# paper.pdf ## Metadata - PDFFormatVersion=1.7 - Language=en - IsLinearized=true - IsAcroFormPresent=false - IsXFAPresent=false - IsCollectionPresent=false - IsSignaturesPresent=false - Custom.CrossMarkDomains[2]=elsevier.com - Custom.CrossmarkMajorVersionDate=2010-04-23 - Custom.EPSprocessor=PStill version 1.84.42 - Custom.ElsevierWebPDFSpecifications=7.0.1 - Custom.CrossmarkDomainExclusive=true - Custom.robots=noindex - Custom.doi=10.1016/j.waojou.2026.101409 - Custom.CrossMarkDomains[1]=sciencedirect.com - CreationDate=D:20260529065600+05'30' - Subject=World Allergy Organization Journal, 19 (2026) 101409. doi:10.1016/j.waojou.2026.101409 - Author=Linghui Meng MD - Creator=Elsevier - Producer=PDFlib+PDI 10.0.2p2 (C++/Win64) - ModDate=D:20260529070106+05'30' - Title=Olfactory mucosal inflammation and barrier disruption correlate with perceived CRSwNP-associated olfactory dysfunction - dc:format=application/pdf - dc:identifier=doi:10.1016/j.waojou.2026.101409 - dc:title=Olfactory mucosal inflammation and barrier disruption correlate with perceived CRSwNP-associated olfactory dysfunction - dc:creator=Linghui Meng MD,Shengyang Liu MD,Peng Yu MM,Jinzhuang Yu MM,Aiping Chen MD,Hongzhi Ji MD,Tao Li MD,Yanyi Tu MD,Yuzhu Wan MD,Dingqian Hao MD,Li Shi MD - dc:subject=Sinusitis,Nasal polyps,Olfactory mucosa,Olfaction disorders,Inflammation - dc:description=World Allergy Organization Journal, 19 (2026) 101409. doi:10.1016/j.waojou.2026.101409 - dc:publisher=The Authors - prism:aggregationtype=journal - prism:publicationname=World Allergy Organization Journal - prism:copyright=© 2026 The Authors. Published by Elsevier Inc. on behalf of World Allergy Organization. - prism:issn=1939-4551 - prism:volume=19 - prism:number=7 - prism:coverdisplaydate=July 2026 - prism:pagerange=101409 - prism:startingpage=101409 - prism:doi=10.1016/j.waojou.2026.101409 - prism:url=https://doi.org/10.1016/j.waojou.2026.101409 - crossmark:majorversiondate=2010-04-23 - crossmark:crossmarkdomainexclusive=true - crossmark:doi=10.1016/j.waojou.2026.101409 - crossmark:crossmarkdomains=elsevier.comsciencedirect.com - jav:journal_article_version=VoR - pdfx:elsevierwebpdfspecifications=7.0.1 - pdfx:doi=10.1016/j.waojou.2026.101409 - pdfx:robots=noindex - pdfx:crossmarkmajorversiondate=2010-04-23 - pdfx:crossmarkdomainexclusive=true - pdfx:epsprocessor=PStill version 1.84.42 - pdfx:crossmarkdomains=sciencedirect.comelsevier.com - xap:creatortool=Elsevier - xap:createdate=2026-05-29T06:56+05:30 - xap:modifydate=2026-05-29T07:01:06+05:30 - xap:metadatadate=2026-05-29T07:01:06+05:30 - xaprights:marked=True - tdm:reservation=1 - tdm:policy=https://www.elsevier.com/tdm/tdmrep-policy.json - pdf:producer=PDFlib+PDI 10.0.2p2 (C++/Win64) - xapmm:documentid=uuid:3fe52185-056e-4997-87d2-1ded939b705a - xapmm:instanceid=uuid:b475796f-9adc-4d34-9442-01d606f36b9f - ali:license_ref=http://creativecommons.org/licenses/by-nc-nd/4.0/ ## Contents ### Page 1 Meng et al. World Allergy Organization Journal (2026) 19:101409 ![Figure]() ![Figure]() Open Access # Olfactory mucosal inflammation and barrierdisruption correlate with perceivedCRSwNP-associated olfactory dysfunction Linghui Meng, MDa,b,d, Shengyang Liu, MDa,b,d, Peng Yu, MMa, Jinzhuang Yu, MMa Aiping Chen, MDa, Hongzhi Ji, MDa, Tao Li, MDa, Yanyi Tu, MDa, Yuzhu Wan, MDa, Dingqian Hao, MDa,c and Li Shi, MDa,b , ## ABSTRACT Objective: This study aimed to characterize the local inflammatory and histopathological features of the olfactory mucosa (OM) in patients with CRSwNP and to clarify how these localchanges are associated with perceived olfactory dysfunction. Methods: OM specimens were collected from patients with CRSwNP during FESS and fromcontrol subjects undergoing endoscopic transnasal skull base surgery, with sampling restricted tothe olfactory region under endoscopic guidance. qRT-PCR was performed in 30 CRSwNP and 13control samples to quantify inflammatory mediators, and immunofluorescence staining wasperformed in 18 CRSwNP and 10 control samples to assess epithelial cell composition, tightjunction proteins, and inflammatory cell infiltration. Clinical symptoms were evaluated using VASand SNOT-22. Results: Compared with controls, the OM of patients with CRSwNP showed significantlyincreased expression of TNF-α, IFN-γ, IL-5, IL-13, CLC, CCL11, and CCL18. More severe smell losswas associated with a type 2 inflammatory endotype, eosinophilic CRSwNP, and older age.Among the inflammatory mediators examined, IL-5 showed the clearest positive association withsmell loss severity, while IL-13, CLC, and CCL11 provided additional support for a type 2 inflammatory pattern linked to olfactory dysfunction. Patients with severe smell loss also exhibited agreater local inflammatory burden, particularly increased IL-5, CLC, and CCL11. Histologically,CRSwNP OM demonstrated reduced OMP-positive olfactory sensory neurons and KRT18-positivesustentacular cells, increased KRT5-positive basal cells, decreased Golf expression, and downregulation of ZO-1, Occludin, Claudin-1, and Claudin-3, together with increased infiltration ofCD45+ cells, CD3+ T cells, CD4+ T cells, and eosinophils. Conclusion: Perceived olfactory dysfunction in CRSwNP was closely associated with an activelocal immune-inflammatory microenvironment in the olfactory mucosa, characterized by predominant type 2/eosinophilic inflammation, epithelial injury, abnormal repair, barrier disruption,and immune cell infiltration. Among the inflammatory markers examined, IL-5 showed the aDepartment of Otolaryngology-Head and Neck Surgery, ShandongProvincial ENT Hospital, Shandong University, Jinan, Shandong, China*Corresponding author. Department of Otolaryngology-Head and NeckSurgery, Liaocheng Hospital of Traditional Chinese Medicine, Liaocheng,Shandong, 252000, China **Corresponding author. Department of Otolaryngology-Head and NeckSurgery, Shandong Provincial ENT Hospital, Shandong University, Jinan,Shandong, 250000, China. Email: d Linghui Meng and Shengyang Liu contributed equally to this work. Full list of author information is available at the end of the article Received 25 November 2025; Received in revised from 2 May 2026;Accepted 7 May 2026 Online publication date xxx 1939-4551/© 2026 The Authors. Published by Elsevier Inc. on behalf ofWorld Allergy Organization. This is an open access article under the CC BYNC-ND license (). ### Page 2 2 Meng et al. World Allergy Organization Journal (2026) 19:101409 strongest association with the severity of olfactory dysfunction, while CLC and CCL11 may serveas candidate local tissue markers of inflammatory burden