Gene-Expression Signatures of Nasal Polyps Associated With Chronic Rhinosinusitis and Aspirin-Sensitive Asthma

Michael Platt; Ralph Metson; Konstantina Stankovic

Disclosures

Curr Opin Allergy Clin Immunol. 2009;9(1):23-28. 

In This Article

Gene-expression Profiling in Nasal Polyps

Gene-expression profiling is a method of monitoring expression of thousands of genes simultaneously on a glass slide called a microarray. The microarray technology has revolutionized the field of genetic analysis, making it possible to define patterns of gene expression, that is, expression signatures, which are unique to a given biological state. The power of expression signatures is two-fold: the enormous complexity of the expression data provides the opportunity to identify patterns of expression that reflect different and novel phenotypic subgroups with distinct biology and expression signatures can be assayed in varied contexts, including human tissue and experimentally manipulated in-vitro systems, which facilitates mechanistic insights by connecting the experimental state with the in-vivo state.[5••] When applied to nasal polyps, gene-expression profiling has a potential to define expression signatures that characterize patient subgroups within the currently heterogeneous clinical groups, predict response to various treatments, and offer novel therapeutic targets.

Several reports[6,7,8,9,10,11] have applied microarray technology to sinonasal tissues to examine expression of either a limited set of genes within small patient populations or to assay the entire human genome in small[12,13] or moderately sized[14•] populations. These studies are summarized in Table 1 , which outlines distinct patient populations that have been analyzed, and genes that have been highlighted as potentially pathogenic. The wide-ranging and typically nonoverlapping results seen in these studies reflect heterogeneity of the studied populations, effects of therapeutic medications, differences in the number of analyzed genes, diversity in the statistical and bioinformatic rigor with which data were analyzed, and disparity in the methods and extent of data validation. The challenge has been to obtain meaningful results from a large volume of data generated by relatively small patient populations. We classify the genes that have been identified as potentially pathogenic into four groups on the basis of their distinct biological roles: genes that play a role in growth and development, genes-encoding cytokines, genes with immune functions, and genes with other or unknown functions.

Mesenchymal-epithelial transition (MET) factor, periostin and protein phosphatase 1 regulatory subunit 9B (PP1R9B) emerged as key genes whose increased expression characterized patients with severe CRS.[14•] Transforming growth factor beta 1 (TGFβ1) was highlighted in a study of nonallergic polyps.[7]

Periostin is a potent regulator of fibrosis and collagen deposition,[15] and overexpression of periostin has been associated with accelerated cell growth, reentry into the cell cycle,[16] and angiogenesis.[17] Upregulation of periostin has also been identified in polyps of patients with ASA[14•] and in airway epithelial cells of patients with asthma.[18•] Downregulation of periostin after treatment of asthmatic patients with corticosteroids[18•] suggests that normalization of periostin expression is a part of the therapeutic effects of corticosteroids. This opens a possibility of specifically targeting periostin in future therapies for nasal polyps and asthma. The relevance of the same drug for diseases of both the upper and lower respiratory tract is consistent with the unified airway theory,[19•] which proposes that common genetic and environmental factors similarly affects the entire respiratory tract.

MET encodes a tyrosine kinase membrane receptor with a high affinity for hepatocyte growth factor (HGF).[20]MET plays an important role in cell growth processes, including wound healing, regeneration, and angiogenesis, as well as morphogenic differentiation processes such as embryonic development, cell migration, and metastasis.[21,22,23,24,25]MET and HGF have been shown to be deregulated in a number of major cancers.[22,26,27] Nicotine and cigarette smoke affect expression of the HGF/MET pathway in the lung.[28] By evoking the unified airway theory, altered MET signaling may underlie negative effects of cigarette smoking on sinusitis. Increased expression of MET in polyps associated with CRS but not ASA[14•] suggests that putative therapeutic strategies aimed at interfering with the HGF/MET pathway[29] may be effective against a subset of nasal polyps.

PP1R9B is a ubiquitously expressed gene that plays a role in cell growth and molecular scaffolding.[30] The existing protein phosphatase 1 inhibitors[31] offer potential novel treatments for CRS.

TGFβ1 is a potent regulator of extracellular matrix, and it is expressed in eosinophils and nasal polyp tissue.[32] Peptide inhibitors of TGFβ1 have been shown to alter immune function in regulatory T-cell activity,[33] and may be useful in decreasing the immune dysregulation in CRS.

