Predictor role of IL-6 and IL-1β in the formation of cellular bronchial inflammation in patients with bronchial asthma in response to inhalation exposure to cold air

• Aleksey B. Pirogov
• Anna G. Prihodko
• Juliy M. Perelman

Abstract

Introduction. Interleukins (IL) can play a significant role in the development of neutrophil inflammation of the bronchi under the influence of cold in patients with asthma.

Aim – to study the predictive role of IL-6 and IL-1β in the formation of cellular bronchial inflammation in asthma patients in response to inhalation exposure to cold air.

Material and methods. The observational study included 78 asthma patients of both sexes aged 39.0 ± 0.8 years. We studied the cellular composition of induced and spontaneously produced sputum, IL in exhaled breath condensate (EBC) before and after a bronchoprovocation test with 3-minute isocapnic hyperventilation with cold (-20 °C) air (IHCA) and an assessment of the airway response according to forced expiratory spirometry (ΔFEV₁).

Results. Group 1 included 32 patients with cold airways hyperresponsiveness (CAHR), group 2 included 46 patients without CAHR (ΔFEV₁ -16 [-22; -10.6] and -4 [-6; -0.4] %, respectively, p < 0.00001). Patients had no intergroup differences in the level of asthma control (ACT 18.3 ± 0.9 and 18.4 ± 0.7 points) and FEV₁ (93.8 ± 2.8 and 96.0 ± 3.1 %; р > 0.05). In individuals with CAHR, after the IHCA test, a significant increase in the contents of neutrophils in sputum was recorded from 40.8 ± 2.0 to 47.8 ± 2.5 % (p = 0.037), in contrast to patients without CAHR. In addition, after the IHCA test, the concentration of IL-6 in the EBC significantly decreased in them (p = 0.018) and the concentration of IL-1β increased two-fold in relation to the initial value, as well as compared with the same indicator in asthma patients without CAHR. The initial values of IL-1β and IL-6 were closely correlated with each other (Rs = -0.84; p = 0.0003).

Conclusion. Bronchial asthma with cold airway hyperresponsiveness probably belong to the Th17 endotype associated with activation of IL-6 and IL-1β and Th1/Th17 immune response. The profile of the functional activity of IL-6 and IL-1β for the entire set of signs can be a predictor of the formation of a mixed/neutrophilic pattern of bronchial inflammation in this category of asthma patients.

Keywords:bronchial asthma; cold airway hyperresponsiveness; cytokines; neutrophilic bronchial inflammation; Th1/Th17 immune response

References

1. Frey A., Lunding L.P., Ehlers J.C., Weckmann M., Zissler U.M., Wegmann M. More than just a barrier: The immune functions of the airway epithelium in asthma pathogenesis. Front Immunol. 2020; 11: 761. DOI: https://doi.org/10.3389/fimmu.2020.00761

2. Irvin C., Zafar I., Good J., Rollins D., Christianson C., Gorska M.M., Martin R.J., Alam R. Increased frequency of dual-positive TH2/TH17 cells in bronchoalveolar lavage fluid characterizes a population of patients with severe asthma. J Allergy Clin Immunol. 2014; 134 (5): 1175–86. DOI: https://doi.org/10.1016/j.jaci.2014.05.038

3. Al-Ramli W., Préfontaine D., Chouiali F., Martin J.G., Olivenstein R., Lemière C., Hamid Q. TH17-associated cytokines (IL-17A and IL-17F) in severe asthma. J Аllergy Сlin Immunol. 2009; 123 (5): 1185–7. DOI: https://doi.org/10.1016/j.jaci.2009.02.024

4. Lindén А., Dahlén В. Interleukin-17 cytokine signalling in patients with asthma. Eur Respir J. 2014; 44: 1319–31. DOI: https://doi.org/10.1183/09031936.00002314

5. Singh P., Hasan S., Sharma S., Nagra S., Yamaguchi D.T., Wong D.T.W., Hahn B.H., Hossain A. Th17 cells in inflammation and autoimmunity. Autoimmun Rev. 2014; 13 (12): 1174–81. DOI: https://doi.org/10.1016/j.autrev.2014.08.019

