Yin Chen

Yin Chen

Assistant Professor, BIO5 Institute
Member of the Graduate Faculty
Professor, Pharmacology and Toxicology
Primary Department
Contact
(520) 626-4715

Research Interest

Research Interest
Yin Chen, PhD. is an Assistant Professor in Pharmacology and Toxicology in the College of Pharmacy at UA. Dr. Chen’s research focus is on epithelial biology. He was a research faculty in University of California, Davis and an Assistant Investigator in Chemical Industry Institute of Toxicology (former CIIT and later Hamner Institute). His long-term research objective is to understand the dysfunction of airway epithelial mucosa in the pathogenesis of a variety of acute and chronic airway diseases. His current research programs are: a) understanding the molecular mechanisms underlying airway mucous cell development and mucous cell metaplasia in chronic diseases including cancer, COPD and asthma; (b) understanding the function and regulation of novel COPD associated genes and developing novel compounds to treat COPD; (c) understanding the impact of fungal exposure on airway innate immunity and its contribution to the development and exacerbation of asthma. Dr. Chen has more than 30 publications including peer-reviewed research articles, reviews and book chapters. He has served as the PI on one R01, two R21, one Flight Attendant Medical Institute (FAMRI) Innovative Clinical Award and one Arizona Biomedical Research Commission Award. He has also served as co-PI on two R01 and one P01 grants. He has built a long productive track record in studying airway mucus production and respiratory viral infection using primary airway epithelial cell model. He routinely cultivate and use primary epithelial cells from eye, salivary gland, airway surface and submucosal gland in different species (e.g. human, monkey, pig, rat and mouse) as our in vitro model to study mucin genes. The differentiated primary culture model demonstrates pseudostratified morphology, is composed of ciliated, non-ciliated, and goblet cells, and has a transepithelial barrier with high electro-resistance. He has also established in vivo exposure system to study the pulmonary effect of the exposure to particulates, pathogens and gases. Using this system, he has developed various airway disease models including CS-induced COPD model, ovalbumin-induced asthma model, fungal-induced asthma model and several infection models such as H1N1, rhinovirus, Aspergillus, and Alternaria.

Publications

Thai, P., Chen, Y., Dolganov, G., & Reen, W. u. (2005). Differential regulation of MUC5AC/Muc5ac and hCLCA-1/mGob 5 expression in airway epithelium. American Journal of Respiratory Cell and Molecular Biology, 33(6), 523-530.

PMID: 16151054;PMCID: PMC2715330;Abstract:

This study demonstrates that the two biomarkers, MUC5AC/ Muc5ac and hCLCA1/Gob5, which are frequently associated with surface mucous/goblet cells in asthmatic airways, are differentially regulated. Intratracheal instillation of IL-13 (0.5 μg/mouse lung) elicited 8- and 110-fold induction of Muc5ac and Gob5 messages, respectively, within 24 h in wild-type mouse lung, whereas these inductions were abrogated in Stat6 knockout mice. The induction of MUC5AC/Muc5ac message could not be duplicated in vitro with primary tracheobronchial epithelial (TBE) cells derived from wild-type mice or humans, despite significant inductions still seen for hCLCA1/Gob5. Further studies with JAK inhibitors and STAT6 signaling showed active signaling of the JAK/STAT6 pathway in these primary TBE cultures by IL-13 in the regulation of hCLCA1 expression. Dual immunofluorescent staining with antibodies specific to MUC5AC and hCLCA1 revealed a differential nature of the expression of these two biomarkers by distinct cell types of primary TBE cultures. Finally, MUC5AC expression could be elevated by a bacterial product, peptidoglycan, without any induction of hCLCA1. Thus, these results suggest that the two biomakers of the metaplastic airway mucous cell type are differentially regulated by JAK/STAT6-dependent and -independent pathways.

Zhu, L., Lee, P., Lee, W., Zhao, Y., Dongfang, Y. u., & Chen, Y. (2009). Rhinovirus-induced major airway mucin production involves a novel TLR3-EGFR-dependent pathway. American Journal of Respiratory Cell and Molecular Biology, 40(5), 610-619.