Cytokines are soluble signaling proteins, which include interleukins and chemokines. Gene-expression profiling of nasal polyps associated with CRS has identified three interleukins with increased expression in polyps: IL-5,[7]IL-17,[6] and IL-18.[13]IL-5 is a potent chemoattractant and inhibitor of apoptosis in eosinophils. There is a strong correlation between the degree of tissue eosinophilia and the severity of CRS [34]so that eosinophils are thought to be involved in polyp formation.[35]IL-5 release from nasal polyps has been shown to be induced by Staphylococcus aureus enterotoxin B,[36•] suggesting a mechanism by which infection contributes to CRS. IL-17 is a proinflammatory cytokine that is secreted by T cells and upregulated in asthma.[37] IL-8 is a chemotaxic agent for leukocytes.

Therapies directed against these specific interleukins are not available. However, a variety of treatments that target the inflammatory cascade, including topical corticosteroids[38] and immunotherapies[39] have resulted in immunomodulation of cytokines. Oral corticosteroid treatment effected chemokine and leukotriene receptor gene expression in sinonasal polyps, including alteration of chemokine (C-C motif) receptor 2 (CCR2), CCR5, chemokine (C-X3-C motif) ligand 1 (CX3CL1), and leukotriene B4 receptor (LTB4R).[8]

Consistent with the view that altered immune function contributes to development of nasal polyps,[40•] gene-expression studies of nasal polyps associated with CRS,[11,12,14•] ASA,[14•] or eosinophilic mucin rhinosinusitis,[9] a variant of CRS similar to allergic fungal sinusitis, have identified several genes with immune functions. These genes include prolactin-induced protein (PIP),[11,14•] lactoferrin,[11] deleted in malignant brain tumor protein 1 (DMBPT1),[11] sialyltransferase 1,[9] uteroglobin (CC10),[11,12] and zinc-alpha-2-glycoprotein (AZGP1).[14•]

PIP encodes a protein that is secreted by various apocrine glands, and has been implicated in host defense against infections and tumor immunity.[41,42] Lactoferrin is an iron-binding protein involved in innate immunity and found in exocrine secretions.[43]DMBT1 is a bacterial-binding protein involved in innate immunity. Sialyltransferase is thought to be involved in B-cell activation and humoral immunity.[44] Uteroglobin is thought to be an anti-inflammatory and immunomodulatory molecule.[45] Uteroglobin was found to be expressed at low levels in CRS polyps,[11] and the expression levels were increased after prolonged intranasal steroid treatment.[12]AZGP1 is a member of major histocompatibility complex class I genes, and its expression is regulated by glucocorticoids.[46] Decreased expression of AZGP1 in nasal polyps associated with CRS and ASA,[14•] along with the demonstration that corticosteroids stimulate AZGP1 protein production in other tissues,[47] suggests that AZGP1 deficiency may contribute to nasal polyps. Therefore, novel therapies targeted to specifically increase AZGP1 expression may help treat nasal polyps.

Liu et al.[11] found increased expression of PIP, lactoferrin, and DMBT1 in polyps of patients with CRS and ASA, whereas Stankovic et al.[14•] found decreased expression of the same genes in a different and larger cohort of patients with CRS and ASA. Differences in the reported results may reflect methodological and demographic differences, including the inflammatory status of the control tissue and use of intranasal steroids.

Genes involved in signal transduction have been identified in nasal polyps associated with CRS[13] or eosinophilic mucin rhinosinusitis,[9] including RGS1[13] and S100.[9] Ganglioside activator protein, GM2, which binds and transports lipids, was increased in eosinophilic mucin rhinosinusitis.[9] Statherin, a gene involved in maintenance of mineral homeostasis and described in nasal secretions,[48] was expressed at high levels in CRS and ASA.[11]

Increased expression of mammaglobin was found in polyps of patients with allergic rhinitis compared with allergic rhinitis patients without polyps,[10] and expression levels of mammaglobin in CRS polyps were increased after a prolonged course of intranasal steroids.[12] Mammaglobin encodes a protein of unknown function; the gene is mapped to chromosome 11q12.3-q13.1.3,[49] which is in close proximity to the beta subunit of the IgE receptor. Mammaglobin is related to epithelia secretory proteins (including uteroglobin) that modulate inflammation[50] and bind steroids,[51] suggesting a possible role in the mechanisms by which corticosteroids decrease polyp load.

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