoles in human whole blood. J Anal Toxicol. 2003;27:440–4.

    Article  CAS  PubMed  Google Scholar 

  31. Youn JI, Collazo M, Shalova IN, Biswas SK, Gabrilovich DI. Characterization of the nature of granulocytic myeloid-derived suppressor cells in tumor-bearing mice. J Leukoc Biol. 2012;91:167–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Zhou J, Nefedova Y, Lei A, Gabrilovich D. Neutrophils and PMN-MDSC: their biological role and interaction with stromal cells. Semin Immunol. 2018;35:19–28.

    Article  CAS  PubMed  Google Scholar 

  33. Leja-Szpak A, Góralska M, Link-Lenczowski P, Czech U, Nawrot-Porąbka K, Bonior J, et al. The opposite effect of L-kynurenine and Ahr inhibitor Ch223191 on apoptotic protein expression in pancreatic carcinoma cells (Panc-1). Anticancer Agents Med Chem. 2019;19:2079–90.

    Article  CAS  PubMed  Google Scholar 

  34. Viola A, Munari F, Sánchez-Rodríguez R, Scolaro T, Castegna A. The metabolic signature of macrophage responses. Front Immunol. 2019;10:1462.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Huang SCC, Smith AM, Everts B, Colonna M, Pearce EL, Schilling JD, et al. Metabolic reprogramming mediated by the mTORC2-IRF4 signaling axis is essential for macrophage alternative activation. Immunity. 2016;45:817–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Rui K, Hong Y, Zhu Q, Shi X, Xiao F, Fu H, et al. Olfactory ecto-mesenchymal stem cell-derived exosomes ameliorate murine Sjogren’s syndrome by modulating the function of myeloid-derived suppressor cells. Cell Mol Immunol. 2021;18:440–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Trikha P, Lee DA. The role of AhR in transcriptional regulation of immune cell development and function. Biochim Biophys Acta Rev Cancer. 2020;1873:188335.

    Article  CAS  PubMed  Google Scholar 

  38. Goettel JA, Gandhi R, Kenison JE, Yeste A, Murugaiyan G, Sambanthamoorthy S, et al. AHR activation is protective against colitis driven by T cells in humanized mice. Cell Rep. 2016;17:1318–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Ye J, Qiu J, Bostick JW, Ueda A, Schjerven H, Li S, et al. The aryl hydrocarbon receptor preferentially marks and promotes gut regulatory T cells. Cell Rep. 2017;21:2277–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Quintana FJ, Murugaiyan G, Farez MF, Mitsdoerffer M, Tukpah AM, Burns EJ, et al. An endogenous aryl hydrocarbon receptor ligand acts on dendritic cells and T cells to suppress experimental autoimmune encephalomyelitis. Proc Natl Acad Sci USA. 2010;107:20768–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Hauben E, Gregori S, Draghici E, Migliavacca B, Olivieri S, Woisetschlager M, et al. Activation of the aryl hydrocarbon receptor promotes allograft-specific tolerance through direct and dendritic cell-mediated effects on regulatory T cells. Blood. 2008;112:1214–22.

    Article  CAS  PubMed  Google Scholar 

  42. Aoki R, Aoki-Yoshida A, Suzuki C, Takayama Y. Indole-3-pyruvic acid, an aryl hydrocarbon receptor activator, suppresses experimental colitis in mice. J Immunol. 2018;201:3683–93.

    Article  CAS  PubMed  Google Scholar 

  43. Shinde R, Hezaveh K, Halaby MJ, Kloetgen A, Chakravarthy A, da Silva Medina T, et al. Apoptotic cell-induced AhR activity is required for immunological tolerance and suppression of systemic lupus erythematosus in mice and humans. Nat Immunol. 2018;19:571–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Hickman-Brecks CL, Racz JL, Meyer DM, LaBranche TP, Allen PM. Th17 cells can provide B cell help in autoantibody induced arthritis. J Autoimmun. 2011;36:65–75.

    Article  CAS  PubMed  Google Scholar 

  45. Wang Y, Schafer CC, Hough KP, Tousif S, Duncan SR, Kearney JF, et al. Myeloid-derived suppressor cells impair B cell responses in lung cancer through IL-7 and STAT5. J Immunol. 2018;201:278–95.

    Article  CAS  PubMed  Google Scholar 

  46. Kaye J, Piryatinsky V, Birnberg T, Hingaly T, Raymond E, Kashi R, et al. Laquinimod arrests experimental autoimmune encephalomyelitis by activating the aryl hydrocarbon receptor. Proc Natl Acad Sci USA. 2016;113:E6145–E6152.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Ioannou M, Alissafi T, Lazaridis I, Deraos G, Matsoukas J, Gravanis A, et al. Crucial role of granulocytic myeloid-derived suppressor cells in the regulation of central nervous system autoimmune disease. J Immunol. 2012;188:1136–46.

    Article  CAS  PubMed  Google Scholar 

  48. Fujii W, Ashihara E, Hirai H, Nagahara H, Kajitani N, Fujioka K, et al. Myeloid-derived suppressor cells play crucial roles in the regulation of mouse collagen-induced arthritis. J Immunol. 2013;191:1073–81.

    Article  CAS  PubMed  Google Scholar 

  49. Guo C, Hu F, Yi H, Feng Z, Li C, Shi L, et al. Myeloid-derived suppressor cells have a proinflammatory role in the pathogenesis of autoimmune arthritis. Ann Rheum Dis. 2016;75:278–85.

    Article  CAS  PubMed  Google Scholar 

  50. Li W, Tanikawa T, Kryczek I, Xia H, Li G, Wu K, et al. Aerobic glycolysis controls myeloid-derived suppressor cells and tumor immunity via a specific CEBPB isoform in triple-negative breast cancer. Cell Metab. 2018;28:87–103.e106.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Xu WD, Pan HF, Ye DQ, Xu Y. Targeting IRF4 in autoimmune diseases. Autoimmun Rev. 2012;11:918–24.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the Chongqing International Institute for Immunology (2020YJC10), the National Natural Science Foundation of China (NSFC) (82071817, 81971542, and 82171771), the Hong Kong Research Grants Council General Research Fund (17113319 and 27111820) and Theme-Based Research Scheme (T12-703/19 R), the Shenzhen Science and Technology Program (YCYJ20210324114602008) and the Centre for Oncology and Immunology under the Health@InnoHK Initiative of the Innovation and Technology Commission, Hong Kong, China.

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Correspondence to Ke Rui, Xiang Lin or Liwei Lu.

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Wei, Y., Peng, N., Deng, C. et al. Aryl hydrocarbon receptor activation drives polymorphonuclear myeloid-derived suppressor cell response and efficiently attenuates experimental Sjögren’s syndrome. Cell Mol Immunol 19, 1361–1372 (2022). https://doi.org/10.1038/s41423-022-00943-5

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Keywords

  • myeloid-derived suppressor cell
  • Sjogren’s syndrome
  • Aryl hydrocarbon receptor

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