Deepa Rastogi1, John Nico2, Andrew D Johnston3, Toni Adrianne M Tobias2, Yurydia Jorge2, Fernando Macian4, John M Greally3. 1. Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY. Electronic address: drastogi@montefiore.org. 2. Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY. 3. Department of Genetics, Albert Einstein College of Medicine, Bronx, NY. 4. Department of Pathology, Albert Einstein College of Medicine, Bronx, NY.
Abstract
BACKGROUND: Pediatric obesity-related asthma is more severe and less responsive to medications than asthma in normal-weight children. Obese asthmatic children have nonatopic TH1-polarized systemic inflammation that correlates with pulmonary function deficits, but the pathways underlying TH1-polarized inflammation are not well understood. OBJECTIVE: We compared the CD4+ T-cell transcriptome in obese children with asthma with that in normal-weight children with asthma to identify key differentially expressed genes associated with TH1-polarized inflammation. METHODS: CD4+ T-cell transcriptome-wide differential gene expression was compared between 21 obese and 21 normal-weight children by using directional RNA sequencing. High-confidence differentially expressed genes were verified in the first cohort and validated in a second cohort of 20 children (10 obese and 10 normal-weight children) by using quantitative RT-PCR. RESULTS: Transcriptome-wide differential gene expression among obese asthmatic children was enriched for genes, including VAV2, DOCK5, PAK3, PLD1, CDC42EP4, and CDC42PBB, which are associated with CDC42, a small guanosine triphosphate protein linked to T-cell activation. Upregulation of MLK3 and PLD1, genes downstream of CDC42 in the mitogen-activated protein kinase and mammalian target of rapamycin pathways and the inverse correlation of CDC42EP4 and DOCK5 transcript counts with FEV1/FVC ratio together support a role of CDC42 in the TH1 polarization and pulmonary function deficits found in patients with obesity-related asthma. CONCLUSIONS: Our study identifies the CDC42 pathway as a novel target that is upregulated in TH cells of obese asthmatic children, suggesting its role in nonatopic TH1-polarized systemic inflammation and pulmonary function deficits found in patients with pediatric obesity-related asthma.
BACKGROUND: Pediatric obesity-related asthma is more severe and less responsive to medications than asthma in normal-weight children. Obese asthmaticchildren have nonatopic TH1-polarized systemic inflammation that correlates with pulmonary function deficits, but the pathways underlying TH1-polarized inflammation are not well understood. OBJECTIVE: We compared the CD4+ T-cell transcriptome in obesechildren with asthma with that in normal-weight children with asthma to identify key differentially expressed genes associated with TH1-polarized inflammation. METHODS:CD4+ T-cell transcriptome-wide differential gene expression was compared between 21 obese and 21 normal-weight children by using directional RNA sequencing. High-confidence differentially expressed genes were verified in the first cohort and validated in a second cohort of 20 children (10 obese and 10 normal-weight children) by using quantitative RT-PCR. RESULTS: Transcriptome-wide differential gene expression among obese asthmaticchildren was enriched for genes, including VAV2, DOCK5, PAK3, PLD1, CDC42EP4, and CDC42PBB, which are associated with CDC42, a small guanosine triphosphate protein linked to T-cell activation. Upregulation of MLK3 and PLD1, genes downstream of CDC42 in the mitogen-activated protein kinase and mammalian target of rapamycin pathways and the inverse correlation of CDC42EP4 and DOCK5 transcript counts with FEV1/FVC ratio together support a role of CDC42 in the TH1 polarization and pulmonary function deficits found in patients with obesity-related asthma. CONCLUSIONS: Our study identifies the CDC42 pathway as a novel target that is upregulated in TH cells of obese asthmaticchildren, suggesting its role in nonatopic TH1-polarized systemic inflammation and pulmonary function deficits found in patients with pediatric obesity-related asthma.
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Authors: Yimin Fang; In-Hyun Park; Ai-Luen Wu; Guangwei Du; Ping Huang; Michael A Frohman; Stephanie J Walker; H Alex Brown; Jie Chen Journal: Curr Biol Date: 2003-12-02 Impact factor: 10.834
Authors: Deepa Rastogi; Andrew D Johnston; John Nico; Lip Nam Loh; Yurydia Jorge; Masako Suzuki; Fernando Macian; John M Greally Journal: Am J Respir Crit Care Med Date: 2020-07-15 Impact factor: 21.405