in CRSwNP-associated olfactorydysfunction. Keywords: Sinusitis, Nasal polyps, Olfactory mucosa, Olfaction disorders, Inflammation ## INTRODUCTION Chronic rhinosinusitis with nasal polyps(CRSwNP) is a chronic inflammatory disease ofnasal mucosa characterized by a high prevalence,high recurrence rate, and marked heterogeneity.1,2 Medication therapy alone is not sufficient,and multiple surgeries are often required, whichnot only markedly reduces the quality of life, butalso places a heavy medical and economicburden on families and society. In contrast toearlier studies focusing mainly on clinicalphenotypes, recent research on CRSwNP hasincreasingly focused on inflammatory endotypes.Moreover, some studies identified severalbiomarkers that could represent CRSwNPinflammatory patterns.3 In addition to nasalcongestion and discharge, olfactory dysfunction(OD) is also a typical symptom of CRSwNP.4 Amulti-center study involving 811 chronic rhinosinusitis (CRS) patients showed that approximately80% of CRSwNP patients had the complaint ofOD.5 The conduction system of olfaction recognizesodor molecules through a subtle physiologicalpathway. After the molecules are recognized byolfactory epithelium (OE), the signals first reacholfactory bulb (OB) through olfactory nerve fibersand finally the olfactory perception-related area inthe brain. OE is a kind of pseudostratifiedcolumnar epithelium, mainly including olfactorysensory neurons (OSNs), sustentacular cells(SUSs), basal cells (BCs), microvillous cells (MCs),and Bowman’s glands (BGs).6 OSNs thatspecifically express olfactory marker protein(OMP) capture odor signals through dendritesand transmit the electrical signals to OB in thefront of the brain via axons, thus formingolfactory reflex.7 The SUSs surrounding matureOSNs specifically express cytokeratin 18 (KRT18),which provide nutrients and mechanical supportfor OE and participate in olfactory signal transduction.8 BCs, a kind of reserve stem cellswith differentiation potential, can be categorizedinto horizontal basal cells (HBCs) and globosebasal cells (GBCs). HBCs specifically expresscytokeratin 5 (KRT5), and are activated when OEis damaged.9 HBCs participate in theregeneration process, and can differentiate intomultiple types of cells, including OSNs, SUSs,and GBCs. Golf is a kind of G protein detectingodor and is a specific marker for the cilia layeron the surface of OE.10 The staining of Golf canreflect the loss of cilia. The lamina propria (LP)beneath OE is a part of connective tissuecomposed of collagen fibers, olfactoryensheathing cells (OECs), and glands. Olfactorymucosa (OM) consists of the OE and LP. At present, the exact mechanism of OD inCRSwNP still remains unclear. Previously, CRSwNPcomplicated with OD was attributed to OMedema, decreased airflow to olfactory cleft (OC),and mechanical obstruction caused by nasalpolyps (NP).11,12 In recent years, accumulatingevidence has suggested that the inflammatoryresponse is closely related to OD in CRSwNP. Ahistopathological study involving OM obtainedfrom CRS patients showed that there wasmarked infiltration of eosinophils in superiorturbinate (ST) mucosa.13 In CRS mouse modelinduced by Type 2 (T2) inflammation, interleukin(IL)-13 induced eosinophilic inflammation andinfluenced the occurrence of OSNs,subsequently leading to different degrees of ODin mice.14 Additionally, the macrophages arealso involved in the inflammation-associated OD.In the OM of CRS mouse model, the macrophagescan migrate under chemokines stimuli and secreteneurotrophins, which then regulate the proliferation of epithelial cells.15 In our previous studies, we identified the associations between inflammatory endotypes andclinical phenotypes, and investigated signalling ### Page 3 Volume 19, No. 7, Month 2026 pathways for epithelial-mesenchymal transition inCRSwNP.16,17 In the present study, weconcentrated on the fundamental molecularmechanisms of CRSwNP-related OD. However,recent research on the mechanism of OD wasmainly conducted in animal models, and therewere limited experimental data on the microscopic changes of OM in human body. Therefore,this study aimed to provide more insights on therole of inflammation in OD through analyzing themolecular characteristics of OM in CRSwNP patients, as well as find new research interests andtherapeutic targets. ## MATERIALS AND METHODS Subjects and sample collection The diagnostic criteria for CRSwNP wereconsistent with the current European Position Paper on Rhinosinusitis and Nasal Polyps (EPOS2020).18 OM tissues were collected from patientswith CRSwNP during functional endoscopic sinussurgery (FESS). Olfactory mucosa specimenswere obtained only in selected CRSwNP patientsin whom surgical access to the olfactory cleftwas already required as part of the standardFESS procedure for disease clearance, such as incases with disease involvement of the olfactorycleft. No additional dissection was performedsolely for research purposes. Tissue samplingwas carried out only when the specimen couldbe safely collected within the routine surgicalfield without increasing surgical risk orcompromising patient safety or surgicaloutcomes. Patients with primary ciliary dyskinesia(PCD), cystic fibrosis (CF), or aspirin-exacerbatedrespiratory disease (AERD) were excluded. TheOM tissues in the control group were obtainedfrom participants receiving skull base surgeryguided by transnasal endoscopy. All control subjects denied nasal inflammatory diseases andother systemic disorders. Both control group andCRSwNP patients did not use glucocorticoidswithin 1 month before surgery. All participantssigned the informed consent form. This study wasapproved by the Ethics Review Committee ofShandong Provincial ENT Hospital. Preoperativeclinical severity was assessed by VAS, SNOT-22,and the clinical characteristics summarized in. 3 Identification of olfactory mucosa Collected specimens were considered representative of olfactory mucosa based on bothanatomical location and histological/immunofluorescent features. Anatomically, tissue was obtained from the olfactory region under directendoscopic visualization, and the sampling site isillustrated in the newly added schematic figure(). Histologically, the specimens showedcharacteristic olfactory epithelial components,including OMP-positive olfactory sensory neurons, KRT18-positive sustentacular cells, KRT5positive basal cells, and apical Golf staining,which together supported OM identity. Quantitative real-time polymerase chain reaction(qRT-PCR) Total RNA from OM tissue was separated andextracted by using TRIzol reagent. The concentration and purity of total RNA were measured bya spectrophotometer. According to the protocolof the iScriptTM cDNA synthesis kit, 1 μg of totalRNA in a 20 μL reaction system was reversetranscribed into cDNA. Afterwards, the targetgene was amplified in PCR instrument utilizingSYBR Green kit. The 2 ΔΔCT method was used toanalyze relative mRNA expression of specificgenes. