Allergy Asthma Immunol Res.  2016 Mar;8(2):132-140. 10.4168/aair.2016.8.2.132.

Increased Expression of miR-146a in Children With Allergic Rhinitis After Allergen-Specific Immunotherapy

Affiliations
  • 1Department of Otolaryngology, Affiliated Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China. daboliu@126.com, allergyli@163.com
  • 2Allergy Center, Otorhinolarygology Hospital, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
  • 3Department of Otolaryngology, the Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China.
  • 4Department of Otolaryngology, the First People's Hospital of Foshan City, Foshan, China.

Abstract

PURPOSE
MicroRNAs (miRs) were recently recognized to be important for immune cell differentiation and immune regulation. However, whether miRs were involved in allergen-specific immunotherapy (SIT) remains largely unknown. This study sought to examine changes in miR-146a and T regulatory cells in children with persistent allergic rhinitis (AR) after 3 months of subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT).
METHODS
Twenty-four HDM-sensitized children with persistent AR were enrolled and treated with SCIT (n=13) or SLIT (n=11) for 3 months. Relative miR-146a and Foxp3 mRNA expression, the TRAF6 protein level, and the ratio of post-treatment to baseline IL-10+CD4+ T cells between the SCIT and SLIT groups were examined in the peripheral blood mononuclear cells (PBMCs) of AR patients using quantitative reverse transcription polymerase chain reaction (qRT-PCR), flow cytometry, and Western blot analysis, respectively. Serum levels of IL-5 and IL-10 were determined using ELISA.
RESULTS
After 3 months of SIT, both the TNSS and INSS scores were significantly decreased compared to the baseline value (P<0.01). The relative expression of miR-146a and Foxp3 mRNA was significantly increased after both SCIT and SLIT (P<0.01). The ratio of post-treatment to baseline IL-10+CD4+ T cells and the serum IL-10 level were significantly increased in both the SCIT and SLIT groups (P<0.01), whereas the TRAF6 protein level and serum IL-5 level were significantly decreased (P<0.01). No significant differences in these biomarkers were observed between the SCIT and SLIT groups.
CONCLUSIONS
Our findings suggest that miR-146a and its related biomarkers may be comparably modulated after both SCIT and SLIT, highlighting miR-146a as a potential therapeutic target for the improved management of AR.

Keyword

Allergic rhinitis; immunotherapy; miR-146a; Foxp3; TRAF6; IL-10

MeSH Terms

Biomarkers
Blotting, Western
Cell Differentiation
Child*
Enzyme-Linked Immunosorbent Assay
Flow Cytometry
Humans
Immunotherapy*
Interleukin-10
Interleukin-5
MicroRNAs
Polymerase Chain Reaction
Reverse Transcription
Rhinitis*
RNA, Messenger
Sublingual Immunotherapy
T-Lymphocytes
TNF Receptor-Associated Factor 6
Interleukin-10
Interleukin-5
MicroRNAs
RNA, Messenger
TNF Receptor-Associated Factor 6

Figure

  • Fig. 1 The expression of miR-146a and Foxp3 mRNA in the PBMCs of AR children (n=24) and healthy controls (n=20). The levels of miR-146a (A) and Foxp3 mRNA (B) were significantly decreased in the PBMCs of AR children compared to the healthy controls. The level of miR-146a was positively associated with the Foxp3 mRNA level (C), but was negatively associated with the disease severity (TNSS) (D). *P<0.01.

  • Fig. 2 The expression and regulation of miR-146a in the nasal mucosa of AR children (n=9) and healthy controls (n=9). (A) The level of miR-146a was significantly decreased in the nasal mucosa of AR children compared to the healthy controls. (B) The level of miR-146a in cultured healthy nasal epithelial cells was significantly inhibited by Th2-related cytokines (IL-5, IL-13, IL-33, and TSLP; 50 ng/mL for 12 hours). The data are expressed as the means (SEM) of the 3 independent experiments. *P<0.01; **P<0.05.

  • Fig. 3 The expression of miR-146a and Foxp3 mRNA in the PBMCs of AR children after a 3-month SIT treatment. After 3-months of SCIT and SLIT treatments, the miR-146a (A) and Foxp3 mRNA (B) levels were significantly increased compared to their baseline values. AR1, untreated AR children; AR2, AR children with a 3-month SCIT treatment; AR3, AR children with a 3-month SLIT treatment. *P<0.01.

  • Fig. 4 The expression of TRAF6 in the PBMCs of the AR children after a 3-month SIT treatment. (A) Representative Western blot analysis of TRAF6 in the PBMCs of AR children and healthy controls was shown. (B) The level of the TRAF6 protein in the PBMCs of the AR patients was significantly increased compared to the healthy controls. (C) Representative Western blot analysis of TRAF6 in the PBMCs of the AR children before and after SIT treatment. (D) After 3 months of SCIT or SLIT treatment, the level of the TRAF6 protein in both the SCIT and SLIT groups was significantly decreased compared to their baseline values. No significant difference in the TRAF6 protein level was observed between the SCIT and SLIT subgroups. AR1, untreated AR children; AR2, AR children with a 3-month SCIT treatment; AR3, AR children with a 3-month SLIT treatment. *P<0.01.