6. Duvall M.G., Krishnamoorthy N., Levy B.D. Non-type 2 inflammation in severe asthma is propelled by neutrophil cytoplasts and maintained by defective resolution. Allergol Int. 2019; 68 (2): 143–9. DOI: https://doi.org/10.1016/j.alit.2018.11.006

7. Еsteban-Gorgojo I., Antolín-Amérigo D., Domínguez-Ortega J., Quirce S. Non-eosinophilic asthma: current perspectives. J Asthma Allergy. 2018; 11: 267–81. DOI: https://doi.org/10.2147/JAA.S153097

8. Nikolskii A.A., Shilovskiy I.P., Jumashev K.V., Vishniakova L.I., Barvinskaia E.D., Kovchina V.I., Korneev A.V., Turenko V.N., Kaganova M.M., Brylina V.E., Nikonova A.A., Kozlov I.B., Kofiadi I.A., Sergeev I.V., Maerle A.V., Petuhova O.A., Kudlay D.A., Khaitov M.R. Effect of local suppression of Stat3 gene expression in a mouse model of pulmonary neutrophilic inflammation. Immunologiya. 2021; 42 (6): 600–14. DOI: https://doi.org/10.33029/0206-4952-2021-42-6-600-614 (in Russian)

9. Nishihara M., Ogura H., Ueda N., Tsuruoka M., Kitabayashi C., Tsuji F., Aono H., Ishihara K., Huseby E., Betz U. A. K., Murakami M., Hirano T. IL-6-gp130-STAT3 in T cells directs the development of IL-17+ Th with a minimum effect on that of Treg in the steady state. Int Immunol. 2007; 19 (6): 695–702. DOI: https://doi.org/10.1093/intimm/dxm045

10. Acosta-Rodriguez E.V., Napolitani G., Lanzavecchia A., Sallusto F. Interleukins 1beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells. Nat Immunol. 2007; 8 (9): 942–9. DOI: https://doi.org/10.1038/ni1496

11. Pirogov A.B., Kolosov V.P., Perelman J.M., Prikhodko A.G., Zinov’ev S.V., Gassan D.A., Mal’tseva T.A. Airway inflammation patterns and clinical and functional features in patients with severe un-controlled asthma and cold-induced airway hyperresponsiveness. Russian Pulmonology. 2016; 26 (6): 701–7. DOI: https://doi.org/10.18093/086901892016266701707 (in Russian)

12. Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention (2022 update). URL: https://ginasthma.org/wp-content/uploads/2022/07/GINA-Main-Report-2022-FINAL-22-07-01-WMS.pdf

13. Sylvester K.P., Clayton N., Cliff I., Hepple M., Kendrick A., Kirkby J., Miller M., Moore A., Rafferty G.F., O’Reilly L., Shakespeare J., Smith L., Watts T., Bucknall M., Butterfield K. ARTP statement on pulmonary function testing 2020. BMJ Open Respir Res. 2020; 7 (1): e000575. DOI: https://doi.org/10.1136/bmjresp-2020-000575

14. Kameneva M.Yu., Cherniak A.V., Aisanov Z.R., Avdeev S.N., Babak S.L., Belevskiy A.S., Beresten N.F., Kalmanova E.N., Malyavin A.G., Perelman Ju.M., Prikhodko A.G., Struchkov P.V., Chikina S.Yu., Chushkin M.I. Spirometry: national guidelines for the testing and interpretation of results. Russian Pulmonology. 2023; 33 (3): 307–40. DOI: https://doi.org/10.18093/0869-0189-2023-33-3-307-340 (in Russian)

15. Prikhodko A.G., Perelman J.M., Kolosov V.P. Airway hyperresponsiveness. Vladivostok: Dal’nauka; 2011: 204 p. (in Russian)

16. Djukanovic R., Sterk P.J., Fahy J.V., Hargreave F.E. Standardised methodology of sputum induction and processing. Eur Respir J. 2002; 20 (37): 1–52. DOI: https://doi.org/10.1183/09031936.02.00000102

