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Interleukin-19 enhances eosinophil infiltration through upregulation of epithelium-derived RANTES expression via the ERK/NF-κB signalling pathway in patients with eosinophilic CRSwNP

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Abstract

Backgroud

The recurrence rate of chronic rhinosinusitis with nasal polyps (CRSwNP) is positively correlated with eosinophil infiltration. Increased interleukin (IL)-19 and eosinophil chemokine RANTES levels have been reported in patients with CRSwNP. This study aimed to clarify the role of IL-19 in mediating RANTES expression and eosinophilic infiltration in eosinophilic CRSwNP (Eos CRSwNP).

Methods

Nasal tissue samples were obtained from patients with CRSwNP and controls. The expression of IL-19, its receptors, ECP, and RANTES in tissues was investigated. Primary human nasal epithelial cells (HNECs) and nasal polyp tissue blocks were cultured, then stimulated by IL-19; ERK phosphorylation, NF-κB pathway activation, RANTES level, eosinophils migration and infiltration were detected using RT-qPCR, ELISA, western blotting, HE, immunohistochemistry, immunofluorescence staining, confocal microscopy, and transwell migration assay.

Results

The expression of IL-19 and its receptors (IL-20R1/IL-20R2), eosinophil cationic protein, and RANTES in nasal tissues from patients with Eos CRSwNP was significantly increased compared to that in non-Eos CRSwNP and control subjects. IL-19 co-localized with RANTES in nasal tissues and significantly elevated RANTES expression in HNECs. IL-19-blocking antibody and siRNA knockdown of IL-20R1 ameliorated the effect of IL-19 on RANTES secretion in HNECs. Moreover, IL-19-induced RANTES upregulation was associated with the activation of the ERK and NF-κB pathways. NF-κB activation was mediated by the ERK pathway in IL-19-treated HNECs, and IL-19 enhanced eosinophil infiltration in nasal polyp tissue blocks.

Conclusions

Our findings indicate that IL-19 promotes RANTES expression via the ERK/NF-κB pathway in HNECs and is implicated in eosinophil infiltration in patients with Eos CRSwNP.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

References

  1. Shi JB, Fu QL, Zhang H, et al. Epidemiology of chronic rhinosinusitis: results from a cross-sectional survey in seven Chinese cities. Allergy. 2015;70(5):533–9. https://doi.org/10.1111/all.12577.

    Article  CAS  PubMed  Google Scholar 

  2. Fokkens WJ, Lund VJ, Hopkins C, et al. European position paper on rhinosinusitis and nasal polyps 2020. Rhinology. 2020;58(Suppl S29):1–464. https://doi.org/10.4193/Rhin20.600.

    Article  PubMed  Google Scholar 

  3. Schleimer RP. Immunopathogenesis of chronic rhinosinusitis and nasal polyposis. Annu Rev Pathol. 2017;12:331–57. https://doi.org/10.1146/annurev-pathol-052016-100401.

    Article  CAS  PubMed  Google Scholar 

  4. Lou H, Meng Y, Piao Y, Zhang N, Bachert C, Wang C, Zhang L. Cellular phenotyping of chronic rhinosinusitis with nasal polyps. Rhinology. 2016;54(2):150–9. https://doi.org/10.4193/Rhino15.271.

    Article  PubMed  Google Scholar 

  5. Lou H, Meng Y, Piao Y, Wang C, Zhang L, Bachert C. Predictive significance of tissue eosinophilia for nasal polyp recurrence in the Chinese population. Am J Rhinol Allergy. 2015;29(5):350–6. https://doi.org/10.2500/ajra.2015.29.4231.

    Article  PubMed  Google Scholar 

  6. Ikeda K, Shiozawa A, Ono N, Kusunoki T, Hirotsu M, Homma H, Saitoh T, Murata J. Subclassification of chronic rhinosinusitis with nasal polyp based on eosinophil and neutrophil. Laryngoscope. 2013;123(11):E1-9. https://doi.org/10.1002/lary.24154.

    Article  CAS  PubMed  Google Scholar 

  7. Lampinen M, Carlson M, Håkansson LD, Venge P. Cytokine-regulated accumulation of eosinophils in inflammatory disease. Allergy. 2004;59(8):793–805. https://doi.org/10.1111/j.1398-9995.2004.00469.x.

    Article  CAS  PubMed  Google Scholar 

  8. Kapp A, Zeck-Kapp G, Czech W, Schöpf E. The chemokine RANTES is more than a chemoattractant: characterization of its effect on human eosinophil oxidative metabolism and morphology in comparison with IL-5 and GM-CSF. J Invest Dermatol. 1994;102(6):906–14. https://doi.org/10.1111/1523-1747.ep12383399.

