Asthma affects an estimated 300 million people worldwide and represents an important challenge for basic science to benefit clinical medicine. Recently, two independent meta-analysis of genome wide association studies GWAS data have identified the genes encoding the IL-1? family cytokine, IL-33, and its receptor, IL1RL1 (ST2), as susceptibility loci for asthma. A plethora of functions have been attributed to IL-33 including activation of type-2 innate lymphoid cells, expansion of Th2 cells, and augmentation of anti-viral function of CD8 T cells. As the cellular and molecular mechanisms connecting IL-33 to asthma etiology become the focus of intense scrutiny, several basic questions remain unanswered. This application focuses on elucidating the regulation of human IL33 expression, both at the transcriptional level as well as the organismal level. While IL33 is known to be constitutively expressed in epithelial cells and structural cells, we and others have recently found IL-33 produced by murine hematopoietic cells. We now demonstrate that IL33 is expressed in human lung leukocytes and that allergens induce IL33 expression in human CD14+ monocytes. These findings suggest a new paradigm of IL33 expression in the lungs, and represent an innovative opportunity to understand the impact tissue specific expression of this cytokine in airway Th2 inflammation. Using ENCODE and 1000 Genomes databases, we have performed in silico interrogation of the regulatory epigenetic landscape of the IL33 locus and have identified two regions of high interest;one region has strong enhancer activity, and a second region contains two defined CTCF binding sites, suggestive of insulator activity. We now demonstrate that the first region can function as an enhancer, and importantly, this activity is modified by a SNP found specifically in individuals of African ancestry. However useful, these public databases fail to highlight regulatory elements that only become evident after induction of gene expression by environmental stimulation. Thus, regulation of IL33 expression in primary cells after allergen stimulation will likely elucidate novel regulatory elements not realized in static cell lines. The central hypothesis of our study posits that noncoding genetic variants within regulatory elements alter the temporal and spatial expression patterns of IL33, and that this is a central mechanism behind the association of SNPs at the IL33 locus with asthma risk. To test this hypothesis the following aims are proposed: 1) identify the epigenetic changes that occur upon IL33 gene expression in stimulated hematopoietic cells and bronchial epithelial cells.;2) determine the role the enhancer element(s) play in the regulation of IL33 expression;and 3) determine the role of CTCF in IL33 expression.
Asthma affects an estimated 300 million people worldwide and represents an important challenge for basic science to benefit clinical medicine. Recently, the genes encoding IL-33 and its receptor IL-1RL1 have been identified as susceptibility loci for asthma. The goal of this application is to understand which cells express IL33, the chromosomal elements that regulate this expression, and how they are influenced by polymorphisms in the population.
| Montefiori, Lindsey E; Sobreira, Debora R; Sakabe, Noboru J et al. (2018) A promoter interaction map for cardiovascular disease genetics. Elife 7: |
| Ober, Carole; Sperling, Anne I; von Mutius, Erika et al. (2017) Immune development and environment: lessons from Amish and Hutterite children. Curr Opin Immunol 48:51-60 |
| Krishack, Paulette A; Wang, Kanix; Rzhetsky, Andrey et al. (2017) Preexisting Type 2 Immune Activation Protects against the Development of Sepsis. Am J Respir Cell Mol Biol 57:628-630 |
| Tjota, Melissa Y; Camacho, Daniel F; Turnquist, Heth R et al. (2017) IL-33 Drives Monocyte Recruitment to Lung Interstitium through Chemokine Upregulation. Immunohorizons 1:101-108 |
| Edelblum, Karen L; Singh, Gurminder; Odenwald, Matthew A et al. (2015) ?? Intraepithelial Lymphocyte Migration Limits Transepithelial Pathogen Invasion and Systemic Disease in Mice. Gastroenterology 148:1417-26 |
| Bailey, Kathleen A; Savic, Daniel; Zielinski, Mark et al. (2015) Evidence of non-pancreatic beta cell-dependent roles of Tcf7l2 in the regulation of glucose metabolism in mice. Hum Mol Genet 24:1646-54 |
| Hrusch, Cara L; Tjota, Melissa Y; Sperling, Anne I (2015) The role of dendritic cells and monocytes in the maintenance and loss of respiratory tolerance. Curr Allergy Asthma Rep 15:494 |
| Stevens, Whitney W; Grammer 3rd, Leslie C (2015) Occupational rhinitis: an update. Curr Allergy Asthma Rep 15:487 |
| Tjota, Melissa Y; Sperling, Anne I (2014) Distinct dendritic cell subsets actively induce Th2 polarization. Curr Opin Immunol 31:44-50 |