17. Ul’yanychev N.V. Systematic research in medicine. Saarbrücken: LAP LAMBERT; 2014. 140 p. (in Russian)

18. Krishnamoorthy N., Douda D.N., Brüggemann T.R., Ricklefs I., Duvall M.G., Abdulnour R.E., Martinod K., Tavares L., Wang X., Cernadas M., Israel E., Mauger D.Т., Bleecker E.R., Castro M., Erzurum S. C., Gaston B.M., Jarjour N.N., Wenzel S., Dunican E., Fahy J.V., Irimia D., Wagner D.D., Levy B.D. Neutrophil cytoplasts induce TH17 differentiation and skew inflammation toward neutrophilia in severe asthma. Sci Immunol. 2018; 3 (26): eaao4747. DOI: https://doi.org/10.1126/sciimmunol.aao4747

19. Fujisawa T., Mann-Jong Chang M., Velichko S., Thai P., Hung Li-Y., Huang F., Phuong N., Chen Y., Wu R. NF-κB mediates IL-1β- and IL-17A-induced MUC5B expression in airway epithelial cells. Am J Respir Cell Mol Biol. 2011; 45 (2): 246–52. DOI: https://doi.org/10.1165/rcmb.2009-0313OC

20. Chang Y., Al-Alwan L., Risse P.-A., Halayko A. J., Martin J.G., Baglole C. J., Eidelman D.H., Hamid Q. Th17-associated cytokines promote human airway smooth muscle cell proliferation. FASEB J. 2012; 26 (12): 5152–60. DOI: https://doi.org/10.1096/fj.12-208033

21. Kostareva O.S., Gabdulkhakov A.G., Kolyadenko I.A., Garber M.B., Tishchenko S.V. Inter-leukin-17: Functional and structural features, application as a therapeutic target. Biochemistry Moscow. 2019; 84 (Suppl.1): 193–205. DOI: https://doi.org/10.1134/S0006297919140116 (in Russian)

22. Schwandner R., Yamaguchi K., Caoa Z. Requirement of tumor necrosis factor receptor-associated factor (TRAF)6 in interleukin 17 signal transduction. J Exp Med. 2000; 191 (7): 1233–40. DOI: https://doi.org/10.1084/jem.191.7.1233

23. Annunziato F., Cosmi L., Liotta F., Maggi E., Romagnani S. The phenotype of human Th17 cells and their precursors, the cytokines that mediate their differentiation and the role of Th17 cells in inflammation. Int Immunol. 2008; 20 (11): 1361–8. DOI: https://doi.org/10.1093/intimm/dxn106

24. Romagnani S., Maggi E., Liotta F., Cosmi L., Annunziato F. Properties and origin of human Th17 cells. Mol Immunol. 2009; 47 (1): 3–7. DOI: https://doi.org/10.1016/j.molimm.2008.12.01927

25. Nasonov E.L. The role of interleukin 1 in the development of human diseases. Rheumatology Science and Practice. 2018; 56: 19–27. DOI: https://doi.org/10.14412/1995-4484-2018-19-27 (in Russian)

26. Toptygina A.P., Semikina E.L., Petrichuk S.V., Zakirov R.Sh., Kurbatova O.V., Kopyltsova E.A., Komakh Yu.A. Age-dependent changes of t-regulatory and Th17 subset levels in peripheral blood from healthy humans. Medical Immunology. 2017; 19 (4): 409–20. DOI: https://doi.org/10.15789/1563-0625-2017-4-409-420 (in Russian)

27. Vitkina T.I., Sidletskaya K.A. The role of interleukin-6 signaling in development of systemic inflammation in chronic obstructive pulmonary disease. Byulleten’ fiziologii i patologii dykhaniya. 2018; (69): 97–106. DOI: https://doi.org/10.12737/article_5b9858ead1b5e3.93619630 (in Russian)

28. Heink S., Yogev N., Garbers C., Herwerth M., Aly L., Gasperi C., Husterer V., Croxford A.L., Möller-Hack-barth K., Bartsch H.S., Sotlar K., Krebs S., Regen T., Blum H., Hemmer B., Misgeld T., Wunderlich T.F., Hidalgo J., Oukka M., Rose-John S., Schmidt-Supprian M., Waisman A., Korn T. Trans-presentation of interleukin-6 by dendritic cells is required for priming pathogenic Th17 cells. Nat Immunol. 2017; 18 (1): 74–85. DOI: https://doi.org/10.1038/ni.3632

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