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Airway epithelial cells prime plasmacytoid dendritic cells to respond to pathogens via secretion of growth factors

Mucosal Immunology (2018) | Download Citation

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Abstract

Plasmacytoid dendritic cells (PDCs) are critical for defense against respiratory viruses because of their propensity to secrete high levels of type I interferons (IFN). The functions of PDCs in the lung can be influenced by airway epithelial cells. We examined the effect of human primary bronchial epithelial cells (PBECs) on PDC functions by performing RNA-sequencing of PDCs after co-culture with air liquid interface differentiated PBECs. Functional analysis revealed that PDCs co-cultured with PBECs displayed upregulation of type I IFN production and response genes. Upregulated transcripts included those encoding cytosolic sensors of DNA, ZBP-1,IRF-3, and NFkB as well as genes involved in amplification of the IFN response, such as IFNAR1, JAK/STAT, ISG15. In keeping with the RNA-seq data, we observe increased secretion of type I IFN and other cytokines in response to influenza in PDCs co-cultured with PBECs. The PDCs also primed Th1 responses in T cells. The enhanced response of PDCs co-cultured with PBECs was due to the action of growth factors, GMCSF, GCSF, and VEGF, which were secreted by PBECs on differentiation. These data highlight possible mechanisms to enhance the production of type-I IFN in the airways, which is critical for host defense against respiratory infections.

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References

  1. 1.

    Gilliet, M., Cao, W. & Liu, Y. J. Plasmacytoid dendritic cells: sensing nucleic acids in viral infection and autoimmune diseases. Nat. Rev. Immunol. 8, 594–606 (2008).

  2. 2.

    Swiecki, M. & Colonna, M. Unraveling the functions of plasmacytoid dendritic cells during viral infections, autoimmunity, and tolerance. Immunol. Rev. 234, 142–162 (2010).

  3. 3.

    Merad, M., Sathe, P., Helft, J., Miller, J. & Mortha, A. The dendritic cell lineage: ontogeny and function of dendritic cells and their subsets in the steady state and the inflamed setting. Annu. Rev. Immunol. 31, 563–604 (2013).

  4. 4.

    Swiecki, M. & Colonna, M. The multifaceted biology of plasmacytoid dendritic cells. Nat. Rev. Immunol. 15, 471–485 (2015).

  5. 5.

    de Heer, H. J. et al. Essential role of lung plasmacytoid dendritic cells in preventing asthmatic reactions to harmless inhaled antigen. J. Exp. Med. 200, 89–98 (2004).

  6. 6.

    Venet, F., Huang, X., Chung, C. S., Chen, Y. & Ayala, A. Plasmacytoid dendritic cells control lung inflammation and monocyte recruitment in indirect acute lung injury in mice. Am. J. Pathol. 176, 764–773 (2010).

  7. 7.

    Chairakaki, A. D. et al. Plasmacytoid dendritic cells drive acute asthma exacerbations. J. Allergy Clin. Immunol. S0091-6749, 31586–5 (2017).

  8. 8.

    Agrawal, S. et al. Airway epithelial cells enhance the immunogenicity of human myeloid dendritic cells under steady state. Clin. Exp. Immunol. 189, 279–289 (2017).

  9. 9.

    Rate, A., Bosco, A., McKenna, K. L., Holt, P. G. & Upham, J. W. Airway epithelial cells condition dendritic cells to express multiple immune surveillance genes. PLoS ONE 7, e44941 (2012).

  10. 10.

    Rate, A., Upham, J. W., Bosco, A., McKenna, K. L. & Holt, P. G. Airway epithelial cells regulate the functional phenotype of locally differentiating dendritic cells: implications for the pathogenesis of infectious and allergic airway disease. J. Immunol. 182, 72–83 (2009).

  11. 11.

    Prakash, S., Agrawal, S., Cao, J. N., Gupta, S. & Agrawal, A. Impaired secretion of interferons by dendritic cells from aged subjects to influenza: role of histone modifications. Age 35, 1785–1797 (2013).

  12. 12.

