Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by type 2 helper T-cell-skewed immune profiles, but the state of the neutrophil activation signaling pathway in CRSwNP is unknown. The purpose of this study was to examine neutrophil activation pathways in the pathogenesis of CRSwNP.
Methods
Institutional review board approved the study in which tissue proteomes were compared between control (inferior turbinate) and CRSwNP (nasal polyps) (n = 10/group) using an aptamer-based proteomic array and confirmed by whole transcriptomic analysis. Protein expression was analyzed using Student’s t test and Benjamini–Hochberg procedures followed by the application of Ingenuity Pathway, MetaCore, and Genemania bioinformatics analyses.
Results
All the patients with CRSwNP (n = 10) had eosinophilic nasal polyps. Compared with controls, proteins associated with the triggering receptor expressed on myeloid cells 1 (TREM-1) neutrophil activation signaling pathway such as Calcineurin B, zeta chain-associated protein kinase of 70 kD (ZAP70), 14-3-3 protein theta, 14-3-3 protein zeta/delta, protein kinase C delta type (PKC-D), Interleukin (IL)-17B, IL-17B receptor, IL-23, and IL-1B were significantly decreased in CRSwNP (fold change [FC] = −1.60, P = .003; FC = −1.85, P = .040; FC = −1.26, P < .001; FC = −1.05, P = .008; and FC = −1.31, P = .004; FC = −1.22, P < .001; FC = −1.09, P = .022; FC = −1.25, P < .001; and FC = −1.31, P = .014; respectively). In contrast, tissue eosinophil count (P < .001) and eosinophil-associated proteins such as C-C motif chemokine 17, periostin, and galectin 10 were all significantly increased in CRSwNP (FC = 1.56, P = .009; FC = 3.95, P < .001; and FC = 2.44, P < .001; respectively). Furthermore, the FC of the studied proteins’ expression significantly and positively correlated with FC of their mRNA expression (P = .001, r = .75).
Conclusions
TREM-1-associated neutrophilic signaling pathway proteins are significantly suppressed in eosinophilic CRSwNP.
DeCondeASMaceJCLevyJMRudmikLAltJASmithTL.Prevalence of polyp recurrence after endoscopic sinus surgery for chronic rhinosinusitis with nasal polyposis.Laryngoscope. 2017;
127:550–555.
4.
FokkensWJLundVJMullolJet al.
European position paper on rhinosinusitis and nasal polyps 2012.Rhinol Suppl. 2012;
23:3 p preceding table of contents, 1–298.
5.
TomassenPVandeplasGVan ZeleTet al.
Inflammatory endotypes of chronic rhinosinusitis based on cluster analysis of biomarkers.J Allergy Clin Immunol. 2016;
137:1449–1456.e4.
6.
ZhangNVan ZeleTPerez-NovoCet al.
Different types of T-effector cells orchestrate mucosal inflammation in chronic sinus disease.J Allergy Clin Immunol. 2008;
122:961–968.
WangXZhangNBoMet al.
Diversity of TH cytokine profiles in patients with chronic rhinosinusitis: a multicenter study in Europe, Asia, and Oceania.J Allergy Clin Immunol. 2016;
138:1344–1353.
9.
DeryckeLEyerichSVan CrombruggenKet al.
Mixed T helper cell signatures in chronic rhinosinusitis with and without polyps.PloS One. 2014;
9:e97581.
10.
WuDWangJZhangM.Altered Th17/Treg ratio in nasal polyps with distinct cytokine profile: association with patterns of inflammation and mucosal remodeling.Medicine. 2016;
95:e2998.
11.
MahdaviniaMSuhLACarterRGet 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.
12.
CaoP-PLiH-BWangB-Fet al.
Distinct immunopathologic characteristics of various types of chronic rhinosinusitis in adult Chinese.J Allergy Clin Immunol. 2009;
124:478–484.e2.
13.