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was used as the housekeepinggene to calibrate the target gene. The sequencesof the primers for all genes are shown in. Immunofluorescent (IF) staining After dewaxing, the sections containing OMtissue were immersed in antigen repair buffer. Thesections were then fixed in 4% paraformaldehyde(PFA) for 15 min. After permeabilization with 0.1%Triton X-100 for 10 min, the sections were blockedwith 10% goat serum for 30 min. The sectionswere incubated with primary antibodies overnightat 4◦ C. On the next day, the sections were incubated with secondary antibody containing fluorophore at room temperature for 1 h in darkness.Finally, the slides were sealed with 4′ ,6-diamidino2-phenylindole dihydrochloride (DAPI), and 5fields were randomly selected for each slide under 400-fold magnification. The images were acquired under a fluorescence microscope. Totalfluorescence intensity (TFI) was used to evaluate ### Page 4 4 Meng et al. World Allergy Organization Journal (2026) 19:101409 | VariableSample size | Control | CRSwNP | P value – | | - | - | - | - | | 13 | 30 | | qRT-PCR | 13 | 30 | – | | IF staining | 10 | 18 | – | | Demographic characteristics | | Age, years | 56 ± 15 | 46 ± 11 | NS | | Gender (male) | 9 | 21 | NS | | Atopy | 0 | 11 | <0.05 | | Smoker | 4 | 9 | NS | | Allergy | 2 | 11 | NS | | Asthma | 0 | 6 | NS | | Recurrence | – | 3 | – | | Disease severity at the time of surgery | | Nasal Polyp Score (NPS) | – | 5.40 ± 1.57 | – | | Lund–Mackay CT score | – | 16.83 ± 4.15 | – | | SNOT-22 score | – | 34.33 ± 14.58 | – | | VAS score | – | 30.53 ± 12.51 | – | | Smell loss score(VAS) | – | 7.20 ± 2.61 | – | | Olfactory severity subgroup (VAS score) | | Mild smell loss, n (%) | – | 5 (16.7) | – | | Moderate smell loss, n (%) | – | 10 (33.3) | – | | Severe smell loss, n (%) | – | 15 (50.0) | – | chronic rhinosinusitis with nasal polyps; CT, computed tomography; NPS, Nasal Polyp Score; VAS, visual analogue scale; SNOT-22, 22-item Sino-NasalOutcome Test. NS = Not significant. the protein expression level of the markers. TFIwas calculated by multiplying the positive area bythe mean fluorescence intensity (MFI). Furthermore, the background fluorescence was subtracted for correction. Details of all antibodies areshown in. Visual analogue scale (VAS) and Sino nasaloutcome test-22 (SNOT-22) VAS and SNOT-22 were used to evaluate theseverity of symptoms in CRSwNP patients. A totalof 7 major clinical symptoms were rated, including nasal congestion, purulent discharge, smell loss,headache/facial pain, sneezing, nasal itching, anditchy eyes. The score of 0 indicated no symptom,and 10 signified the most serious symptom. Totalsymptom scores (TSS) was the summation of thescores for all the evaluated symptoms. The SNOT22 evaluation indexes were divided into 5 subgroups, including: nasal (necessity to blow nose,nasal blockage, sneezing, clear nasal dischargeand decreased sense of smell/taste), extra-nasal(cough, post nasal drip and purulent nasaldischarge), ear/facial (stuffy ears, dizziness, ear ### Page 5 Volume 19, No. 7, Month 2026 5 ![Figure]() pain and facial pain/pressure), psychological (fatigue, decreased productivity, loss of concentration, frustrated/restless/irritable, anxiety andfeeling uneasy or embarrassed) and sleep-related(difficulties in falling asleep, wake up at night,poor sleep quality and exhaustion after wakingup). In each subgroup, the score of each itemrange from 0 to 5. The score of each subgroupand the total scores of all scoring items in SNOT22 were calculated. Statistical analysis All data were statistically analyzed by usingGraphPad Prism7. Chi-square test and MannWhitney U test were utilized to compare the differences between the 2 groups. For comparisonsamong 3 or more groups, the Kruskal–Wallis testfollowed by appropriate multiple-comparisonpost hoc testing was used. Spearman test wasapplied to validate the correlation between data.The predictive values of the markers were evaluated by receiver operating characteristic (ROC)curve. The data were ultimately presented asmean ± standard deviation (SD). P < 0.05 indicated that the differences were statisticallysignificant. ## RESULTS The mRNA expression and diagnostic value ofcytokines in OM of CRSwNP patients In OM tissue of patients with CRSwNP (n = 30),the expression levels of T1 inflammatory cytokinestumor necrosis factor (TNF)-α (P < 0.01;A) and interferon (IFN)-γ (P < 0.05;B), as wellas the expressions of T2 inflammatory mediatorsIL-5 (P < 0.05;D), IL-13 (P < 0.05;E),and Charcot-Leyden crystal galectin (CLC)(P < 0.001;G) were increased, as comparedwith the control group (n = 13). Furthermore,expressions of chemokines C-C motif chemokineligand (CCL) 11 (P < 0.05;H) and CCL18(P < 0.001;I) were up-regulated. There wasno significant difference in the expression levels ofIL-4 (C) and IL-17A (F). Thedemographic and clinical characteristics of theCRSwNP patients are summarized in.Preoperative disease severity at the time ofsurgery was characterized by NPS, Lund–MackayCT score, VAS, SNOT-22, and smell loss score. The mRNA levels of cytokines in OM wereassociated with clinical features in CRSwNP In CRSwNP patients (n = 30), TNF-α (R2 = 0.130,P < 0.05,A) and IFN-γ (R2 = 0.199, P < 0.05,B) were negatively correlated with age.However, IFN-γ was positively correlated withpsychological score (R2 = 0.155, P < 0.05,C). Among T2-related markers, IL-5 expression showed significant positive correlations withtotal symptom score and SNOT-22 total score(R2 = 0.198 and 0.190, respectively; bothP < 0.05) (D and E), while IL-13 expressionwas positively correlated with nasal itching score(R2 = 0.257, P < 0.01) (F). In addition, CCL18expression was positively associated with bodymass index (R2 = 0.162, P < 0.05) (G). T3inflammation, IL-17A expression showed ### Page 6 6 Meng et al. World Allergy Organization Journal (2026) 19:101409 ![Figure]() significant positive correlations with SNOT-22 total score and post-nasal drip score (R2 = 0.164and 0.149, respectively; both P < 0.05) (Hand I). These findings suggest that distinctinflammatory mediators in the olfactory mucosaare associated with different clinicalmanifestations in CRSwNP. Smell loss