    Sridharan, A. et al. Age-associated impaired plasmacytoid dendritic cell functions lead to decreased CD4 and CD8 T cell immunity. Age 33, 363–376 (2011).

  13. 13.

    Blank, F. et al. Macrophages and dendritic cells express tight junction proteins and exchange particles in an in vitro model of the human airway wall. Immunobiology 216, 86–95 (2011).

  14. 14.

    Rothen-Rutishauser, B. M., Kiama, S. G. & Gehr, P. A three-dimensional cellular model of the human respiratory tract to study the interaction with particles. Am. J. Respir. Cell Mol. Biol. 32, 281–289 (2005).

  15. 15.

    Araujo, E. F. et al. Tolerogenic plasmacytoid dendritic cells control paracoccidioides brasiliensis infection by inducting regulatory T cells in an IDO-dependent manner. PLoS Pathog. 12, e1006115 (2016).

  16. 16.

    Lippens, C. et al. IDO-orchestrated crosstalk between pDCs and Tregs inhibits autoimmunity. J. Autoimmun. 75, 39–49 (2016).

  17. 17.

    Ivashkiv, L. B. & Donlin, L. T. Regulation of type I interferon responses. Nat. Rev. Immunol. 14, 36–49 (2014).

  18. 18.

    Kesavardhana, S. et al. ZBP1/DAI ubiquitination and sensing of influenza vRNPs activate programmed cell death. J. Exp. Med. 214, 2217–2229 (2017).

  19. 19.

    Grouard, G. et al. The enigmatic plasmacytoid T cells develop into dendritic cells with interleukin (IL)-3 and CD40-ligand. J. Exp. Med. 185, 1101–1111 (1997).

  20. 20.

    Matta, B. M., Castellaneta, A. & Thomson, A. W. Tolerogenic plasmacytoid DC. Eur. J. Immunol. 40, 2667–2676 (2010).

  21. 21.

    Lynch, J. P. et al. Plasmacytoid dendritic cells protect from viral bronchiolitis and asthma through semaphorin 4a-mediated T reg expansion. J. Exp. Med. 215, 537–557 (2018).

  22. 22.

    Kuriakose, T. et al. ZBP1/DAI is an innate sensor of influenza virus triggering the NLRP3 inflammasome and programmed cell death pathways. Sci. Immunol. 1, aag2045 (2016).

  23. 23.

    Honda, K. & Taniguchi, T. IRFs: master regulators of signalling by Toll-like receptors and cytosolic pattern-recognition receptors. Nat. Rev. Immunol. 6, 644–658 (2006).

  24. 24.

    Engel, A. & Barton, G. M. Compartment-specific control of signaling from a DNA-sensing immune receptor. Sci. Signal. 3, pe45 (2010).

  25. 25.

    Birmachu, W. et al. Transcriptional networks in plasmacytoid dendritic cells stimulated with synthetic TLR 7 agonists. BMC Immunol. 8, 26 (2007).

  26. 26.

    Fabricius, D. et al. Prostaglandin E2 inhibits IFN-alpha secretion and Th1 costimulation by human plasmacytoid dendritic cells via E-prostanoid 2 and E-prostanoid 4 receptor engagement. J. Immunol. 184, 677–684 (2010).

  27. 27.

    Cao, W. et al. Plasmacytoid dendritic cell-specific receptor ILT7-Fc epsilonRI gamma inhibits Toll-like receptor-induced interferon production. J. Exp. Med. 203, 1399–1405 (2006).

  28. 28.

    Prele, C. M. et al. SOCS1 regulates the IFN but not NFkappaB pathway in TLR-stimulated human monocytes and macrophages. J. Immunol. 181, 8018–8026 (2008).

  29. 29.

    Yu, X. et al. Cross-regulation of two type I interferon signaling pathways in plasmacytoid dendritic cells controls anti-malaria immunity and host mortality. Immunity 45, 1093–1107 (2016).

  30. 30.

    Kim, S. et al. Self-priming determines high type I IFN production by plasmacytoid dendritic cells. Eur. J. Immunol. 44, 807–818 (2014).

