Distinct type 2-high inflammation associated molecular signatures of chronic rhinosinusitis with nasal polyps with comorbid asthma

Abstract

Background: Patients with chronic rhinosinusitis with nasal polyps (CRSwNP) and comorbid asthma have more severe disease and are difficult to treat. However, the molecular endotypes associated with CRSwNP with comorbid asthma (CRSwNP + AS) are not clear. This study aimed to investigate the characteristics of type 2 inflammation and the molecular signatures associated with CRSwNP + AS. Methods: A total of 195 subjects; including 65 CRSwNP + AS patients, 99 CRSwNP-alone patients, and 31 healthy control subjects; were enrolled in the study. Nasal tissues from patients with CRSwNP + AS, CRSwNP-alone and control subjects were assessed for infiltration of inflammatory cells and concentrations of total IgE. Whole-transcriptome sequencing was performed and differentially expressed (DE) mRNAs and long non-coding RNAs (lncRNAs) and their associated pathways were analyzed. The correlations between type 2 cytokines and local eosinophils, tissue IgE, and transcriptome signatures were evaluated. Results: Significantly higher local eosinophil infiltration and higher levels of total IgE were found in nasal tissues from CRSwNP + AS patients than in nasal tissues from CRSwNP-alone patients. Furthermore, atopy and recurrence were significantly more frequent in patients with CRSwNP + AS than in patients with CRSwNP-alone (62.5% vs 28.6% and 66.7% vs 26.9%, respectively). RNA sequencing analysis identified 1988 common DE-mRNAs, and 176 common DE-lncRNAs shared by CRSwNP + AS versus control and CRSwNP-alone versus control. Weighted gene coexpression network analysis (WGCNA) identified LINC01146 as hub lncRNA dysregulated in both subtypes of CRSwNP. Overall, 968 DE-mRNAs and 312 DE-lncRNAs were identified between CRSwNP + AS and CRSwNP-alone. Both pathway enrichment analysis and WGCNA indicated that the phenotypic traits of CRSwNP + AS were mainly associated with higher activities of arachidonic acid metabolism, type 2 cytokines related pathway and fibrinolysis pathway, and lower activity of IL-17 signalling pathway. Furthermore, the expression of type 2 cytokines; IL5 and IL13, was positively correlated with local eosinophil infiltration, tissue IgE level, and the expression of DE-mRNAs that related to arachidonic acid metabolism. Moreover, WGCNA identified HK3-006 as hub lncRNA in yellow module that most positively correlated with phenotypic traits of CRSwNP + AS.

Transcriptional Changes in Chronic Rhinosinusitis with Asthma Favor a Type 2 Molecular Endotype Independent of Polyp Status

“… 20 , 26 IKBKB has been shown to be upregulated in patients with asthma, 16 , 20 and prior CRS data has shown a similar overrepresentation of type 2 inflammation in CRSwNP-A compared to CRSwNP. 4 , 18 , 19 , 25 At the same time, in the present cohort, upregulation of these genes associated with type 2 inflammation was complemented by a simultaneous downregulation of genes associated with type 1 and type 3 inflammation. For example, compared to CRSwNP, patients with CRSwNP-A demonstrated downregulation of genes associated with Th17 differentiation ( MAPK11 ) 27 and Th1 signaling ( PSMB8 and B2M ).…”

“…In contrast, cytokine profiles typically associated with CRSsNP can present as a mixture of type 1 (Th1 cell-mediated), Th2, and type 3 (Th17 cell-mediated) inflammation. 4 , 7 These inflammatory endotypes themselves are influenced by molecular endotypes and associated upstream transcriptional changes that occur in these disease cohorts. 4 Despite this, there is currently very limited data on molecular endotypes among patients with CRS with asthma (CRS-A), with no studies examining this topic in patients with CRSsNP and asthma (CRSsNP-A).…”

“…3 CRS is subtyped by phenotype [ie, CRS without nasal polyposis (CRSsNP) vs CRS with nasal polyposis (CRSwNP)], as well as by molecular and inflammatory endotypes. 4 These subtypes are important to consider as they provide us with some information regarding prognosis. CRSwNP is known to present with greater disease severity and higher recurrence rates compared to CRSsNP.…”

“…CRSwNP is known to present with greater disease severity and higher recurrence rates compared to CRSsNP. [4][5][6] Historically, CRSwNP has been more closely linked to asthma, with initial findings demonstrating a similar inflammatory milieu in patients with asthma and those with CRSwNP, 4 having a cytokine profile heavily dominated by a type 2 (Th2 cell-mediated) inflammatory response.…”

The Role of Biologics in Chronic Rhinosinusitis With Nasal Polyps

“…Wang and colleagues observed that subjects with combined CRSwNP and asthma endotype have more severe T2 inflammatory patterns compared to CRSwNP-alone endotype based on findings from whole-transcriptome RNA sequencing. 35 Based on this evidence, systemic biologic therapy in patients with both upper and lower airway disease may be a reasonable consideration as it can improve both conditions due to shared pathogenic pathways.…”