severity across inflammatoryendotypes and clinical subgroups in CRSwNP To further characterize the clinical distributionof olfactory dysfunction in CRSwNP, smell lossscores were compared across different inflammatory and demographic subgroups. Inflammatory endotypes were classified as T1, T2, and T3according to the criteria established in our previous study.16 Patients with a T2 inflammatorypattern showed significantly higher smell lossscores than those with a T1 pattern, whereas thedifference between T2 and T3 patterns showedonly a borderline trend, and no significantdifference was observed between T1 and T3 patterns (A). Similarly, eosinophilicCRSwNP exhibited significantly higher smell lossscores than non-eosinophilic CRSwNP (B).When stratified by age, patients aged 60–80years had significantly higher smell loss scoresthan those aged 18–45 years, while thedifferences between adjacent age groups werenot significant (C). In contrast, smell lossscores were not significantly associated withallergy status, asthma, recurrence, sex, smokingstatus, or BMI subgroup (D–I). Thesefindings further support that more severeolfactory impairment in CRSwNP is more closelyassociated with T2/eosinophilic inflammatoryendotype and older age, rather than with othercommon clinical characteristics. Correlation of smell loss severity withinflammatory mediators in the olfactory mucosaof CRSwNP To further assess the relationship betweensmell loss severity and local inflammatory patterns ### Page 7 Volume 19, No. 7, Month 2026 7 in CRSwNP (n = 30), correlation analyses wereperformed between smell loss score and inflammatory mediator expression in the olfactory mucosa. Among the markers examined, IL-5 showeda significant positive correlation with smell lossscore (R2 = 0.132, P < 0.05;D). In addition,several other markers, including IL-13, CLC, andCCL11, showed positive trends with increasingsmell loss score, although these associations didnot reach statistical significance (E–G). IL-17Aalso showed a positive trend (H), suggestingthat non-T2 inflammatory pathways maycontribute to olfactory impairment in at least asubset of patients. By contrast, no significant correlations were observed between smell loss scoreand the T1-related markers IFN-γ and TNF-α, orwith IL-4 and IL-22 (). Taken together,these findings indicate that perceived smell lossin CRSwNP is most closely linked to the localinflammatory burden of the olfactory mucosa,with IL-5 showing the strongest associationamong the mediators examined. Comparison of inflammatory mediatorexpression among smell loss severity subgroupsin CRSwNP To further evaluate the relationship betweenthe severity of olfactory dysfunction and local inflammatory status, patients with CRSwNP werestratified into mild (0–3, n = 5), moderate (4–7,n = 10), and severe (8–10, n = 15) smell lossgroups, and the expression of inflammatory mediators in the olfactory mucosa was comparedamong groups. The results showed that,compared with controls, patients with severesmell loss exhibited increased expression of multiple inflammatory markers. IFN-γ and TNF-α weresignificantly elevated in the severe smell lossgroup (A and B). Among T2-related inflammatory mediators, IL-5 was significantly higher inthe severe smell loss group than in both controlsand the mild smell loss group (D), while IL-13was also significantly increased in the severe smellloss group compared with controls (E). ![Figure]() ### Page 8 8 Meng et al. World Allergy Organization Journal (2026) 19:101409 ![Figure]() Notably, CLC was markedly elevated in allCRSwNP subgroups (F). In addition, CCL11was significantly higher in the severe smell lossgroup than in controls and the mild smell lossgroup (G). By contrast, IL-4, IL-17A, and IL22 did not show significant differences amongthe smell loss subgroups (C, H, I). Takentogether, the subgroup, correlation, and severitystratified analyses consistently suggest that moresevere perceived olfactory dysfunction in CRSwNPis associated with a greater local inflammatoryburden in the olfactory mucosa, particularly a type2/eosinophilic pattern reflected by mediatorssuch as IL-5, CLC, and CCL11. ROC curve analysis of olfactory mucosa cytokinesfor discriminating CRSwNP patients with smellloss To further assess the discriminatory value oflocal inflammatory mediators for CRSwNPassociated olfactory impairment, ROC curve analysis was performed between control subjects(n = 13) and patients with CRSwNP who had smellloss (n = 30). Among the tested markers, CLCshowed the highest discriminatory performance,with an AUC of 0.977 (95% CI: 0.941–1.000,P < 0.001) and a cut-off value of 5.465. CCL18also showed good discriminatory ability, with anAUC of 0.851 (95% CI: 0.737–0.965, P < 0.001)and a cut-off value of 2.975. Among the T2-relatedmediators, IL-5 and CCL11 showed significantdiscriminatory performance, with AUCs of 0.733(95% CI: 0.573–0.893, P < 0.05) and 0.703 (95%CI: 0.542–0.863, P < 0.05), respectively. IL-13 alsoremained significant, although its discriminatoryperformance was lower (AUC = 0.691, 95% CI:0.518–0.864, P < 0.05). In comparison, TNF-α andIFN-γ showed AUC values of 0.780 (95% CI:0.631–0.928, P < 0.01) and 0.726 (95% CI: 0.543–0.908, P < 0.05) (). Overall, these findingssuggest that several local inflammatorymediators, particularly CLC, CCL18, IL-5, and ### Page 9 Volume 19, No. 7, Month 2026 9 ![Figure]() E. The correlation between IL-13 mRNA expression and smell loss score. F. The correlation between CLC mRNA expression and smell lossscore. G. The correlation between CCL11 mRNA expression and smell loss score. H. The correlation between IL-17A mRNA expressionand smell loss score. I. The correlation between IL-22 mRNA expression and smell loss score CCL11, have discriminatory value for distinguishing CRSwNP patients with olfactory impairmentfrom control subjects. Epithelial damage in the olfactory epithelium ofCRSwNP In the OE of the control group (n = 10), themorphology of dendrites, cell bodies, and axonsof OSNs was clearly observed (A). However,in the CRSwNP group (n = 18), the structuresabove were vague (A). Moreover, thecounting of OMP+ (P < 0.001;E) OSNswas decreased. The expression of KRT18 wasfound in all the layers of OE in the control group(B). In the OE of the CRSwNP group,KRT18 was mainly located in the middle andupper layers (B). Additionally, the countingof KRT18+ (P < 0.001;F) SUSs was decreased. HBCs were located at the bottomlayer of OE (C). Compared with the controlgroup, the number of KRT5+ (P < 0.05;G)HBCs was increased in CRSwNP patients. Thecilia were situated in the apical