Rational targeting Cdc42 restrains Th2 cell differentiation and prevents allergic airway inflammation

Yang, Jun‐Qi; Kalim, Khalid W.; Li, Yuan; Duan, Xin; Nguyen, Phuong; Hershey, Gurjit K. Khurana; Kroner, John; Ruff, Brandy P.; Zhang, Li; Salomonis, Nathan; Rochman, Mark; Wen, Ting; Zheng, Yi; Guo, Fukun

doi:10.1111/cea.13293

Cited by 27 publications

(50 citation statements)

References 39 publications

(102 reference statements)

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“…The role of methylations of ACOT7 gene in asthma has been reported by several genome-wide epigenomic studies on serum immunoglobin E (IgE) levels [42][43][44] . One of the top five loci based on the NEC data, cg00625963, is located in the LCK Proto-Oncogene, Src Family Tyrosine Kinase (LCK) gene, which can mediate the allergic airway inflammation in asthma [45][46][47] . The AEC data show that Rap Guanine Nucleotide Exchange Factor 3 (RAPGEF3) gene might act in concert with another candidate gene, cadherin-6 www.nature.com/scientificreports www.nature.com/scientificreports/ (CDH6) gene, to jointly influence the risk of asthma.…”

Section: Discussionmentioning

confidence: 99%

Comparing DNA methylation profiles across different tissues associated with the diagnosis of pediatric asthma

Lin

Shu

Mersha

2020

Sci Rep

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DNA methylation (DNAm) profiles in central airway epithelial cells (AECs) may play a key role in pathological processes in asthma. The goal of the current study is to compare the diagnostic performance of DNAm markers across three tissues: AECs, nasal epithelial cells (NECs), and peripheral blood mononuclear cells (PBMCs). Additionally, we focused on the results using the machine learning algorithm in the context of multi-locus effects to evaluate the diagnostic performance of the optimal subset of CpG sites. We obtained 74 subjects with asthma and 41 controls from AECs, 15 subjects with asthma and 14 controls from NECs, 697 subjects with asthma and 97 controls from PBMCs. Epigenomewide DNA methylation levels in AECs, NECs and PBMCs were measured using the Infinium Human Methylation 450 K BeadChip. Overlap analysis across the three different sample sources at the locus and pathway levels were studied to investigate shared or unique pathophysiological processes of asthma across tissues. Using the top 100 asthma-associated methylation markers as classifiers from each dataset, we found that both AEC-and NEC-based DNAm signatures exerted a lower classification error than the PBMC-based DNAm markers (p-value = 0.0002). The area-under-the-curve (AUC) analysis based on out-of-bag errors using the random forest classification algorithm revealed that PBMC-, NEC-, and AEC-based methylation data yielded 31 loci (AUC: 0.87), 8 loci (AUC: 0.99), and 4 loci (AUC: 0.97) from each optimal subset of tissue-specific markers, respectively. We also discovered the locus-locus interaction of DNAm levels of the CDH6 gene and RAPGEF3 gene might interact with each other to jointly predict the risk of asthma -which suggests the pivotal role of cell-cell junction in the pathological changes of asthma. Both AECs and NECs might provide better diagnostic accuracy and efficacy levels than PBMCs. Further research is warranted to evaluate how these tissue-specific DNAm markers classify and predict asthma risk.Asthma affects 11 million children in the U.S., and has been on the rise over the past two decades 1 . Although the heritability estimate may reach 80% 2 , the rapid increment in its incidence cannot be simply explained by genetic factors alone. Epigenetics may account for the mechanisms underlying environmental effects on genetic functions 3 , and hence may play a role in the environment-related pathogenesis of asthma 4 . DNA methylation (DNAm) is the first identified epigenetic mechanism that been extensively studied in allergic disease [5][6][7][8] . Emerging evidence has suggested that DNAm can be considered as a robust epigenetic marker that could aid clinical applications, such as diagnostics 9 .One of the major challenges of DNAm research on asthma is the selection of the target tissue for DNA samples. The direct access to the lung tissue DNA which is primarily involved in asthma pathophysiology is limited 10 . Surrogate markers from easily accessible tissues are the markers of choice for studies involving large-scale screening and c...