PMID: 18978302;PMCID: PMC2677440;Abstract:

Mucociliary clearance is a critical innate defense system responsible for clearing up invading pathogens including bacteria and virus. Although the right amount of mucusis good, excessivemucus causes airway obstruction and tends to precipitate disease symptoms. Rhinovirus (RV) is a common cold virus that causes asthma and chronic obstructive pulmonary disease exacerbation. Mucus overproduction has been linked to the pathogenesis of RV-induced diseases and disease exacerbations. However, the molecular mechanism is not clear. In this study, using one of the major airway mucin-MUC5AC as marker, we found that both major and minor groups of RV induced mucin production in primary human epithelial cells and cell line. RV1A (a minor group of RV) could induce mucous cell metaplasia in vivo. Viral replication was needed for RV-induced mucin expression, and this induction was also dependent on TLR3, suggesting the involvement of double-stranded (ds) RNA signaling. Indeed, dsRNA alone could also induce mucin expression. TLR3-mediated mucin induction was negatively regulated by MyD88, and only partially dependent on TRIF, which suggests a departure from well-documented TLR3 signaling paradigm that mediates inflammatory and other innate defense gene inductions. In addition, TLR3 signaling activated epidermal growth factor receptor (EGFR) through inductions of the expression of EGFR ligands (transforming growth factor-α and amphiregulin), which in turn activated EGFR-ERK signaling and mucin expression through an autocrine/paracrine loop. This novel coupling of antiviral defense machinery (i.e., TLR3) and major epithelial proliferation/repair pathway (i.e., EGFR) might play an important role in viral-induced airway remodeling and airway disease exacerbation.

Klionsky, D. J., Abdelmohsen, K., Abe, A., Abedin, M. J., Abeliovich, H., Acevedo Arozena, A., Adachi, H., Adams, C. M., Adams, P. D., Adeli, K., Adhihetty, P. J., Adler, S. G., Agam, G., Agarwal, R., Aghi, M. K., Agnello, M., Agostinis, P., Aguilar, P. V., Aguirre-Ghiso, J., , Airoldi, E. M., et al. (2016). Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy, 12(1), 1-222.
BIO5 Collaborators
Yin Chen, Walter Klimecki
Oslund, K. L., Zhou, X., Lee, B., Zhu, L., Duong, T., Shih, R., Baumgarth, N., Hung, L., Wu, R., & Chen, Y. (2014). Synergistic up-regulation of CXCL10 by virus and IFN γ in human airway epithelial cells. PloS one, 9(7), e100978.

Airway epithelial cells are the first line of defense against viral infections and are instrumental in coordinating the inflammatory response. In this study, we demonstrate the synergistic stimulation of CXCL10 mRNA and protein, a key chemokine responsible for the early immune response to viral infection, following treatment of airway epithelial cells with IFN γ and influenza virus. The synergism also occurred when the cells were treated with IFN γ and a viral replication mimicker (dsRNA) both in vitro and in vivo. Despite the requirement of type I interferon (IFNAR) signaling in dsRNA-induced CXCL10, the synergism was independent of the IFNAR pathway since it wasn't affected by the addition of a neutralizing IFNAR antibody or the complete lack of IFNAR expression. Furthermore, the same synergistic effect was also observed when a CXCL10 promoter reporter was examined. Although the responsive promoter region contains both ISRE and NFκB sites, western blot analysis indicated that the combined treatment of IFN γ and dsRNA significantly augmented NFκB but not STAT1 activation as compared to the single treatment. Therefore, we conclude that IFN γ and dsRNA act in concert to potentiate CXCL10 expression in airway epithelial cells via an NFκB-dependent but IFNAR-STAT independent pathway and it is at least partly regulated at the transcriptional level.

Tao, S., Zhu, L., Lee, P., Lee, W., Knox, K., Chen, J., Di, Y. P., & Chen, Y. (2012). Negative control of TLR3 signaling by TICAM1 down-regulation. American Journal of Respiratory Cell and Molecular Biology, 46(5), 660-667.

PMID: 22205631;PMCID: PMC3359907;Abstract:

Toll-IL-1 receptor (TIR) domain-containing adaptor molecule-1 (TICAM1, also called TRIF) is an important adaptor protein in TLR3 and TLR4 signaling pathways that mediate proinflammatory cytokine and IFN responses. Negative regulation of TICAM1 by exogenous viral protease or by endogenous caspase and proteasome have been reported to shut down TICAM1-mediated signaling. In this study, we discovered that down-regulation of TICAM1, but not other components in this signaling pathway, occurred in a natural process of TLR3 activation induced by double-stranded RNA or human rhinovirus (RV) infection in airway epithelial cells and various other cell types. TICAM1 was essential for IFN expression, and the loss of TICAM1 significantly elevated RV production. The low level of TICAM1 protein expression, caused by the prior double-stranded RNA treatment, led to a lack of IFN production upon additional treatment, suggesting receptor desensitization. In follow-up studies, TICAM1 down-regulation was found to be dependent on TLR3 but not RIG1, MDA5, or PKR and appeared to be regulated post-translationally. Neither proteasome nor caspase inhibitors could prevent TICAM1 down-regulation. Instead, a lysosome-mediated process appeared to be involved, suggesting a novel mechanism that is different from previous reports. In conclusion, TICAM1 down-regulation is an essential step in TLR3 activation, and its function is to stop TLR3-mediated IFN production. Copyright © 2012 by the American Thoracic Society.