Allergy Asthma Immunol Res.  2019 Mar;11(2):201-211. 10.4168/aair.2019.11.2.201.

Comparison Between Signature Cytokines of Nasal Tissues in Subtypes of Chronic Rhinosinusitis

• Kim DK
• Eun KM
• Kim MK
• Cho D
• Han SA
• Han SY
• Seo Y
• Lee DH
• Cho SH
• Kim DW

• KMID: 2431852
• DOI: http://doi.org/10.4168/aair.2019.11.2.201

Abstract

PURPOSE
Endotype in chronic rhinosinusitis (CRS) has been established in the last decade. However, the exact immunologic profile of CRS still has controversy because it has a considerable immunologic heterogeneity. Therefore, we investigated various inflammatory mediators according to different nasal tissues in chronic rhinosinusitis and compared them within the same subject.
METHODS
We collected uncinate process mucosa (UP) and nasal polyp (NP) tissues from controls, CRS without NP (CRSsNP) and CRS with NP (CRSwNP). Expression levels of 28 inflammatory mediators including T helper (Th) 1, Th2, Th17, proinflammatory cytokines and remodeling markers were determined by multiplex immunoassay and were analyzed using paired tests as well as principal component analysis (PCA) to investigate endotype in each subtype of CRS.
RESULTS
Signature inflammatory mediators are interleukin (IL)-5, C-C motif chemokine ligand (CCL)-24, monocyte chemoattractant protein (MCP)-4, and vascular cell adhesion molecule (VCAM)-1 in eosinophilic NP, whereas IL-17A, IL-1β, and matrix metallopeptidase (MMP)-9 were detected as signature inflammatory markers in non-eosinophilic NP. Despite differences in inflammatory cytokine profile between eosinophilic and non-eosinophilic NP, the common upregulation of IL-5, CCL-11, IL-23, IL-2Rα, VCAM-1, MMP-3 and MMP-9 were shown in NP compared to UP within the same subject. In the PCA, we observed that Th2 immune response was helpful in discriminating between nasal tissues in subtypes of CRS and that there was a partial overlap between non-eosinophilic NP and eosinophilic NP in terms of Th2 mediators.
CONCLUSIONS
Commonly upregulated mediators in NP were Th2-associated, compared with UP regardless of CRS subtypes, whereas signature markers were distinct in each NP subtype. These findings imply that Th2 inflammatory responses may play a role in the development of NP regardless of CRSwNP subtypes.

Keyword

Cytokines; rhinitis; sinusitis; nasal polyp

MeSH Terms

Cytokines*
Eosinophils
Immunoassay
Interleukin-17
Interleukin-23
Interleukin-5
Interleukins
Monocytes
Mucous Membrane
Nasal Polyps
Passive Cutaneous Anaphylaxis
Population Characteristics
Principal Component Analysis
Rhinitis
Sinusitis
Up-Regulation
Vascular Cell Adhesion Molecule-1
Cytokines
Interleukin-17
Interleukin-23
Interleukin-5
Interleukins
Vascular Cell Adhesion Molecule-1

Figure

• 

  Fig. 1 PCA consists of first and second PCA components of inflammatory mediator levels according to the different sinonasal tissues. UP, uncinate process tissue; NP, nasal polyps; CRSsNP, chronic rhinosinusitis without nasal polyps; E, eosinophilic; NE, non-eosinophilic; CRSwNP, chronic rhinosinusitis with nasal polyps.

Reference

1. Fokkens WJ, Lund VJ, Mullol J, Bachert C, Alobid I, Baroody F, et al. EPOS 2012: European position paper on rhinosinusitis and nasal polyps 2012. A summary for otorhinolaryngologists. Rhinology. 2012; 50:1–12.

2. Brandsted R, Sindwani R. Impact of depression on disease-specific symptoms and quality of life in patients with chronic rhinosinusitis. Am J Rhinol. 2007; 21:50–54.

3. Kim DH, Han K, Kim SW. Effect of chronic rhinosinusitis with or without nasal polyp on quality of life in South Korea: 5th Korea National Health and Nutrition Examination Survey Korean. Clin Exp Otorhinolaryngol. 2016; 9:150–156.

4. Van Zele T, Claeys S, Gevaert P, Van Maele G, Holtappels G, Van Cauwenberge P, et al. Differentiation of chronic sinus diseases by measurement of inflammatory mediators. Allergy. 2006; 61:1280–1289.

5. Polzehl D, Moeller P, Riechelmann H, Perner S. Distinct features of chronic rhinosinusitis with and without nasal polyps. Allergy. 2006; 61:1275–1279.

6. Van Bruaene N, Pérez-Novo CA, Basinski TM, Van Zele T, Holtappels G, De Ruyck N, et al. T-cell regulation in chronic paranasal sinus disease. J Allergy Clin Immunol. 2008; 121:1435–1441.

7. Kim DK, Kang SI, Kong IG, Cho YH, Song SK, Hyun SJ, et al. Two-track medical treatment strategy according to the clinical scoring system for chronic rhinosinusitis. Allergy Asthma Immunol Res. 2018; 10:490–502.

8. Tomassen P, Vandeplas G, Van Zele T, Cardell LO, Arebro J, Olze H, et al. Inflammatory endotypes of chronic rhinosinusitis based on cluster analysis of biomarkers. J Allergy Clin Immunol. 2016; 137:1449–1456.e4.

9. Liao B, Liu JX, Li ZY, Zhen Z, Cao PP, Yao Y, et al. Multidimensional endotypes of chronic rhinosinusitis and their association with treatment outcomes. Allergy. 2018; 73:1459–1469.