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Section: Discussionmentioning

confidence: 99%

Comparing DNA methylation profiles across different tissues associated with the diagnosis of pediatric asthma

Lin

Shu

Mersha

2020

Sci Rep

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“…Cytokines in the culture supernatants and sera were measured using ELISA as we previously reported [30,31]. IL-4 and IFN-γ were measured with OptEIA kits (BD Bioscience, San Jose, CA, USA); IL-17, IL-17F, and IL-21 were measured with DuoSet ELISA kits (R&D Systems, Minneapolis, MN, USA).…”

Section: Methodsmentioning

confidence: 99%

Inhibition of Rho-Kinase Downregulates Th17 Cells and Ameliorates Hepatic Fibrosis by Schistosoma japonicum Infection

Zhou

Yang

Mei

et al. 2019

Cells

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Background: Schistosomiasis is an immunopathogenic disease in which Th17 cells play vital roles. Hepatic granuloma formation and subsequent fibrosis are its main pathologic manifestations and the leading causes of hepatic cirrhosis, and effective therapeutic interventions are lacking. In this study, we explored the effects of fasudil, a selective RhoA–Rho-associated kinase (ROCK) inhibitor, on Th17 cells and the pathogenesis of schistosomiasis. Methods: Mice were infected with Schistosoma japonicum and treated with fasudil. The worm burden, hepatic granuloma formation, and fibrosis were evaluated. The roles of fasudil on Th17, Treg, and hepatic stellate cells were analyzed. Results: Fasudil therapy markedly reduced the granuloma size and collagen deposit in livers from mice infected with S. japonicum. However, fasudil therapy did not affect the worm burden in infected mice. The underlying cellular and molecular mechanisms were investigated. Fasudil suppressed the activation and induced the apoptosis of CD4+ T cells. Fasudil inhibited the differentiation and effector cytokine secretion of Th17 cells, whereas it upregulated Treg cells in vitro. It also restrained the in vivo interleukin (IL)-4 and IL-17 levels in infected mice. Fasudil directly induced the apoptosis of hepatic stellate cells and downregulated the expressions of hepatic fibrogenic genes, such as collagen type I (Col-I), Col-III, and transforming growth factor-1 (TGF-β1). These effects may contribute to its anti-pathogenic roles in schistosomiasis. Conclusions: Fasudil inhibits hepatic granuloma formation and fibrosis with downregulation of Th17 cells. Fasudil might serve as a novel therapeutic agent for hepatic fibrosis due to schistosome infections and perhaps other disorders.

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“…The protein Cdc42 is a member of the Rho family of small GTPases. Cdc42 controls signal-transduction pathways that lead to rearrangement of the cell cytoskeleton, cell differentiation and cell proliferation by binding to downstream effector proteins [149,150,151]. These functions of Cdc42 are associated with diabetes (Table 1).…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Cdc42: A Novel Regulator of Insulin Secretion and Diabetes-Associated Diseases

Huang

Lai

Qian

et al. 2019

IJMS

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Cdc42, a member of the Rho GTPases family, is involved in the regulation of several cellular functions including cell cycle progression, survival, transcription, actin cytoskeleton organization and membrane trafficking. Diabetes is a chronic and metabolic disease, characterized as glycometabolism disorder induced by insulin deficiency related to β cell dysfunction and peripheral insulin resistance (IR). Diabetes could cause many complications including diabetic nephropathy (DN), diabetic retinopathy and diabetic foot. Furthermore, hyperglycemia can promote tumor progression and increase the risk of malignant cancers. In this review, we summarized the regulation of Cdc42 in insulin secretion and diabetes-associated diseases. Organized researches indicate that Cdc42 is a crucial member during the progression of diabetes, and Cdc42 not only participates in the process of insulin synthesis but also regulates the insulin granule mobilization and cell membrane exocytosis via activating a series of downstream factors. Besides, several studies have demonstrated Cdc42 as participating in the pathogenesis of IR and DN and even contributing to promote cancer cell proliferation, survival, invasion, migration, and metastasis under hyperglycemia. Through the current review, we hope to cast light on the mechanism of Cdc42 in diabetes and associated diseases and provide new ideas for clinical diagnosis, treatment, and prevention.

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Rational targeting Cdc42 restrains Th2 cell differentiation and prevents allergic airway inflammation

Cited by 27 publications

References 39 publications

Comparing DNA methylation profiles across different tissues associated with the diagnosis of pediatric asthma

Comparing DNA methylation profiles across different tissues associated with the diagnosis of pediatric asthma

Inhibition of Rho-Kinase Downregulates Th17 Cells and Ameliorates Hepatic Fibrosis by Schistosoma japonicum Infection

Cdc42: A Novel Regulator of Insulin Secretion and Diabetes-Associated Diseases

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