region of the OE(D). In the OE of CRSwNP, cilia loss wasobserved (D) and TFI of Golf (P < 0.01;H) was decreased. Tight junction disruption in the olfactoryepithelium of CRSwNP To evaluate epithelial barrier damage, immunofluorescence staining was performed in controls (n = 10) and patients with CRSwNP (n = 18),focusing on the integrity of tight junctions. Themolecular biomarkers detected were zonulaoccludens (ZO)-1, Occludin, Claudin-1, andClaudin-3. In the control and CRSwNP groups, ### Page 10 10 Meng et al. World Allergy Organization Journal (2026) 19:101409 ![Figure]() ZO-1 was localized at the apical area of OE(A) and its TFI was reduced (P < 0.01;E). Occludin was expressed in all the layersof OE in the control group (B). However, inCRSwNP, it was located at the superficial layer ofOE (B) and its TFI was decreased(P < 0.01;F). Claudin-1 was distributed atthe apical and basal layers of OE in the controlgroup (C), while the staining of Claudin-1was only found at the superficial side of OE(C) and its TFI was decreased in CRSwNP(P < 0.05;G). Similar to ZO-1, Claudin-3was distributed at the apical side of OE (D).Compared with the control group, the TFI ofClaudin-3 was reduced in the CRSwNP group(P < 0.01;H). Infiltration of immune cells in OM of CRSwNPgroup Immunofluorescence staining in controls(n = 10) and patients with CRSwNP (n = 18)showed that the cell membrane of inflammatorycells was specifically marked by CD45 (A). Compared with the control group, the CRSwNPgroup showed a marked increase in CD45+inflammatory cells in the OM (P < 0.001;E). CD3 (B) and CD4 (C)were the specific markers for T-lymphocytes andhelper T cells, respectively. In addition, thecounts of CD3+ (P < 0.001;F) Tlymphocytes and CD4+ (P < 0.01;G)helper T cells were increased in the OM ofCRSwNP group. Eosinophil major basic protein(EMBP) was specifically expressed in thecytoplasm of eosinophils (D). In the OMof patients with CRSwNP, the number ofEMBP + eosinophils was significantly increased(P < 0.001;H). ## DISCUSSION Chronic inflammation plays an important role inthe pathogenesis of CRSwNP, and different cytokine patterns are commonly used to define T1, T2,and T3 inflammatory endotypes.19–21 The cellularcomposition of OM is special, but the ### Page 11 Volume 19, No. 7, Month 2026 11 ![Figure]() inflammatory response is similar to that in themucosa of respiratory tract.22 This study usedhuman olfactory mucosal tissue to examine therelationship between local inflammation,structural changes in the olfactory epithelium. Inthis study, the central finding was that perceivedolfactory dysfunction in CRSwNP was moreclosely associated with the level of localinflammatory activity in the olfactory mucosathan with sinonasal inflammation alone.Specifically, patients with more severe smell losswere more likely to exhibit a type 2/eosinophilicinflammatory pattern, and among the mediatorsexamined, IL-5 showed the strongest positive association with the severity of olfactory dysfunction.IL-13, CLC, and CCL11 provided further supportfor a local T2 inflammatory environment linked toolfactory impairment. At the tissue level, theseinflammatory changes were accompanied byepithelial injury, abnormal repair, barrier disruption, and immune cell infiltration, supporting the view that the olfactory mucosa is an activelocal microenvironment closely associated witholfactory dysfunction in CRSwNP. Our data further suggest that the severity ofperceived olfactory dysfunction is associated withthe level of local inflammatory activity in the olfactory mucosa. Among the mediators examined, IL-5showed the most consistent association with smellloss severity, whereas IL-13, CLC, and CCL11showed similar but weaker associations. In subgroup analyses, severe smell loss was associatedwith a greater local inflammatory burden, especially increased IL-5, IL-13, CLC, and CCL11expression. IL-5 and CCL11 also showed gooddiscriminatory ability between mild and severe olfactory loss, whereas CLC differences amongseverity groups were not significant in pairwisecomparisons. These findings are consistent withprevious studies showing that inflammation in the ### Page 12 12 Meng et al. World Allergy Organization Journal (2026) 19:101409 olfactory cleft is closely associated with olfactorydysfunction.23 Increased eosinophilicinflammation and higher levels of inflammatorymediators, including CCL2, CCL11, TNF-α, IL-5,and IL-13, have been linked to poorer olfactoryfunction.24,25 Although olfactory cleft secretionsampling is minimally invasive and clinicallypractical, it is still an indirect approach, which mayexplain why previous studies detected a broaderrange of inflammatory molecules related toolfactory dysfunction.26,27 In contrast, our tissuebased analysis directly interrogated the olfactorymucosa itself and therefore provides complementary evidence by helping narrow these signals tothose more closely linked to the local diseaserelevant compartment. Importantly, despite thedifferent sampling approaches, our findings arebroadly consistent with the current olfactory cleftmucus literature, particularly in supporting a type 2/eosinophilic inflammatory pattern associated withsmell loss. In this context, the concordant associations of IL-5, CCL11, and CLC/Galectin-10 with olfactory dysfunction may be especially meaningful,as they are supported by both secretion-based andtissue-based observations. Beyond olfactory dysfunction, our results suggest that different inflammatory mediators in theolfactory mucosa may be linked to distinct symptom patterns in CRSwNP, reflecting the heterogeneity of local inflammatory pathways. IL-13was positively associated with nasal itchingscores, which is consistent with its role as a keyeffector cytokine in T2 inflammation of the upperairway and may be related to increased mucosalsensory sensitivity through neuro–immune interactions.28 By contrast, IL-17A was correlatedwith the total SNOT-22 score and postnasal drip,suggesting that T3 inflammation may be moreinvolved in overall symptom burden and impairedmucociliary clearance. Recent studies also indicate that IL-17A, rather than IL-22, can affectepithelial ciliogenesis and ciliary function, whichmay promote secretion retention and worsenpostnasal drip.29 In addition, TNF-α and IFN-γshowed negative correlations with age,indicating that local T1 inflammatory activity maydecrease with aging. The positive correlationbetween CCL18 and BMI may also indicate thatsystemic metabolic status influences the localinflammatory microenvironment. This finding isconsistent with the lipid metabolic disturbancescommonly