    Article  CAS  PubMed  Google Scholar 

  9. Ebisawa M, Yamada T, Bickel C, Klunk D, Schleimer RP. Eosinophil transendothelial migration induced by cytokines. III. Effect of the chemokine RANTES. J Immunol. 1994;153(5):2153–60.

    Article  CAS  PubMed  Google Scholar 

  10. Bystrom J, Amin K, Bishop-Bailey D. Analysing the eosinophil cationic protein–a clue to the function of the eosinophil granulocyte. Respir Res. 2011;12:10. https://doi.org/10.1186/1465-9921-12-10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Terada N, Maesako K, Hamano N, Ikeda T, Sai M, Yamashita T, Fukuda S, Konno A. RANTES production in nasal epithelial cells and endothelial cells. J Allergy Clin Immunol. 1996;98(6 Pt 2):S230–7. https://doi.org/10.1016/s0091-6749(96)70071-4.

    Article  CAS  PubMed  Google Scholar 

  12. Kuna P, Alam R, Ruta U, Gorski P. RANTES induces nasal mucosal inflammation rich in eosinophils, basophils, and lymphocytes in vivo. Am J Respir Crit Care Med. 1998;157(3 Pt 1):873–9. https://doi.org/10.1164/ajrccm.157.3.9610052.

    Article  CAS  PubMed  Google Scholar 

  13. Rutz S, Wang X, Ouyang W. The IL-20 subfamily of cytokines–from host defence to tissue homeostasis. Nat Rev Immunol. 2014;14(12):783–95. https://doi.org/10.1038/nri3766.

    Article  CAS  PubMed  Google Scholar 

  14. Autieri MV. IL-19 and other IL-20 family member cytokines in vascular inflammatory diseases. Front Immunol. 2018;9:700. https://doi.org/10.3389/fimmu.2018.00700.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Datta Mitra A, Raychaudhuri SP, Abria CJ, Mitra A, Wright R, Ray R, Kundu-Raychaudhuri S. 1α,25-Dihydroxyvitamin-D3-3-bromoacetate regulates AKT/mTOR signaling cascades: a therapeutic agent for psoriasis. J Invest Dermatol. 2013;133(6):1556–64. https://doi.org/10.1038/jid.2013.3.

    Article  CAS  PubMed  Google Scholar 

  16. Li HH, Cheng HH, Sun KH, Wei CC, Li CF, Chen WC, Wu WM, Chang MS. Interleukin-20 targets renal mesangial cells and is associated with lupus nephritis. Clin Immunol. 2008;129(2):277–85. https://doi.org/10.1016/j.clim.2008.07.006.

    Article  CAS  PubMed  Google Scholar 

  17. Weng YH, Chen WY, Lin YL, Wang JY, Chang MS. Blocking IL-19 signaling ameliorates allergen-induced airway inflammation. Front Immunol. 2019;10:968. https://doi.org/10.3389/fimmu.2019.00968.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Li X, Huang J, Chen X, Lai X, Huang Z, Li Y, Li S, Chang L, Zhang G. IL-19 induced by IL-13/IL-17A in the nasal epithelium of patients with chronic rhinosinusitis upregulates MMP-9 expression via ERK/NF-κB signaling pathway. Clin Transl Allergy. 2021;11(1): e12003. https://doi.org/10.1002/clt2.12003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Lai X, Li X, Chang L, et al. IL-19 Up-regulates mucin 5AC production in patients with chronic rhinosinusitis via STAT3 pathway. Front Immunol. 2019;10:1682. https://doi.org/10.3389/fimmu.2019.01682.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Cao PP, Li HB, Wang BF, Wang SB, You XJ, Cui YH, Wang DY, Desrosiers M, Liu Z. Distinct immunopathologic characteristics of various types of chronic rhinosinusitis in adult Chinese. J Allergy Clin Immunol. 2009;124(3):478–84, 484.e12. https://doi.org/10.1016/j.jaci.2009.05.017.

    Article  CAS  PubMed  Google Scholar 

  21. Chen X, Chang L, Li X, et al. Tc17/IL-17A up-regulated the expression of MMP-9 via NF-κB pathway in nasal epithelial cells of patients with chronic rhinosinusitis. Front Immunol. 2018;9:2121. https://doi.org/10.3389/fimmu.2018.02121.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Yang LY, Li X, Li WT, Huang JC, Wang ZY, Huang ZZ, Chang LH, Zhang GH. Vγ1+ γδT cells are correlated with increasing expression of eosinophil cationic protein and metalloproteinase-7 in chronic rhinosinusitis with nasal polyps inducing the formation of edema. Allergy Asthma Immunol Res. 2017;9(2):142–51. https://doi.org/10.4168/aair.2017.9.2.142.

