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Chemokines and chemokine receptors in allergic rhinitis: from mediators to potential therapeutic targets

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Abstract

Allergic rhinitis (AR) is an immune-mediated inflammatory condition characterized by immune cell infiltration of the nasal mucosa, with symptoms of rhinorrhea, sneezing, nasal obstruction, and itchiness. Currently, common medication for AR is anti-inflammatory treatment including intranasal steroids, oral, or intranasal anti-histamines, and immunotherapy. These strategies are effective to the majority of patients with AR, but some patients under medication cannot achieve symptom relieve and suffer from bothersome side effects, indicating a demand for novel anti-inflammatory treatment as alternatives. Chemokines, a complex superfamily of small, secreted proteins, were initially recognized for their chemotactic effects on various immune cells. Chemokines constitute both physiological and inflammatory cell positioning systems and mediate cell localization to certain sites via interaction with their receptors, which are expressed on responding cells. Chemokines and their receptors participate in the sensitization, early phase response, and late phase response of AR by promoting inflammatory cell recruitment, differentiation, and allergic mediator release. In this review, we first systemically summarize chemokines and chemokine receptors that are important in AR pathophysiology and then discuss potential strategies targeting chemokines and their receptors for AR therapy.

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References

  1. Bousquet J, Anto JM, Bachert C, Baiardini I, Bosnic-Anticevich S, Walter Canonica G et al (2020) Allergic rhinitis. Nat Rev Dis Primers 6:95. https://doi.org/10.1038/s41572-020-00227-0

    Article  PubMed  Google Scholar 

  2. Seidman MD, Gurgel RK, Lin SY, Schwartz SR, Baroody FM, Bonner JR et al (2015) Clinical practice guideline: allergic rhinitis. Otolaryngol Head Neck Surg 152:S1-43. https://doi.org/10.1177/0194599814561600

    Article  PubMed  Google Scholar 

  3. Bousquet J, Schünemann HJ, Togias A, Bachert C, Erhola M, Hellings PW et al (2020) Next-generation Allergic Rhinitis and Its Impact on Asthma (ARIA) guidelines for allergic rhinitis based on Grading of Recommendations Assessment, Development and Evaluation (GRADE) and real-world evidence. J Allergy Clin Immunol 145:70-80.e3. https://doi.org/10.1016/j.jaci.2019.06.049

    Article  PubMed  Google Scholar 

  4. Droessaert V, Timmermans M, Dekimpe E, Seys S, Ceuppens JJ, Fokkens WJ et al (2016) Real-life study showing better control of allergic rhinitis by immunotherapy than regular pharmacotherapy. Rhinology 54:214–220. https://doi.org/10.4193/Rhino14.282

    Article  CAS  PubMed  Google Scholar 

  5. Meltzer EO, Blaiss MS, Derebery MJ, Mahr TA, Gordon BR, Sheth KK et al (2009) Burden of allergic rhinitis: results from the Pediatric Allergies in America survey. J Allergy Clin Immunol 124:S43-70. https://doi.org/10.1016/j.jaci.2009.05.013

    Article  PubMed  Google Scholar 

  6. Moser B, Wolf M, Walz A, Loetscher P (2004) Chemokines: multiple levels of leukocyte migration control. Trends Immunol 25:75–84. https://doi.org/10.1016/j.it.2003.12.005

    Article  CAS  PubMed  Google Scholar 

  7. Schall TJ, Proudfoot AE (2011) Overcoming hurdles in developing successful drugs targeting chemokine receptors. Nat Rev Immunol 11:355–363. https://doi.org/10.1038/nri2972

    Article  CAS  PubMed  Google Scholar 

  8. Zheng J, Zeng M, Nian JB, Zeng LY, Fu Z, Huang QJ et al (2020) The CXCR4/miR-125b/FoxP3 axis regulates the function of the epithelial barrier via autophagy in allergic rhinitis. Am J Transl Res 12:2570–2584

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Liu C, Zhang X, Xiang Y, Qu X, Liu H, Liu C et al (2018) Role of epithelial chemokines in the pathogenesis of airway inflammation in asthma (Review). Mol Med Rep 17:6935–6941. https://doi.org/10.3892/mmr.2018.8739

    Article  CAS  PubMed  Google Scholar 

  10. Kim B, Yeon JW, Lee JH, Lee HJ, Byun J, Lee K (2020) CCL2 mitigates cyclic AMP-suppressed Th2 immune response in human dendritic cells. Allergy 75:2108–2111. https://doi.org/10.1111/all.14284