observed in obesity and highlightsthe need to consider body weight and metabolicstatus in comprehensive disease management.30Overall, inflammation in the olfactory mucosa ofCRSwNP appears to involve multiple pathways, ![Figure]() ### Page 13 Volume 19, No. 7, Month 2026 13 ![Figure]() F. Total fluorescence intensity of Occludin. G. Total fluorescence intensity of Claudin-1. H. Total fluorescence intensity of Claudin-3.Controls (n = 10), CRSwNP (n = 18). *P < 0.05, **P < 0.01, ***P < 0.001. Scale bar = 20 μm and different inflammatory mediators maycontribute to symptom development throughdistinct mechanisms. Another important finding was that the severityof olfactory dysfunction differed across inflammatory endotypes and patient subgroups. Severeimpairment was more common in patients with T2inflammatory pattern, eosinophilic CRSwNP, andolder age, whereas allergic status, asthma,recurrence, sex, and smoking status were notsignificantly associated with olfactory severity.These results suggest that olfactory dysfunction inCRSwNP is less related to routine clinical featuresand more influenced by local inflammatoryendotypes and age-related susceptibility. Thisobservation may help explain why some patientsshow marked improvement in smell after treatment with corticosteroids or biologics, whileothers have limited recovery. In the former group,olfactory loss may mainly result from reversibleinflammatory changes; when T2 inflammation isreduced, improvement of the local microenvironment may allow olfactory function torecover.31 In contrast, patients with poor recoverymay have persistent structural damage of theolfactory mucosa, including changes in the localmicroenvironment, epithelial remodeling, and reduced regenerative capacity.32–34 In summary,olfactory dysfunction in CRSwNP may involve 2related processes: one is a relatively reversibleloss of function caused by inflammation, and theother is a more persistent impairmentassociated with epithelial damage and abnormalrepair. To further explain why some patients may notachieve full olfactory recovery even after localinflammation is reduced, we next examined thestructural basis of olfactory dysfunction in the olfactory epithelium. Normal olfactory function depends on the coordinated integrity of olfactorysensory neurons (OSNs), sustentacular cells(SUSs), basal progenitor cells, and the apicalciliary layer. Although no well-established mousemodel fully recapitulates CRSwNP, experimentalmodels of sinonasal and olfactory inflammationhave consistently shown that increased inflammatory cytokine production, immune cell infiltration, and epithelial structural injury contribute toOSN loss, SUS damage, and impaired olfactorysignaling.35,36 HBCs serve as a reserve stem/progenitor cell population in the OE, with potentself-renewal, proliferation and differentiationproperties. The damaged epithelial cell components such as OSNs and SUSs can be replenished ### Page 14 14 Meng et al. World Allergy Organization Journal (2026) 19:101409 ![Figure]() through HBC-mediated regeneration. Long-terminflammatory stimulation has been shown to increase HBC abundance while blocking their differentiation, shifting their role from epithelialregeneration toward NF-κB-mediated immunedefense.32 Furthermore, the regeneration anddifferentiation in HBCs were strictly regulated bythe transcription factors, p63 and Notch1.37,38 Inour study, reduced numbers of OMP-positive olfactory sensory neurons and KRT18-positive sustentacular cells suggested injury to matureolfactory epithelial cells, while increased KRT5positive horizontal basal cells indicated abnormalrepair or regenerative stress under chronicinflammation. Decreased Golf expression in the apical ciliary layer further suggested impaired olfactory signal transduction. Together, these findings suggest that prolonged inflammation maydrive the olfactory epithelium from normal maintenance and regeneration toward injury responseand inefficient repair,32 which may help explainwhy olfactory function does not fully recover insome patients even after inflammation iscontrolled. In addition to neuroepithelial injury andabnormal repair, barrier dysfunction may furthercontribute to persistent olfactory impairment.Tight junction proteins, including ZO-1, Occludin,and Claudins, are essential for maintaining ### Page 15 Volume 19, No. 7, Month 2026 15 epithelial cohesion and limiting inflammatoryinjury.39 IL-17C was significantly up-regulated inmice treated by Poly(I:C), which contributed toinfiltration of immune cells and destroying the TJsof OM by downregulating the expression levels ofZO-1, Claudin-1 and Claudin-11.40 In addition,chemokine-mediated recruitment of immunecells is an important feature of inflammatory disease progression. CCL11 and CCL18 have beenshown to recruit eosinophils and lymphocytes.41,42 Consistent with these findings,previous studies reported more severe olfactoryepithelial damage and more prominenteosinophil infiltration in CRS patients witholfactory dysfunction, while single-cellsequencing further suggested that lymphocytesand macrophages may also contribute toinflammation-related olfactory dysfunction.43,44This study showed that ZO-1, Occludin, Claudin1, and Claudin-3 were significantly reduced inthe olfactory epithelium of patients with CRSwNP,indicating disruption of tight junction integrity.Given the specialized structure and neural function of the olfactory region, such barrier disruptionmay increase tissue vulnerability to inflammatoryinjury. Together with epithelial remodeling, thisprocess may contribute to the fragility of the olfactory mucosa and the persistence of chronicolfactory dysfunction. Furthermore, we observed marked infiltration ofCD45+ leukocytes, CD3+ T cells, CD4+ T cells, andeosinophils in the olfactory mucosa of patients withCRSwNP. Although the presence of eosinophils andT cells has been reported previously in CRSwNP, therelevance of our findings lies in their localizationwithin the olfactory mucosa, where they coexist withepithelial injury, impaired barrier integrity, and olfactory epithelial alterations.This spatially restrictedinflammatory pattern suggests that the olfactorymucosa is not merely passively affected by generalized sinonasal inflammation, but may serve as alocal inflammatory microenvironment directlyrelated to olfactory dysfunction. In this context, immune cell infiltration may not only reflect ongoinglocal inflammation, but also contribute to tissueremodeling, epithelial fragility, and the persistenceof smell loss. Several limitations of this study should beacknowledged. First, olfactory