  • Fig. 5 Serum IL-5 and IL-10 levels in AR children after a 3-month SIT treatment. After a 3-month SCIT or SLIT treatment, a significant decrease in the IL-5 level and an increase in the IL-10 level were observed in both the SCIT and SLIT groups compared to their baseline values. No significant difference in serum IL-5 and IL-10 levels was observed between the SCIT and SLIT groups. AR1, untreated AR children; AR2, AR children with a 3-month SCIT treatment; AR3, AR children with a 3-month SLIT treatment. *P<0.01.

  • Fig. 6 The ratio of IL-10+CD4+ T cells in the PBMCs of AR children before and after a 3-month SIT treatment. (A) Representative flow cytometric analysis of IL-10+CD4+ T cells in the PBMCs of the AR children was shown. (B) After a 3-month SCIT or SLIT treatment, the ratios of IL-10+CD4+ T cells in both the SCIT and SLIT subgroups were significantly increased compared to their baseline values. No significant difference in the ratio of IL-10+CD4+ T cells was observed between the SCIT and SLIT subgroups. AR1, untreated AR children; AR2, AR children with a 3-month SCIT treatment; AR3, AR children with a 3-month SLIT treatment. *P<0.01.


Cited by  1 articles

Chinese Society of Allergy Guidelines for Diagnosis and Treatment of Allergic Rhinitis
Lei Cheng, Jianjun Chen, Qingling Fu, Shaoheng He, Huabin Li, Zheng Liu, Guolin Tan, Zezhang Tao, Dehui Wang, Weiping Wen, Rui Xu, Yu Xu, Qintai Yang, Chonghua Zhang, Gehua Zhang, Ruxin Zhang, Yuan Zhang, Bing Zhou, Dongdong Zhu, Luquan Chen, Xinyan Cui, Yuqin Deng, Zhiqiang Guo, Zhenxiao Huang, Zizhen Huang, Houyong Li, Jingyun Li, Wenting Li, Yanqing Li, Lin Xi, Hongfei Lou, Meiping Lu, Yuhui Ouyang, Wendan Shi, Xiaoyao Tao, Huiqin Tian, Chengshuo Wang, Min Wang, Nan Wang, Xiangdong Wang, Hui Xie, Shaoqing Yu, Renwu Zhao, Ming Zheng, Han Zhou, Luping Zhu, Luo Zhang
Allergy Asthma Immunol Res. 2018;10(4):300-353.    doi: 10.4168/aair.2018.10.4.300.