    Article  CAS  PubMed  Google Scholar 

  11. Hirata H, Yukawa T, Tanaka A, Miyao T, Fukuda T, Fukushima Y et al (2019) Th2 cell differentiation from naive CD4(+) T cells is enhanced by autocrine CC chemokines in atopic diseases. Clin Exp Allergy 49:474–483. https://doi.org/10.1111/cea.13313

    Article  CAS  PubMed  Google Scholar 

  12. Burks AW, Holgate ST, O’Hehir RE, Bacharier LB, Broide DH, Hershey GK et al (2019) Middleton’s allergy E-Book: principles and practice. Elsevier, Edinburgh

    Google Scholar 

  13. Romagnani S (2002) Cytokines and chemoattractants in allergic inflammation. Mol Immunol 38:881–885. https://doi.org/10.1016/s0161-5890(02)00013-5

    Article  CAS  PubMed  Google Scholar 

  14. Wang D, Smitz J, Waterschoot S, Clement P (1997) An approach to the understanding of the nasal early-phase reaction induced by nasal allergen challenge. Allergy 52:162–167. https://doi.org/10.1111/j.1398-9995.1997.tb00970.x

    Article  CAS  PubMed  Google Scholar 

  15. Miyazaki D, Nakamura T, Toda M, Cheung-Chau KW, Richardson RM, Ono SJ (2005) Macrophage inflammatory protein-1alpha as a costimulatory signal for mast cell-mediated immediate hypersensitivity reactions. J Clin Invest 115:434–442. https://doi.org/10.1172/jci18452

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Kuna P, Reddigari SR, Schall TJ, Rucinski D, Viksman MY, Kaplan AP (1992) RANTES, a monocyte and T lymphocyte chemotactic cytokine releases histamine from human basophils. J Immunol 149:636–642

    CAS  PubMed  Google Scholar 

  17. Castellani ML, De Lutiis MA, Toniato E, Conti F, Felaco P, Fulcheri M et al (2010) Impact of RANTES, MCP-1 and IL-8 in mast cells. J Biol Regul Homeost Agents 24:1–6

    CAS  PubMed  Google Scholar 

  18. Pawankar R, Mori S, Ozu C, Kimura S (2011) Overview on the pathomechanisms of allergic rhinitis. Asia Pac Allergy 1:157–167. https://doi.org/10.5415/apallergy.2011.1.3.157

    Article  PubMed  PubMed Central  Google Scholar 

  19. Blanchard C, Rothenberg ME (2009) Biology of the eosinophil. Adv Immunol 101:81–121. https://doi.org/10.1016/s0065-2776(08)01003-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Pease JE (2006) Asthma, allergy and chemokines. Curr Drug Targets 7:3–12. https://doi.org/10.2174/138945006775270204

    Article  CAS  PubMed  Google Scholar 

  21. Dai M, Zhu X, Yu J, Yuan J, Zhu Y, Bao Y et al (2022) CCR3 gene knockout in bone marrow cells ameliorates combined allergic rhinitis and asthma syndrome (CARAS) by reducing airway inflammatory cell infiltration and Th2 cytokines expression in mice model. Int Immunopharmacol 104:108509. https://doi.org/10.1016/j.intimp.2021.108509

    Article  CAS  PubMed  Google Scholar 

  22. Perić A, Sotirović J, Špadijer-Mirković C, Matković-Jožin S, Perić AV, Vojvodić D (2016) Nonselective chemokine levels in nasal secretions of patients with perennial nonallergic and allergic rhinitis. Int Forum Allergy Rhinol 6:392–397. https://doi.org/10.1002/alr.21684

    Article  PubMed  Google Scholar 

  23. Yi S, Zhai J, Niu R, Zhu G, Wang M, Liu J et al (2018) Eosinophil recruitment is dynamically regulated by interplay among lung dendritic cell subsets after allergen challenge. Nat Commun 9:3879. https://doi.org/10.1038/s41467-018-06316-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Chen Y, Yang M, Deng J, Wang K, Shi J (2020) Elevated levels of activated and pathogenic eosinophils characterize moderate-severe house dust mite allergic rhinitis. J Immunol Res 2020:8085615. https://doi.org/10.1155/2020/8085615

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Perić A, Mirković C, Đurđević BV, Perić AV, Vojvodić D (2017) Eosinophil chemokines and Clara cell protein 16 production in nasal mucosa of patients with persistent allergic rhinitis. Eurasian J Med 49:178–182. https://doi.org/10.5152/eurasianjmed.2017.17203