    Article  CAS  PubMed  Google Scholar 

  23. Yeh DY, Wu CC, Chin YP, Lu CJ, Wang YH, Chen MC. Mechanisms of human lymphotoxin beta receptor activation on upregulation of CCL5/RANTES production. Int Immunopharmacol. 2015;28(1):220–9. https://doi.org/10.1016/j.intimp.2015.06.010.

    Article  CAS  PubMed  Google Scholar 

  24. Khunchai S, Junking M, Suttitheptumrong A, Kooptiwut S, Haegeman G, Limjindaporn T, Yenchitsomanus PT. NF-κB is required for dengue virus NS5-induced RANTES expression. Virus Res. 2015;197:92–100. https://doi.org/10.1016/j.virusres.2014.12.007.

    Article  CAS  PubMed  Google Scholar 

  25. Wang QJ, Zhang AL, Kang ZQ, Zhang ZT, Wang YS. Exogenous IL-19 mediates downregulation of TGF-β through Erk and p38 pathway to inhibit epidural fibrosis. Eur Rev Med Pharmacol Sci. 2019;23(17):7184–90. https://doi.org/10.26355/eurrev_201909_18819.

    Article  PubMed  Google Scholar 

  26. Liao B, Liu JX, Li ZY, et al. Multidimensional endotypes of chronic rhinosinusitis and their association with treatment outcomes. Allergy. 2018;73(7):1459–69. https://doi.org/10.1111/all.13411.

    Article  CAS  PubMed  Google Scholar 

  27. Luo X, Xu Z, Zuo K, Deng J, Gao W, Jiang L, Xu L, Huang Z, Shi J, Lai Y. The changes of clinical and histological characteristics of chronic rhinosinusitis in 18 years: was there an inflammatory pattern shift in southern China. World Allergy Organ J. 2021;14(4): 100531. https://doi.org/10.1016/j.waojou.2021.100531.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Suzukawa M, Ohta K, Fukutomi Y, et al. Classifications of moderate to severe asthma phenotypes in Japan and analysis of serum biomarkers: a Nationwide Cohort Study in Japan (NHOM Asthma Study). Allergol Int. 2022. https://doi.org/10.1016/j.alit.2022.06.002.

    Article  PubMed  Google Scholar 

  29. Fahey LM, Guzek R, Ruffner MA, Sullivan KE, Spergel J, Cianferoni A. EMSY is increased and activates TSLP & CCL5 expression in eosinophilic esophagitis. Pediatr Allergy Immunol. 2018;29(5):565–8. https://doi.org/10.1111/pai.12907.

    Article  PubMed  Google Scholar 

  30. Longino ES, Labby AB, Wu J, Chapurin N, Li P, Chandra RK, Turner JH, Chowdhury NI. Association of cytokine profile with prior treatment failure and revision surgery in chronic rhinosinusitis. Int Forum Allergy Rhinol. 2022. https://doi.org/10.1002/alr.23035.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Chao PZ, Chou CM, Chen CH. Plasma RANTES and eotaxin levels are correlated with the severity of chronic rhinosinusitis. Eur Arch Otorhinolaryngol. 2012;269(11):2343–8. https://doi.org/10.1007/s00405-012-1927-5.

    Article  PubMed  Google Scholar 

  32. Liao SC, Cheng YC, Wang YC, et al. IL-19 induced Th2 cytokines and was up-regulated in asthma patients. J Immunol. 2004;173(11):6712–8. https://doi.org/10.4049/jimmunol.173.11.6712.

    Article  CAS  PubMed  Google Scholar 

  33. Kaymak T, Kaya B, Wuggenig P, et al. IL-20 subfamily cytokines impair the oesophageal epithelial barrier by diminishing filaggrin in eosinophilic oesophagitis. Gut. 2023;72(5):821–33. https://doi.org/10.1136/gutjnl-2022-327166.

    Article  CAS  PubMed  Google Scholar 

  34. Xiao M, Zhang W, Liu W, et al. Osteocytes regulate neutrophil development through IL-19: a potent cytokine for neutropenia treatment. Blood. 2021;137(25):3533–47. https://doi.org/10.1182/blood.2020007731.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Azuma YT, Fujita T, Izawa T, et al. IL-19 contributes to the development of nonalcoholic steatohepatitis by altering lipid metabolism. Cells. 2021. https://doi.org/10.3390/cells10123513.