10. Ikeda K, Shiozawa A, Ono N, Kusunoki T, Hirotsu M, Homma H, et al. Subclassification of chronic rhinosinusitis with nasal polyp based on eosinophil and neutrophil. Laryngoscope. 2013; 123:E1–E9.

11. Cao PP, Li HB, Wang BF, Wang SB, You XJ, Cui YH, et al. Distinct immunopathologic characteristics of various types of chronic rhinosinusitis in adult Chinese. J Allergy Clin Immunol. 2009; 124:478–484.

12. Shi LL, Xiong P, Zhang L, Cao PP, Liao B, Lu X, et al. Features of airway remodeling in different types of Chinese chronic rhinosinusitis are associated with inflammation patterns. Allergy. 2013; 68:101–109.

13. Zhang N, Van Zele T, Perez-Novo C, Van Bruaene N, Holtappels G, DeRuyck N, et al. Different types of T-effector cells orchestrate mucosal inflammation in chronic sinus disease. J Allergy Clin Immunol. 2008; 122:961–968.

14. Kim DK, Jin HR, Eun KM, Mutusamy S, Cho SH, Oh S, et al. Non-eosinophilic nasal polyps shows increased epithelial proliferation and localized disease pattern in the early stage. PLoS One. 2015; 10:e0139945.

15. Wang X, Zhang N, Bo M, Holtappels G, Zheng M, Lou H, et al. Diversity of T_H cytokine profiles in patients with chronic rhinosinusitis: a multicenter study in Europe, Asia, and Oceania. J Allergy Clin Immunol. 2016; 138:1344–1353.

16. Mahdavinia M, Suh LA, Carter RG, Stevens WW, Norton JE, Kato A, et al. Increased noneosinophilic nasal polyps in chronic rhinosinusitis in US second-generation Asians suggest genetic regulation of eosinophilia. J Allergy Clin Immunol. 2015; 135:576–579.

17. Shin HW, Kim DK, Park MH, Eun KM, Lee M, So D, et al. IL-25 as a novel therapeutic target in nasal polyps of patients with chronic rhinosinusitis. J Allergy Clin Immunol. 2015; 135:1476–1485.e7.

18. Kim DK, Jin HR, Eun KM, Mo JH, Cho SH, Oh S, et al. The role of interleukin-33 in chronic rhinosinusitis. Thorax. 2017; 72:635–645.

19. Lam M, Hull L, Imrie A, Snidvongs K, Chin D, Pratt E, et al. Interleukin-25 and interleukin-33 as mediators of eosinophilic inflammation in chronic rhinosinusitis. Am J Rhinol Allergy. 2015; 29:175–181.

20. Jeong WJ, Lee CH, Cho SH, Rhee CS. Eosinophilic allergic polyp: a clinically oriented concept of nasal polyp. Otolaryngol Head Neck Surg. 2011; 144:241–246.

21. Liu X, Dong H, Wang M, Gao Y, Zhang T, Hu G, et al. IL-1α-induced microvascular endothelial cells promote neutrophil killing by increasing MMP-9 concentration and lysozyme activity. Immunol Res. 2016; 64:133–142.

22. Owen CA. Roles for proteinases in the pathogenesis of chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis. 2008; 3:253–268.

23. Van Bruaene N, Derycke L, Perez-Novo CA, Gevaert P, Holtappels G, De Ruyck N, et al. TGF-beta signaling and collagen deposition in chronic rhinosinusitis. J Allergy Clin Immunol. 2009; 124:253–259.

24. Wang H, Li ZY, Jiang WX, Liao B, Zhai GT, Wang N, et al. The activation and function of IL-36γ in neutrophilic inflammation in chronic rhinosinusitis. J Allergy Clin Immunol. 2018; 141:1646–1658.

25. Shi LL, Song J, Xiong P, Cao PP, Liao B, Ma J, et al. Disease-specific T-helper cell polarizing function of lesional dendritic cells in different types of chronic rhinosinusitis with nasal polyps. Am J Respir Crit Care Med. 2014; 190:628–638.

26. Tan BK, Klingler AI, Poposki JA, Stevens WW, Peters AT, Suh LA, et al. Heterogeneous inflammatory patterns in chronic rhinosinusitis without nasal polyps in Chicago, Illinois. J Allergy Clin Immunol. 2017; 139:699–703.e7.

27. Stevens WW, Ocampo CJ, Berdnikovs S, Sakashita M, Mahdavinia M, Suh L, et al. Cytokines in chronic rhinosinusitis. role in eosinophilia and aspirin-exacerbated respiratory disease. Am J Respir Crit Care Med. 2015; 192:682–694.

28. Nagarkar DR, Poposki JA, Tan BK, Comeau MR, Peters AT, Hulse KE, et al. Thymic stromal lymphopoietin activity is increased in nasal polyps of patients with chronic rhinosinusitis. J Allergy Clin Immunol. 2013; 132:593–600.e12.

29. Tan BK, Chandra RK, Pollak J, Kato A, Conley DB, Peters AT, et al. Incidence and associated premorbid diagnoses of patients with chronic rhinosinusitis. J Allergy Clin Immunol. 2013; 131:1350–1360.

30. Kim DW, Cho SH. Emerging endotypes of chronic rhinosinusitis and its application to precision medicine. Allergy Asthma Immunol Res. 2017; 9:299–306.

31. Stammberger H. Endoscopic endonasal surgery--concepts in treatment of recurring rhinosinusitis. Part I. Anatomic and pathophysiologic considerations. Otolaryngol Head Neck Surg. 1986; 94:143–147.

32. Stammberger H, Posawetz W. Functional endoscopic sinus surgery. Concept, indications and results of the Messerklinger technique. Eur Arch Otorhinolaryngol. 1990; 247:63–76.