KatotomichelakisMTantilipikornPHoltappelsGet al.
Inflammatory patterns in upper airway disease in the same geographical area may change over time. Am J Rhinol Allergy. 2013;
27:354–360.
14.
Klesney-TaitJKeckKLiXet al.
Transepithelial migration of neutrophils into the lung requires TREM-1.J Clin Invest. 2012;
123:138–149.
15.
FortinCFLesurOFulopTJr.
Effects of TREM-1 activation in human neutrophils: activation of signaling pathways, recruitment into lipid rafts and association with TLR4.Int Immunol. 2006;
19:41–50.
16.
BouchonADietrichJColonnaM.Cutting edge: inflammatory responses can be triggered by TREM-1, a novel receptor expressed on neutrophils and monocytes.J Immunol. 2000;
164:4991–4995.
17.
ColonnaMFacchettiF.TREM-1 (triggering receptor expressed on myeloid cells): a new player in acute inflammatory responses.J Infect Dis. 2003;
187:S397–S401.
18.
ArtsRJJoostenLAvan der MeerJWNeteaMG.TREM-1: intracellular signaling pathways and interaction with pattern recognition receptors.J Leukoc Biol. 2013;
93:209–215.
19.
BucovaMSuchankovaMDzurillaMet al.
Inflammatory marker sTREM-1 reflects the clinical stage and respiratory tract obstruction in allergic asthma bronchiale patients and correlates with number of neutrophils.Mediators Inflamm.
2012;2012:628754.
20.
RaedlerDBallenbergerNKluckerEet al.
Identification of novel immune phenotypes for allergic and nonallergic childhood asthma.J Allergy Clin Immunol. 2015;
135:81–91.
21.
PonikauJUSherrisDAKephartGMet al.
Features of airway remodeling and eosinophilic inflammation in chronic rhinosinusitis: is the histopathology similar to asthma?J Allergy Clin Immunol. 2003;
112:877–882.
22.
TerzakisDGeorgalasC.Polyps, asthma, and allergy: what’s new.Curr Opin Otolaryngol Head Neck Surg. 2017;
25:12–18.
23.
WuDLiLZhangMWangJWeiY.Two inflammatory phenotypes of nasal polyps and comorbid asthma.Ann Allergy Asthma Immunol. 2017;
118:318–325.
24.
OrlandiRRKingdomTTHwangPHet al.
International consensus statement on allergy and rhinology: rhinosinusitis.Int Forum Allergy Rhinol. 2016;
6(Suppl 1):S22–S209.
25.
QiaoZPanXParlayanCOjimaHKondoT.Proteomic study of hepatocellular carcinoma using a novel modified aptamer-based array (SOMAscan™) platform.Biochim Biophys Acta. 2017;
1865:434–443.
26.
GünelCBleierBSMeteogluI.Antibiotics in eosinophilic chronic rhinosinusitis: rethinking maximal antimicrobial medical therapy.Laryngoscope. 2017;
127:794–796.
27.
LundVJMackayIS.Staging in rhinosinusitis.Rhinology. 1993;
31:183–183.
28.
LundVJKennedyDW. Staging for rhinosinusitis. Otolaryngol Head Neck Surg. 1997;
117:S35–S40.
29.
FarahCSKordbachehFJohnKBennettNFoxSA. Molecular classification of autofluorescence excision margins in oral potentially malignant disorders [published online ahead of print December 14, 2017]. Oral Dis. doi:10.1111/odi.12818
30.
CaoCGuJZhangJ.Soluble triggering receptor expressed on myeloid cell-1 (sTREM-1): a potential biomarker for the diagnosis of infectious diseases. Front Med. 2017;
11:169–177.
31.
DamskerJMHansenAMCaspiRR.Th1 and Th17 cells. Ann N Y Acad Sci. 2010;
1183:211–221.
32.