Reference

1. Bousquet J, Khaltaev N, Cruz AA, Denburg J, Fokkens WJ, Togias A, et al. Allergic Rhinitis and its Impact on Asthma (ARIA) 2008 update (in collaboration with the World Health Organization, GA(2)LEN and AllerGen). Allergy. 2008; 63:Suppl 86. 8–160.
2. Zhang Y, Zhang L. Prevalence of allergic rhinitis in china. Allergy Asthma Immunol Res. 2014; 6:105–113.
3. Cibella F, Ferrante G, Cuttitta G, Bucchieri S, Melis MR, La Grutta S, et al. The burden of rhinitis and rhinoconjunctivitis in adolescents. Allergy Asthma Immunol Res. 2015; 7:44–50.
4. Braido F, Arcadipane F, Marugo F, Hayashi M, Pawankar R. Allergic rhinitis: current options and future perspectives. Curr Opin Allergy Clin Immunol. 2014; 14:168–176.
5. Wang C, Zhang L. Specific immunotherapy for allergic rhinitis in children. Curr Opin Otolaryngol Head Neck Surg. 2014; 22:487–494.
6. Di Bona D, Plaia A, Scafidi V, Leto-Barone MS, Di Lorenzo G. Efficacy of sublingual immunotherapy with grass allergens for seasonal allergic rhinitis: a systematic review and meta-analysis. J Allergy Clin Immunol. 2010; 126:558–566.
7. Di Bona D, Plaia A, Leto-Barone MS, La Piana S, Di Lorenzo G. Efficacy of subcutaneous and sublingual immunotherapy with grass allergens for seasonal allergic rhinitis: a meta-analysis-based comparison. J Allergy Clin Immunol. 2012; 130:1097.e2–1107.e2.
8. Akdis CA, Akdis M. Mechanisms of allergen-specific immunotherapy. J Allergy Clin Immunol. 2011; 127:18–27.
9. Rebane A, Akdis CA. MicroRNAs: essential players in the regulation of inflammation. J Allergy Clin Immunol. 2013; 132:15–26.
10. Lu TX, Rothenberg ME. Diagnostic, functional, and therapeutic roles of microRNA in allergic diseases. J Allergy Clin Immunol. 2013; 132:3–13.
11. Lu LF, Boldin MP, Chaudhry A, Lin LL, Taganov KD, Hanada T, et al. Function of miR-146a in controlling Treg cell-mediated regulation of Th1 responses. Cell. 2010; 142:914–929.
12. Rebane A, Runnel T, Aab A, Maslovskaja J, Rückert B, Zimmermann M, et al. MicroRNA-146a alleviates chronic skin inflammation in atopic dermatitis through suppression of innate immune responses in keratinocytes. J Allergy Clin Immunol. 2014; 134:836.e11–847.e11.
13. Park H, Huang X, Lu C, Cairo MS, Zhou X. MicroRNA-146a and microRNA-146b regulate human dendritic cell apoptosis and cytokine production by targeting TRAF6 and IRAK1 proteins. J Biol Chem. 2015; 290:2831–2841.
14. Lin Z, Zhou L, Luo X, Xia W, Chen D, Xu R, et al. Suppression of TIM-1 predicates clinical efficacy of sublingual immunotherapy for allergic rhinitis in children. Int J Pediatr Otorhinolaryngol. 2013; 77:1345–1349.
15. Peng H, Li CW, Lin ZB, Li TY. Long-term efficacy of specific immunotherapy on house dust mite-induced allergic rhinitis in China. Otolaryngol Head Neck Surg. 2013; 149:40–46.
16. Luo Q, Zhang J, Wang H, Chen F, Luo X, Miao B, et al. Expression and regulation of transcription factor foxA2 in chronic rhinosinusitis with and without nasal polyps. Allergy Asthma Immunol Res. 2015; 7:458–466.
17. Xiao L, Wei Y, Zhang YN, Luo X, Yang BY, Yu SF, et al. Increased IL-21 expression in chronic rhinosinusitis with nasalpolyps. Clin Exp Allergy. 2015; 45:404–413.
18. Quirino T, Iemoli E, Siciliani E, Parmiani S, Milazzo F. Sublingual versus injective immunotherapy in grass pollen allergic patients: a double blind (double dummy) study. Clin Exp Allergy. 1996; 26:1253–1261.
19. Akdis CA. Therapies for allergic inflammation: refining strategies to induce tolerance. Nat Med. 2012; 18:736–749.
20. Palomares O, Martín-Fontecha M, Lauener R, Traidl-Hoffmann C, Cavkaytar O, Akdis M, et al. Regulatory T cells and immune regulation of allergic diseases: roles of IL-10 and TGF-β. Genes Immun. 2014; 15:511–520.
21. Bohle B, Kinaciyan T, Gerstmayr M, Radakovics A, Jahn-Schmid B, Ebner C. Sublingual immunotherapy induces IL-10-producing T regulatory cells, allergen-specific T-cell tolerance, and immune deviation. J Allergy Clin Immunol. 2007; 120:707–713.
22. O'Hehir RE, Gardner LM, de Leon MP, Hales BJ, Biondo M, Douglass JA, et al. House dust mite sublingual immunotherapy: the role for transforming growth factor-beta and functional regulatory T cells. Am J Respir Crit Care Med. 2009; 180:936–947.
23. Li S, Yue Y, Xu W, Xiong S. MicroRNA-146a represses mycobacteria-induced inflammatory response and facilitates bacterial replication via targeting IRAK-1 and TRAF-6. PLoS One. 2013; 8:e81438.
24. Dalbeth N, Pool B, Shaw OM, Harper JL, Tan P, Franklin C, et al. Role of miR-146a in regulation of the acute inflammatory response to monosodium urate crystals. Ann Rheum Dis. 2015; 74:786–790.
25. Baldeón RL, Weigelt K, de Wit H, Ozcan B, van Oudenaren A, Sempértegui F, et al. Decreased serum level of miR-146a as sign of chronic inflammation in type 2 diabetic patients. PLoS One. 2014; 9:e115209.
26. Tsitsiou E, Williams AE, Moschos SA, Patel K, Rossios C, Jiang X, et al. Transcriptome analysis shows activation of circulating CD8+ T cells in patients with severe asthma. J Allergy Clin Immunol. 2012; 129:95–103.
27. Shaoqing Y, Ruxin Z, Guojun L, Zhiqiang Y, Hua H, Shudong Y, et al. Microarray analysis of differentially expressed microRNAs in allergic rhinitis. Am J Rhinol Allergy. 2011; 25:e242–e246.
28. Teng Y, Zhang R, Liu C, Zhou L, Wang H, Zhuang W, et al. miR-143 inhibits interleukin-13-induced inflammatory cytokine and mucus production in nasal epithelial cells from allergic rhinitis patients by targeting IL13Rα1. Biochem Biophys Res Commun. 2015; 457:58–64.
29. Suojalehto H, Toskala E, Kilpeläinen M, Majuri ML, Mitts C, Lindström I, et al. MicroRNA profiles in nasal mucosa of patients with allergic and nonallergic rhinitis and asthma. Int Forum Allergy Rhinol. 2013; 3:612–620.
30. Rhee CS. Current specific immunotherapy for allergic rhinitis: perspectives from otorhinolaryngologists. Allergy Asthma Immunol Res. 2014; 6:273–275.
Full Text Links
  • AAIR
Actions
Cited
CITED
export Copy
Close
Share
  • Twitter
  • Facebook
Similar articles
Copyright © 2024 by Korean Association of Medical Journal Editors. All rights reserved.     E-mail: koreamed@kamje.or.kr