Allergy Asthma Immunol Res.  2020 May;12(3):507-522. 10.4168/aair.2020.12.3.507.

Role of IL-17A in Chronic Rhinosinusitis With Nasal Polyp

Affiliations
  • 1Department of Otorhinolaryngology-Head and Neck Surgery, Soonchunhyang University College of Medicine, Cheonan, Korea.
  • 2Department of Otorhinolaryngology, Dankook University College of Medicine, Cheonan, Korea. jihunmo@gmail.com
  • 3Beckman Laser Institute Korea, Dankook University College of Medicine, Cheonan, Korea.

Abstract

PURPOSE
Th17-associated inflammation is increased in chronic rhinosinusitis with nasal polyp (CRSwNP), and is associated with disease severity and steroid resistance. Overexpressed interleukin (IL)-17A affects CRSwNP by tissue remodeling, eosinophilic accumulation, and neutrophilic infiltration. We aimed to identify the role of IL-17A in CRSwNP and to evaluate the effects of anti-IL-17A blocking antibody on nasal polyp (NP) formation using a murine NP model. Moreover, we sought to investigate whether the inhibition of mechanistic target of the rapamycin (mTOR) signal pathway could suppress IL-17A expression and NP formation.
METHODS
Human sinonasal tissues from control subjects and patients with chronic rhinosinusitis (CRS) were analyzed using immunohistochemistry (IHC) and immunofluorescence staining. The effects of IL-17A neutralizing antibody and rapamycin were evaluated in a murine NP model. Mouse samples were analyzed using IHC, quantitative real-time polymerase chain reaction, and enzyme-linked immunosorbent assay.
RESULTS
IL-17A+ inflammatory cells were significantly increased in number in NP from patients with CRSwNP compared to that in uncinate process tissues from control subjects and patients with CRS without NP or CRSwNP. CD68+ M1 macrophages dominantly expressed IL-17A, followed by neutrophils and T helper cells, in NP tissues. Neutralization of IL-17A effectively reduced the number of NPs, inflammatory cytokines, and IL-17A-producing cells, including M1 macrophages. Inhibition of IL-17A via the mTOR pathway using rapamycin also attenuated NP formation and inflammation in the murine NP model.
CONCLUSIONS
IL-17A possibly plays a role in the pathogenesis of CRSwNP, the major cellular source being M1 macrophage in NP tissues. Targeting IL-17A directly or indirectly may be an effective therapeutic strategy for CRSwNP.

Keyword

Sinusitis; nasal polyps; IL-17A; TNF-α; rapamycin; mice; immunohistochemistry; real-time polymerase chain reaction

MeSH Terms

Animals
Antibodies, Neutralizing
Cytokines
Enzyme-Linked Immunosorbent Assay
Eosinophils
Fluorescent Antibody Technique
Humans
Immunohistochemistry
Inflammation
Interleukin-17*
Interleukins
Macrophages
Mice
Nasal Polyps*
Neutrophils
Real-Time Polymerase Chain Reaction
Signal Transduction
Sinusitis
Sirolimus
T-Lymphocytes, Helper-Inducer
Antibodies, Neutralizing
Cytokines
Interleukin-17
Interleukins
Sirolimus

Figure

  • Fig. 1 Expression of IL-17A-associated inflammatory markers in human sinonasal tissues. (A and B) The number of IL-17A+ and IL-23+ cells (red arrows) according to the different types of tissues. (C) Expression of TNF-α. (D) Expression of phosphorylated-mTOR. (E) Correlation analysis of the number of IL-17A-positive cells with that of IL-23, TNF-α, and mTOR-positive cells in all human sinonasal tissues (n = 48, n = 24 for TNF-α). (F) Dual immunofluorescent staining for IL-17A and IL-23.IL, interleukin; TNF, tumor necrosis factor; mTOR, mechanistic target of rapamycin; CRSsNP, chronic rhinosinusitis without nasal polyp; CRSwNP, chronic rhinosinusitis with nasal polyp; UP, uncinate process; NP, nasal polyp.*P < 0.05, †P < 0.01, and ‡P < 0.001.

  • Fig. 2 Dual immunofluorescent staining for each cell marker. (A) Double positive cells (white arrow) of IL-17A with CD68, ELA2 (elastase), CD4, CD56, CD11c, and CD163. (B) Total number of IL-17A-double positive cells.IL, interleukin; DAPI, 4′,6-diamidino-2-phenylindole.*P < 0.05, †P < 0.01, and ‡P < 0.001.

  • Fig. 3 Effect of anti-IL-17A and anti-TNF-α in the murine model. (A) Protocol of the murine model of chronic rhinosinusitis with nasal polyp. OVA and SEB were instilled into the nasal cavity to induce nasal polyposis. Anti-IL-17A and anti-TNF-α were administered intraperitoneally. (B) Number of polypoid lesions. (C and D) IL-17A+ and CD68+ cell counts. (E and F) Number of infiltrated neutrophils and eosinophils.Subjects were divided into 5 groups; (−) Con: negative control group, (+) Con: positive control (nasal polyp) group, IL-17 Ab: IL-17 neutralizing antibody treatment group, TNF-α Ab: TNF-α neutralizing antibody treatment group, and Dex: dexamethasone treatment (therapeutic control) group.OVA, ovalbumin; IL, interleukin; TNF, tumor necrosis factor; ALM, aluminum hydroxide; SEB, Staphylococcus aureus enterotoxin B; i.p., intraperitoneal; i.n., intranasal.*P < 0.05, †P < 0.01, and ‡P < 0.001.

  • Fig. 4 Effect of blocking mTOR pathway using rapamycin in the murine model. (A) Protocol of the murine model and rapamycin was administered intraperitoneally. (B) Number of polypoid lesions. (C and D) IL-17A+ and CD68+ cell counts. (E) Number of elastase+ neutrophils.Subjects were divided into 3 groups; (−) Con: negative control group, (+) Con, positive control (nasal polyp) group, and Rapamycin: rapamycin treatment group.mTOR, mechanistic target of rapamycin; IL, interleukin; OVA, ovalbumin; i.n., intranasal; i.p., intraperitoneal; ALM, aluminum hydroxide; SEB, Staphylococcus aureus enterotoxin B.*P < 0.01, and †P < 0.001.


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