RamezanpourMMoraitisSSmithJLWormaldPVreugdeS. Th17 cytokines disrupt the airway mucosal barrier in chronic rhinosinusitis. Mediators Inflamm. 2016;2016:9798206.
33.
PierobonDBoscoMCBlengioFet al.
Chronic hypoxia reprograms human immature dendritic cells by inducing a proinflammatory phenotype and TREM-1 expression.Eur J Immunol. 2013;
43:949–966.
34.
WuMPengASunMet al.
TREM-1 amplifies corneal inflammation after Pseudomonas aeruginosa infection by modulating Toll-like receptor signaling and Th1/Th2-type immune responses.Infect Immun. 2011;
79:2709–2716.
35.
HulseKStevensWTanBSchleimerR.Pathogenesis of nasal polyposis.Clin Exp Allergy. 2015;
45:328–346.
36.
MaxfieldAZLandeggerLDBrookCDet al.
Periostin as a biomarker for nasal polyps in chronic rhinosinusitis.Otolaryngol Head Neck Surg. 2018;
158:181–186.
37.
XuMZhangWChenDZhouHChenL.Diagnostic significance of serum periostin in eosinophilic chronic sinusitis with nasal polyps. Acta Otolaryngol. 2017;138:1–5.
38.
Negrete-GarciaMCJiménez-TorresCYAlvarado-VásquezNet al. Galectin-10 is released in the nasal lavage fluid of patients with aspirin-sensitive respiratory disease. ScientificWorldJournal. 2012;2012:474020.
39.
BachertCGevaertPHoltappelsGJohanssonSVan CauwenbergeP.Total and specific IgE in nasal polyps is related to local eosinophilic inflammation.J Allergy Clin Immunol. 2001;
107:607–614.
40.
Van ZeleTClaeysSGevaertPet al.
Differentiation of chronic sinus diseases by measurement of inflammatory mediators.Allergy. 2006;
61:1280–1289.
41.
Van BruaeneNPérez-NovoCABasinskiTMet al.
T-cell regulation in chronic paranasal sinus disease.J Allergy Clin Immunol. 2008;
121:1435–1441.e3.
42.
PaponJFCosteAGendronMCet al.
HLA-DR and ICAM-1 expression and modulation in epithelial cells from nasal polyps.Laryngoscope. 2002;
112:2067–2075.
43.
PoposkiJAUzzamanANagarkarDRet al.
Increased expression of the chemokine CCL23 in eosinophilic chronic rhinosinusitis with nasal polyps.J Allergy Clin Immunol. 2011;
128:73–81.e4.
44.
AllenJSEismaRLeonardGKreutzerD.Interleukin-3, interleukin-5, and granulocyte-macrophage colony-stimulating factor expression in nasal polyps.Am J Otolaryngol. 1997;
18:239–246.
PhillipsonMHeitBParsonsSAet al.
Vav1 is essential for mechanotactic crawling and migration of neutrophils out of the inflamed microvasculature.J Immunol. 2009;
182:6870–6878.
47.
JiaGEricksonRWChoyDFet al.
Periostin is a systemic biomarker of eosinophilic airway inflammation in asthmatic patients.J Allergy Clin Immunol. 2012;
130:647–654.e10.
48.
WangMWangXZhangNet al.
Association of periostin expression with eosinophilic inflammation in nasal polyps.J Allergy Clin Immunol. 2015;
136:1700–1703.e9.
49.
SolerZMSauerDAMaceJSmithTL.Relationship between clinical measures and histopathologic findings in chronic rhinosinusitis.Otolaryngol Head Neck Surg. 2009;
141:454–461.
50.
SnidvongsKLamMSacksRet al.
Structured histopathology profiling of chronic rhinosinusitis in routine practice.Int Forum Allergy Rhinol. 2012;
2:376–385.
51.
WuDWeiYBleierBS.Emerging role of proteases in the pathogenesis of chronic rhinosinusitis with nasal polyps.Front Cell Infect Microbiol. 2018;
7:538.