  31. 31.

    Giannakopoulos, N. V. et al. Proteomic identification of proteins conjugated to ISG15 in mouse and human cells. Biochem. Biophys. Res. Commun. 336, 496–506 (2005).

  32. 32.

    Shi, H. X. et al. Positive regulation of interferon regulatory factor 3 activation by Herc5 via ISG15 modification. Mol. Cell. Biol. 30, 2424–2436 (2010).

  33. 33.

    Dos Santos, P. F. & Mansur, D. S. Beyond ISGlylation: functions of free intracellular and extracellular ISG15. J. Interferon Cytokine Res. 37, 246–253 (2017).

  34. 34.

    Lu, G. et al. ISG15 enhances the innate antiviral response by inhibition of IRF-3 degradation. Cell Mol. Biol. 52, 29–41 (2006).

  35. 35.

    Agrawal, A. Dendritic cell-airway epithelial cell cross-talk changes with age and contributes to chronic lung inflammatory diseases in the elderly. Int. J. Mol. Sci. 18, 1206–1218 (2017).

  36. 36.

    Geng, D., Joshi, S. K., Podolsky, R. & She, J. X. GCSF receptor regulates antigen uptake and expression of cytokines and costimulatory molecules in dendritic cells. Mol. Immunol. 44, 521–529 (2007).

  37. 37.

    Ghirelli, C., Zollinger, R. & Soumelis, V. Systematic cytokine receptor profiling reveals GM-CSF as a novel TLR-independent activator of human plasmacytoid predendritic cells. Blood 115, 5037–5040 (2010).

  38. 38.

    Eloranta, M. L. et al. Regulation of the interferon-alpha production induced by RNA-containing immune complexes in plasmacytoid dendritic cells. Arthritis Rheum. 60, 2418–2427 (2009).

  39. 39.

    Ruben, J. M. et al. Human plasmacytoid dendritic cells acquire phagocytic capacity by TLR9 ligation in the presence of soluble factors produced by renal epithelial cells. Kidney Int. 93, 355–364 (2018).

  40. 40.

    Min, L. et al. Cutting edge: granulocyte-macrophage colony-stimulating factor is the major CD8+T cell-derived licensing factor for dendritic cell activation. J. Immunol. 184, 4625–4629 (2010).

  41. 41.

    Dzionek, A. et al. BDCA-2, BDCA-3, and BDCA-4: three markers for distinct subsets of dendritic cells in human peripheral blood. J. Immunol. 165, 6037–6046 (2000).

  42. 42.

    Chapoval, S. P. et al. Lung vascular endothelial growth factor expression induces local myeloid dendritic cell activation. Clin. Immunol. 132, 371–384 (2009).

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Acknowledgements

This study was supported by grant from the NIH AG045216 (to AA), and from the National Center for Research Resources and the National Center for Advancing Translational Sciences # UL1 TR000153. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. We are grateful to ICTS UC Irvine for providing the blood samples.

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Author notes

  1. These authors contributed equally: Farah Rahmatpanah, Sudhanshu Agrawal, Natasha Jaiswal

Affiliations

  1. Department of pathology, University of California, Irvine, CA, 92697, USA

    • Farah Rahmatpanah
  2. Division of Basic and Clinical Immunology, Department of Medicine, University of California, Irvine, CA, 92697, USA

    • Sudhanshu Agrawal
    • , Natasha Jaiswal
    • , Hannah M. Ngyuen
    •  & Anshu Agrawal
  3. Microbiology & Molecular Genetics, University of California, Irvine, CA, 92697, USA

    • Michael McClelland

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Contributions

F.R. performed sequencing analysis, N.J. performed the functional studies, S.A. sorted pDCs for sequencing and helped perform functional studies, H.N. helped in cell purification, M.M. helped in sequencing analysis, A.A. wrote the manuscript and supervised the experiments. All authors helped in the discussing and editing of manuscript.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Anshu Agrawal.

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DOI

https://doi.org/10.1038/s41385-018-0097-1