Gene Transcription Changes in Asthmatic Chronic Rhinosinusitis with Nasal Polyps and Comparison to Those in Atopic Dermatitis

Abstract

BackgroundAsthmatic chronic rhinosinusitis with nasal polyps (aCRSwNP) is a common disruptive eosinophilic disease without effective medical treatment. Therefore, we sought to identify gene expression changes, particularly those occurring early, in aCRSwNP. To highlight expression changes associated with eosinophilic epithelial inflammation, we further compared the changes in aCRSwNP with those in a second eosinophilic epithelial disease, atopic dermatitis (AD), which is also closely related to asthma.Methods/Principal FindingsGenome-wide mRNA levels measured by exon array in both nasosinus inflamed mucosa and adjacent polyp from 11 aCRSwNP patients were compared to those in nasosinus tissue from 17 normal or rhinitis subjects without polyps. Differential expression of selected genes was confirmed by qRT-PCR or immunoassay, and transcription changes common to AD were identified. Comparison of aCRSwNP inflamed mucosa and polyp to normal/rhinitis tissue identified 447 differentially transcribed genes at ≥2 fold-change and adjusted p-value<0.05. These included increased transcription of chemokines localized to chromosome 17q11.2 (CCL13, CCL2, CCL8, and CCL11) that favor eosinophil and monocyte chemotaxis and chemokines (CCL18, CCL22, and CXCL13) that alternatively-activated monocyte-derived cells have been shown to produce. Additional transcription changes likely associated with Th2-like eosinophilic inflammation were prominent and included increased IL1RL1 (IL33 receptor) and EMR1&3 and decreased CRISP2&3. A down-regulated PDGFB-centric network involving several smooth muscle-associated genes was also implicated. Genes at 17q11.2, genes associated with alternative activation or smooth muscle, and the IL1RL1 gene were also differentially transcribed in AD.Conclusions/SignificanceOur data implicate several genes or gene sets in aCRSwNP and eosinophilic epithelial inflammation, some that likely act in the earlier stages of inflammation. The identified gene expression changes provide additional diagnostic and therapeutic targets for aCRSwNP and other eosinophilic epithelial diseases.

IL-33–Responsive Innate Lymphoid Cells Are an Important Source of IL-13 in Chronic Rhinosinusitis with Nasal Polyps

“…We demonstrated elevated expression of ST2 in inflamed ethmoid sinus mucosa from patients with CRSwNP compared with CRSsNP and HC, which complements previously published microarray data indicating that ST2 expression is up-regulated in diseased mucosa from patients with asthma with CRSwNP compared with HC (29). We showed that ST2 is expressed on a lineage neg CD127…”

Gene transcription abnormalities in canine atopic dermatitis and related human eosinophilic allergic diseases

“…This included increased transcription of genes associated with so-called alternatively activated monocyte-derived cells (aaMDCs) such as ARG1, members of the monocyte chemotactic protein (MCP) gene cluster (CCL2, CCL7, and CCL8), CCL17, CHI3L1, CLEC4G, and TFEC (Table 1 and Tables S2 and/or S4), and most of these are also expressed by human aaMDCs (Martinez et al, 2009). While the precise structure and particular genes comprising the MCP gene cluster varies somewhat between dogs (chromosome 9) and humans (chromosome 17q11.2), the MCP gene cluster appears important in the early inflammatory response of human eosinophilic allergic disease (Plager et al, 2010). Most recently, the importance of mouse CCL8 in the recruitment of IL5 + Th2 cells and in cutaneous eosinophilic inflammation also has been demonstrated (Islam et al, 2011).…”

“…Eosinophils appear to contribute to allergic disease pathology, and our recent analyses of human aCRSwNP showed increased transcription of the G-protein coupled receptors EMR1 and EMR3 (Plager et al, 2010), which are preferentially expressed by eosinophils (Hamann et al, 2007). The orthologous EMR1 and EMR3 genes in dogs also showed increased transcription in canine AD (Table 1 and Tables S2 and S5).…”

“…a combined list) from the two AD to normal skin comparisons was generated. A similar list of differentially transcribed genes from the comparison of aCRSwNP to normal/rhinitis nasosinus tissue (Fc ≥ 2.0 and corrected p -value ≤0.05) was also used (Plager et al, 2010). Finally, a union set of the differentially transcribed genes identified here by comparing ALAD and Normal, NLAD and Normal, or ALAD and NLAD skin from dogs was generated (Fc ≥ 2.0 and corrected p -value ≤0.1), and this union set list from canine AD skin was compared to the Gene Symbol lists of differentially transcribed genes from human AD or aCRSwNP.…”

“…Because identifying and controlling events relatively early in the inflammatory process is appealing, both acute lesional and nearby visibly nonlesional AD skin from dogs were analyzed here and compared to healthy skin from dogs using microarrays. Subsequent comparisons of these data to human AD (Olsson et al, 2006; Plager et al, 2007) and asthmatic chronic rhinosinusitis with nasal polyps (aCRSwNP) (Plager et al, 2010) data were performed to identify molecular networks common to canine AD and human eosinophilic allergic disease.…”