    Article  PubMed  PubMed Central  Google Scholar 

  36. An W, Yu Y, Zhang Y, Zhang Z, Yu Y, Zhao X. Exogenous IL-19 attenuates acute ischaemic injury and improves survival in male mice with myocardial infarction. Br J Pharmacol. 2019;176(5):699–710. https://doi.org/10.1111/bph.14549.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Valent P, Degenfeld-Schonburg L, Sadovnik I, Horny HP, Arock M, Simon HU, Reiter A, Bochner BS. Eosinophils and eosinophil-associated disorders: immunological, clinical, and molecular complexity. Semin Immunopathol. 2021;43(3):423–38. https://doi.org/10.1007/s00281-021-00863-y.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Yun YH, Kim HY, Do BS, Kim HS. Angiotensin II inhibits chemokine CCL5 expression in vascular smooth muscle cells from spontaneously hypertensive rats. Hypertens Res. 2011;34(12):1313–20. https://doi.org/10.1038/hr.2011.132.

    Article  CAS  PubMed  Google Scholar 

  39. Casola A, Henderson A, Liu T, Garofalo RP, Brasier AR. Regulation of RANTES promoter activation in alveolar epithelial cells after cytokine stimulation. Am J Physiol Lung Cell Mol Physiol. 2002;283(6):L1280–90. https://doi.org/10.1152/ajplung.00162.2002.

    Article  CAS  PubMed  Google Scholar 

  40. Kudo T, Lu H, Wu JY, Graham DY, Casola A, Yamaoka Y. Regulation of RANTES promoter activation in gastric epithelial cells infected with Helicobacter pylori. Infect Immun. 2005;73(11):7602–12. https://doi.org/10.1128/IAI.73.11.7602-7612.2005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Fessele S, Boehlk S, Mojaat A, Miyamoto NG, Werner T, Nelson EL, Schlondorff D, Nelson PJ. Molecular and in silico characterization of a promoter module and C/EBP element that mediate LPS-induced RANTES/CCL5 expression in monocytic cells. FASEB J. 2001;15(3):577–9. https://doi.org/10.1096/fj.00-0459fje.

    Article  CAS  PubMed  Google Scholar 

  42. Liu S, Flores JJ, Li B, Deng S, Zuo G, Peng J, Tang J, Zhang JH. IL-20R activation via rIL-19 enhances hematoma resolution through the IL-20R1/ERK/Nrf2 pathway in an experimental GMH rat pup model. Oxid Med Cell Longev. 2021;2021:5913424. https://doi.org/10.1155/2021/5913424.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Lavoie H, Gagnon J, Therrien M. ERK signalling: a master regulator of cell behaviour, life and fate. Nat Rev Mol Cell Biol. 2020;21(10):607–32. https://doi.org/10.1038/s41580-020-0255-7.

    Article  CAS  PubMed  Google Scholar 

  44. Capece D, Verzella D, Flati I, Arboretto P, Cornice J, Franzoso G. NF-κB: blending metabolism, immunity, and inflammation. Trends Immunol. 2022;43(9):757–75. https://doi.org/10.1016/j.it.2022.07.004.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We sincerely thank Hongwei Bao and Zhouzhou Yao for the human sample collection. We also would like to thank the biobank of clinical resources of the third affiliated hospital of Sun Yat-sen University for human samples conservation. We would like to thank Editage for English language editing.

Funding

This study was supported by the National Natural Science Foundation of China (82101194, 81970859, 82101196, and 82071020), and the Medical Science and Technology Research Foundation of Guangdong Province (A2021024).

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  1. Zizhen Huang, Xia Li, and Yue Li contributed equally to this work.

Authors and Affiliations

  1. Department of Otolaryngology‑Head and Neck Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China

    Zizhen Huang, Xia Li, Yue Li, Weiqiang Huang, Xiaoping Lai, Haotian Wu, Xiaohong Chen, Yana Zhang, Lihong Chang & Gehua Zhang

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  1. Zizhen Huang
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Contributions

ZH, XL, and YL performed RT-qPCR, western blotting, and confocal microscopy, and prepared the manuscript; WH and XL performed IHC; HW and XC participated in sample collection; YZ instructed data analysis; GZ and LC designed the study and revised the manuscript. All authors reviewed the manuscript.

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Correspondence to Lihong Chang or Gehua Zhang.

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The authors declare that they have no competing interests.

Ethics approval

This study was approved by the Ethical Committee of the Third Affiliated Hospital of Sun Yat-sen University (File No. [2022] 02-267-01). All patients were enrolled in the study only after informed consent were obtained.

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Huang, Z., Li, X., Li, Y. et al. Interleukin-19 enhances eosinophil infiltration through upregulation of epithelium-derived RANTES expression via the ERK/NF-κB signalling pathway in patients with eosinophilic CRSwNP. Inflamm. Res. 73, 499–513 (2024). https://doi.org/10.1007/s00011-024-01851-2

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