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Špadijer Mirković C, Perić A, Vukomanović Đurđević B, Vojvodić D (2017) Effects of fluticasone Furoate nasal spray on parameters of eosinophilic inflammation in patients with nasal polyposis and perennial allergic rhinitis. Ann Otol Rhinol Laryngol 126:573–580. https://doi.org/10.1177/0003489417713505

    Article  PubMed  Google Scholar 

  27. Koya T, Takeda K, Kodama T, Miyahara N, Matsubara S, Balhorn A et al (2006) RANTES (CCL5) regulates airway responsiveness after repeated allergen challenge. Am J Respir Cell Mol Biol 35:147–154. https://doi.org/10.1165/rcmb.2005-0394OC

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Zhang RX, Yu SQ, Jiang JZ, Liu GJ (2007) Complementary DNA microarray analysis of chemokines and their receptors in allergic rhinitis. J Investig Allergol Clin Immunol 17:329–336

    CAS  PubMed  Google Scholar 

  29. de Campos L, Galvão CES, Mairena EC, Voegels R, Kalil J, Castro FM et al (2019) Increased gene expression of inflammatory markers in nasal turbinate of patients with persistent allergic rhinitis and chronic obstruction. Eur Arch Otorhinolaryngol 276:3247–3249. https://doi.org/10.1007/s00405-019-05581-8

    Article  PubMed  Google Scholar 

  30. Azazi EA, Bakir SM, Mohtady HA, Almonem AA (2007) Circulating chemokine eotaxin and chemokine receptor CCR3 in allergic patients. Egypt J Immunol 14:73–82

    PubMed  Google Scholar 

  31. Berghi NO, Dumitru M, Vrinceanu D, Ciuluvica RC, Simioniuc-Petrescu A, Caragheorgheopol R et al (2020) Relationship between chemokines and T lymphocytes in the context of respiratory allergies (review). Exp Ther Med 20:2352–2360. https://doi.org/10.3892/etm.2020.8961

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Tworek D, Kuna P, Młynarski W, Górski P, Pietras T, Antczak A (2013) MIG (CXCL9), IP-10 (CXCL10) and I-TAC (CXCL11) concentrations after nasal allergen challenge in patients with allergic rhinitis. Arch Med Sci 9:849–853. https://doi.org/10.5114/aoms.2013.37198

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Banfield G, Watanabe H, Scadding G, Jacobson MR, Till SJ, Hall DA et al (2010) CC chemokine receptor 4 (CCR4) in human allergen-induced late nasal responses. Allergy 65:1126–1133. https://doi.org/10.1111/j.1398-9995.2010.02327.x

    Article  CAS  PubMed  Google Scholar 

  34. Yu X, Wang M, Cao Z (2020) Reduced CD4(+)T cell CXCR3 expression in patients with allergic rhinitis. Front Immunol 11:581180. https://doi.org/10.3389/fimmu.2020.581180

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Pirayesh A, Ferdosi S, Shirzad H, Amani S, Bahadivand Chegini H, Bagheri N et al (2018) Differential expression of CCL18 in moderate/severe and mild persistent allergic rhinitis and its correlation with disease parameters. J Immunoassay Immunochem 39:485–495. https://doi.org/10.1080/15321819.2018.1506931

    Article  CAS  PubMed  Google Scholar 

  36. Sadeghi HR, Pirayesh A, Shahsavan S, Amani S, Amini SA, Samani KG et al (2020) Correlation of acidic mammalian chitinase expression with disease severity in patients with moderate/severe persistent allergic rhinitis. Cent Eur J Immunol 45:294–300. https://doi.org/10.5114/ceji.2020.101251

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Miao M, De Clercq E, Li G (2020) Clinical significance of chemokine receptor antagonists. Expert Opin Drug Metab Toxicol 16:11–30. https://doi.org/10.1080/17425255.2020.1711884

    Article  PubMed  Google Scholar 

  38. Gauthier M, Kale SL, Oriss TB, Scholl K, Das S, Yuan H et al (2022) Dual role for CXCR3 and CCR5 in asthmatic type 1 inflammation. J Allergy Clin Immunol 149:113-124.e7. https://doi.org/10.1016/j.jaci.2021.05.044

    Article  CAS  PubMed  Google Scholar 

  39. Zou LP, Wang LX, Zhang Y, Du WL (2011) Expression of SDF-1 in lung tissues and intervention of AMD3100 in asthmatic rats. Zhongguo Dang Dai Er Ke Za Zhi 13:321–325