function was evaluated mainly by symptom-based measures rather than standardized psychophysical olfactorytesting. Although symptom scores can reflectpatient-perceived disease burden, they are lesssensitive and less reliable than objective olfactoryassessment and therefore may not fully capturethe severity of olfactory impairment. Second, thiswas a single-center cross-sectional study with arelatively limited sample size, which may restrictthe generalizability of our findings. Third, althoughthe sampling site was carefully defined underendoscopic guidance and supported by characteristic olfactory epithelial markers, regional heterogeneity of the human olfactory mucosa cannotbe completely excluded. In addition, the absenceof longitudinal follow-up prevented evaluation ofhow local inflammatory changes, epithelial injury,and barrier dysfunction evolve over time or relateto treatment response and olfactory recovery.Finally, because the present study was designedas a tissue-based analysis, olfactory cleft secretionsamples were not available for parallel validation.Future studies incorporating standardized objective olfactory testing, parallel tissue and secretionsampling, larger multicenter cohorts, and longitudinal assessment will be important to furtherclarify the role of local olfactory mucosal pathology in CRSwNP-associated olfactory dysfunction. ## CONCLUSION In conclusion, our study identified several molecular and histopathological features of the olfactory mucosa in patients with CRSwNP,including increased expression of inflammatorymediators, olfactory epithelial injury, tight junctiondisruption, and immune cell infiltration. Amongthe inflammatory mediators examined, IL-5showed the clearest association with smell lossseverity, while CLC and CCL11 may serve ascomplementary indicators of local inflammatoryactivity. These findings help refine the interpretation of CRSwNP-associated olfactory dysfunctionas a locally driven inflammatory and structuralprocess within the olfactory mucosa. Furtherin vivo studies are needed to verify the underlyingmolecular mechanisms and to support the development of more effective therapeutic strategiesfor patients with CRSwNP Abbreviations CRSwNP, chronic rhinosinusitis with nasal polyps; CRS,chronic rhinosinusitis; OD, olfactory dysfunction; OM, ### Page 16 16 Meng et al. World Allergy Organization Journal (2026) 19:101409 olfactory mucosa; OE, olfactory epithelium; OSNs,olfactory sensory neurons; SUSs, sustentacular cells; HBCs,horizontal basal cells; OMP, olfactory marker protein; TNFα, tumor necrosis factor-α; IFN-γ, interferon-γ; IL,interleukin; CLC, Charcot–Leyden crystal galectin; CCL, CC motif chemokine ligand; ZO-1, zonula occludens-1; qRTPCR, quantitative real-time polymerase chain reaction; IF,immunofluorescence; FESS, functional endoscopic sinussurgery; VAS, visual analogue scale; SNOT-22, 22-itemSino-Nasal Outcome Test; ROC, receiver operating characteristic; AUC, area under the curve. ## Funding This work was supported by grants from theNatural Science Foundation of China (No.82371117). ## Data availability All data generated or analyzed during this study areincluded in this published article and its supplementaryinformation files. ## Author contributions All authors made a significant contribution to the workreported, whether that is in the conception, study design,execution, acquisition of data, analysis and interpretation,or in all these areas; they took part in drafting, revising orcritically reviewing the article; gave final approval of theversion to be published; have agreed on the journal towhich the report has been submitted; and agree to beaccountable for all aspects of the work. Ethics approval We briefed all participants in detail on the samplecollection process, and all participants provided writteninformed consent following the declaration of Helsinki. Allprocedures in this study related to human participantsfollowed the ethical standards of the institutional and/ornational research committees. The approval of this studywas obtained from the institutional review committee ofthe participating hospitals (China approval number: XYK20210703). ## Declaration of competing interests The authors declare that they have no competing interests. Disclosure statement The authors declare that the research was conductedwithout any commercial or financial relationshipsconstrued as a potential conflict of interest. Declaration of Generative AI and AI-assisted technologiesin the writing process We confirm that no generative artificial intelligence (AI) orAI-assisted tools were used in the writing or editing of thismanuscript. Nothing to disclose. Appendix A. Supplementary data Supplementary data to this article can be found online at. Author details aDepartment of Otolaryngology-Head and Neck Surgery,Shandong Provincial ENT Hospital, Shandong University,Jinan, Shandong, China.bShandong Provincial Key Medical and Health Discipline of Allergy, ShandongSecond Provincial General Hospital, Jinan, Shandong,China.cDepartment of Otolaryngology-Head and NeckSurgery, Liaocheng Hospital of Traditional ChineseMedicine, Liaocheng, Shandong, China. REFERENCES ## 1. Kato A, Peters AT, Stevens WW, Schleimer RP, Tan BK, Kern RC. Endotypes of chronic rhinosinusitis: relationships todisease phenotypes, pathogenesis, clinical findings, andtreatment approaches. Allergy. 2022;77(3):812–826. - 2. Xu X, Reitsma S, Wang Y, Fokkens WJ. Highlights in the advancesof chronic rhinosinusitis. Allergy. 2021;76(11):3349–3358. - 3. Stevens WW, Peters AT, Tan BK, et al. Associations betweeninflammatory endotypes and clinical presentations in chronicrhinosinusitis. J Allergy Clin Immunol Pract. 2019;7(8):2812–2820.e2813. - 4. Hummel T, Whitcroft KL, Andrews P, et al. Position paper onolfactory dysfunction. Rhinology. 2016;56(1):1–30. - 5. Macchi A, Giorli A, Cantone E, et al. Sense of smell in chronicrhinosinusitis: a multicentric study on 811 patients. FrontAllergy. 2023;4, 1083964. - 6. Song J, Wang M, Wang C, Zhang L. Olfactory dysfunction inchronic rhinosinusitis: insights into the underlyingmechanisms and treatments. Expert Rev Clin Immunol.2023;19(8):993–1004. - 7. Jung AY, Kim YH. Reversal of olfactory disturbance in allergicrhinitis related to OMP suppression by intranasal budesonidetreatment. Allergy Asthma Immunol Res. 2020;12(1):110–124. - 8. Chen M, Shen W, Rowan NR, et al. Elevated ACE-2 expressionin the olfactory neuroepithelium: implications for anosmia andupper respiratory SARS-CoV-2 entry and replication. EurRespir J. 2020;56(3). - 9. Joiner AM, Green WW, McIntyre JC, Allen BL, Schwob JE,Martens JR. Primary cilia on horizontal basal cells regulateregeneration of the olfactory epithelium. J Neurosci.2015;35(40):13761–13772. - 10. Bryche B, St Albin A, Murri S, et al. Massive transient damageof the olfactory epithelium associated with infection ofsustentacular cells by SARS-CoV-2 in golden Syrian hamsters.Brain Behav Immun. 