    CAS  PubMed  Google Scholar 

  40. Sakai H, Yabe S, Sato K, Kai Y, Sato F, Yumoto T et al (2018) ELR(+) chemokine-mediated neutrophil recruitment is involved in 2,4,6-trinitrochlorobenzene-induced contact hypersensitivity. Clin Exp Pharmacol Physiol 45:27–33. https://doi.org/10.1111/1440-1681.12839

    Article  CAS  PubMed  Google Scholar 

  41. Keglowich L, Roth M, Philippova M, Resink T, Tjin G, Oliver B et al (2013) Bronchial smooth muscle cells of asthmatics promote angiogenesis through elevated secretion of CXC-chemokines (ENA-78, GRO-α, and IL-8). PLoS ONE 8:e81494. https://doi.org/10.1371/journal.pone.0081494

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Hu JS, Freeman CM, Stolberg VR, Chiu BC, Bridger GJ, Fricker SP et al (2006) AMD3465, a novel CXCR4 receptor antagonist, abrogates schistosomal antigen-elicited (type-2) pulmonary granuloma formation. Am J Pathol 169:424–432. https://doi.org/10.2353/ajpath.2006.051234

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Ding C, Li J, Zhang X (2004) Bertilimumab Cambridge antibody technology Group. Curr Opin Investig Drugs 5:1213–1218

    CAS  PubMed  Google Scholar 

  44. Gong H, Qi H, Sun W, Zhang Y, Jiang D, Xiao J et al (2012) Design and synthesis of a series of pyrido[2,3-d]pyrimidine derivatives as CCR4 antagonists. Molecules 17:9961–9970. https://doi.org/10.3390/molecules17089961

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Qi H, Zheng Y, Xu E, Guo C, Zhang Y, Sun Q et al (2012) An antagonist for CCR4 alleviates murine allergic rhinitis by intranasal administration. Int Arch Allergy Immunol 159:297–305. https://doi.org/10.1159/000337455

    Article  CAS  PubMed  Google Scholar 

  46. Zheng Y, Guo C, Zhang Y, Qi H, Sun Q, Xu E et al (2011) Alleviation of murine allergic rhinitis by C19, a C-terminal peptide of chemokine-like factor 1 (CKLF1). Int Immunopharmacol 11:2188–2193. https://doi.org/10.1016/j.intimp.2011.09.017

    Article  CAS  PubMed  Google Scholar 

  47. Morokata T, Suzuki K, Masunaga Y, Taguchi K, Morihira K, Sato I et al (2006) A novel, selective, and orally available antagonist for CC chemokine receptor 3. J Pharmacol Exp Ther 317:244–250. https://doi.org/10.1124/jpet.105.097048

    Article  CAS  PubMed  Google Scholar 

  48. Gu X, Xiao F, Lu W, Xu Y, Li X, Yu C et al (2020) Nanomedicine-mediated prevention of inflammatory monocytes infiltration ameliorate ovalbumin-induced allergic rhinitis in mouse model. Autoimmunity 53:218–224. https://doi.org/10.1080/08916934.2020.1750009

    Article  CAS  PubMed  Google Scholar 

  49. Nibbs RJ, Graham GJ (2013) Immune regulation by atypical chemokine receptors. Nat Rev Immunol 13:815–829. https://doi.org/10.1038/nri3544

    Article  CAS  PubMed  Google Scholar 

  50. Bonecchi R, Graham GJ (2016) Atypical chemokine receptors and their roles in the resolution of the inflammatory response. Front Immunol 7:224. https://doi.org/10.3389/fimmu.2016.00224

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank Dr. Xiaofeng Yu for discussions and suggestions for the project.

Funding

This work was supported by the National Natural Science Foundation of China (81902133) to Dr. Yajing Fu.

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Authors and Affiliations

  1. Department of Laboratory Medicine, China Medical University, Shenyang, China

    Zhan Li, Sihua Yu, Yongjun Jiang & Yajing Fu

  2. Department of Clinical Immunology, The First Affiliated Hospital of China Medical University, China Medical University, Shenyang, China

    Yongjun Jiang & Yajing Fu

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  1. Zhan Li
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  2. Sihua Yu
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ZL and YF wrote the manuscript based on discussions with SY and prepared the table. YJ revised and examined the manuscript. All authors contributed to the article and approved the submitted version.

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Correspondence to Yajing Fu.

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Li, Z., Yu, S., Jiang, Y. et al. Chemokines and chemokine receptors in allergic rhinitis: from mediators to potential therapeutic targets. Eur Arch Otorhinolaryngol 279, 5089–5095 (2022). https://doi.org/10.1007/s00405-022-07485-6

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