2020;89:579–586. - 11. AlBader A, Levine CG, Casiano RR. Does endoscopic sinussurgery improve olfaction in nasal polyposis? Laryngoscope.Oct 2017;127(10):2203–2204. - 12. Mullol J, Mariño-Sánchez F, Valls M, Alobid I, Marin C. Thesense of smell in chronic rhinosinusitis. J Allergy ClinImmunol. 2020;145(3):773–776. - 13. Lavin J, Min JY, Lidder AK, et al. Superior turbinate eosinophiliacorrelates with olfactory deficit in chronic rhinosinusitis patients.Laryngoscope. 2017;127(10):2210–2218. - 14. Saraswathula A, Liu MM, Kulaga H, Lane AP. Chronicinterleukin-13 expression in mouse olfactory mucosa resultsin regional aneuronal epithelium. Int Forum Allergy Rhinol.2023;13(3):230–241. - 15. Borders AS, Getchell ML, Etscheidt JT, van Rooijen N,Cohen DA, Getchell TV. Macrophage depletion in the murineolfactory epithelium leads to increased neuronal death and ### Page 17 Volume 19, No. 7, Month 2026 17 decreased neurogenesis. J Comp Neurol. Mar 102007;501(2):206–218. - 16. Hao D, Wu Y, Li P, et al. An integrated analysis of inflammatoryendotypes and clinical characteristics in chronic rhinosinusitiswith nasal polyps. J Inflamm Res. 2022;15:5557–5565. - 17. Wu Y, Sun K, Tu Y, et al. miR-200a-3p regulates epithelialmesenchymal transition and inflammation in chronicrhinosinusitis with nasal polyps by targeting ZEB1 via ERK/p38pathway. Int Forum Allergy Rhinol. 2024;14(1):41–56. - 18. Fokkens WJ, Lund VJ, Hopkins C, et al. European positionpaper on rhinosinusitis and nasal polyps 2020. Rhinology.2020;58(Suppl S29):1–464. - 19. Klingler AI, Stevens WW, Tan BK, et al. Mechanisms andbiomarkers of inflammatory endotypes in chronicrhinosinusitis without nasal polyps. J Allergy Clin Immunol.2021;147(4):1306–1317. - 20. Wang M, Bu X, Luan G, et al. Distinct type 2-high inflammationassociated molecular signatures of chronic rhinosinusitis withnasal polyps with comorbid asthma. Clin Transl Allergy.2020;10:26. - 21. Delemarre T, Holtappels G, De Ruyck N, et al. Type 2inflammation in chronic rhinosinusitis without nasal polyps:another relevant endotype. J Allergy Clin Immunol.2020;146(2):337–343.e336. - 22. Kern RC. Chronic sinusitis and anosmia: pathologic changes inthe olfactory mucosa. Laryngoscope. 2000;110(7):1071–1077. - 23. Wu D, Liu Z, Bleier BS, Huang X, Hong J. Olfactory cleft mucuseosinophil-derived neurotoxin better reflects olfactory loss thanblood eosinophil counts in patients with chronic rhinosinusitis.Int Forum Allergy Rhinol. Dec 2023;13(12):2144–2155. - 24. Han X, Wu D, Sun Z, et al. Type 1/type 2 inflammatorycytokines correlate with olfactory function in patients withchronic rhinosinusitis. Am J Otolaryngol. 2020;41(5), 102587. - 25. Soler ZM, Yoo F, Schlosser RJ, et al. Correlation of mucusinflammatory proteins and olfaction in chronic rhinosinusitis.Int Forum Allergy Rhinol. 2020;10(3):343–355. - 26. Soler ZM, Schlosser RJ, Bodner TE, et al. Endotyping chronicrhinosinusitis based on olfactory cleft mucus biomarkers.J Allergy Clin Immunol. 2021;147(5):1732–1741.e1731. - 27. Yoo F, Soler ZM, Mulligan JK, et al. Olfactory cleft mucusproteins associated with olfactory dysfunction in a cohortwithout chronic rhinosinusitis. Int Forum Allergy Rhinol.2019;9(10):1151–1158. - 28. Bousquet J, Anto JM, Bachert C, et al. Allergic rhinitis. Nat RevDis Primers. 2020;6(1):95. - 29. Qiu H, Liu J, Wu Q, et al. An in vitro study of the impact of IL17A and IL-22 on ciliogenesis in nasal polyps epithelium viathe Hippo-YAP pathway. J Allergy Clin Immunol. 2024;154(5):1180–1194. - 30. Mora g B, Kozubek P, Gomułka K. Obesity and selected Î allergic and immunological diseases-etiopathogenesis, course and management. Nutrients. 2023;15(17). - 31. Hara Y, Jha MK, Huang JY, et al. The IL-4-IL-4Rα axismodulates olfactory neuroimmune signaling to induce loss ofsmell. Allergy. 2025;80(2):440–461. - 32. Chen M, Reed RR, Lane AP. Chronic inflammation directs anolfactory stem cell functional switch from neuroregenerationto immune defense. Cell Stem Cell. 2019;25(4):501–513.e505. - 33. Chang SY, Glezer I. The balance between efficient antiinflammatory treatment and neuronal regeneration in theolfactory epithelium. Neural Regen Res. 2018;13(10):1711–1714. - 34. Han X, He X, Zhan X, et al. Disturbed microbiota-metabolitesimmune interaction network is associated with olfactorydysfunction in patients with chronic rhinosinusitis. FrontImmunol. 2023;14, 1159112. - 35. Yeh CF, Huang WH, Lan MY, Hung W. Lipopolysaccharideinitiated rhinosinusitis causes neuroinflammation andolfactory dysfunction in mice. Am J Rhinol Allergy. 2023;37(3):298–306. - 36. Kanaya K, Kondo K, Suzukawa K, et al. Innate immuneresponses and neuroepithelial degeneration andregeneration in the mouse olfactory mucosa induced byintranasal administration of Poly(I:C). Cell Tissue Res.2014;357(1):279–299. - 37. Schnittke N, Herrick DB, Lin B, et al. Transcription factor p63controls the reserve status but not the stemness of horizontalbasal cells in the olfactory epithelium. Proc Natl Acad Sci USA.Sep 8 2015;112(36):E5068–E5077. - 38. Herrick DB, Lin B, Peterson J, Schnittke N, Schwob JE. Notch1maintains dormancy of olfactory horizontal basal cells, areserve neural stem cell. Proc Natl Acad Sci USA. Jul 112017;114(28):E5589–E5598. - 39. Otani T, Furuse M. Tight junction structure and functionrevisited. Trends Cell Biol. 2020;30(10):805–817. - 40. Bryche B, Dewaele A, Saint-Albin A, Le Poupon Schlegel C,Congar P, Meunier N. IL-17c is involved in olfactory mucosaresponses to Poly(I:C) mimicking virus presence. Brain BehavImmun. 2019;79:274–283. - 41. Nazarinia D, Behzadifard M, Gholampour J, Karimi R,Gholampour M. Eotaxin-1 (CCL11) in neuroinflammatorydisorders and possible role in COVID-19 neurologiccomplications. Acta Neurol Belg. 2022;122(4):865–869. - 42. Tsicopoulos A, Chang Y, Ait Yahia S, de Nadai P,Chenivesse C. Role of CCL18 in asthma and lung immunity.Clin Exp Allergy. 2013;43(7):716–722. - 43. Yee KK, Pribitkin EA, Cowart BJ, et al. Neuropathology of theolfactory mucosa in chronic rhinosinusitis. Am J RhinolAllergy. 2010;24(2):110–120. - 44. Durante MA, Kurtenbach S, Sargi ZB, et al. Single-cell analysisof olfactory neurogenesis and differentiation in adult humans.Nat Neurosci. 2020;23(3):323–326.