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Dendritic Cell-Derived TSLP Negatively Regulates HIF-1α and IL-1β During Dectin-1 Signaling.
Front Immunol 2019; 10:921FI

Abstract

Thymic stromal lymphopoietin (TSLP) is a functionally pleotropic cytokine important in immune regulation, and TSLP dysregulation is associated with numerous diseases. TSLP is produced by many cell types, but has predominantly been characterized as a secreted factor from epithelial cells which activates dendritic cells (DC) that subsequently prime T helper (TH) 2 immunity. However, DC themselves make significant amounts of TSLP in response to microbial products, but the functional role of DC-derived TSLP remains unclear. We show that TSLPR signaling negatively regulates IL-1β production during dectin-1 stimulation of human DC. This regulatory mechanism functions by dampening Syk phosphorylation and is mediated via NADPH oxidase-derived ROS, HIF-1α and pro-IL-1β expression. Considering the profound effect TSLPR signaling has on the metabolic status and the secretome of dectin-1 stimulated DC, these data suggest that autocrine TSLPR signaling could have a fundamental role in modulating immunological effector responses at sites removed from epithelial cell production of TSLP.

Authors+Show Affiliations

Department of Medicine, School of Clinical Medicine, Addenbrookes Hospital, University of Cambridge, Cambridge, United Kingdom. Early Oncology R&D Division, AstraZeneca, Cambridge, United Kingdom.Department of Medicine, School of Clinical Medicine, Addenbrookes Hospital, University of Cambridge, Cambridge, United Kingdom. Department of Veterinary Medicine, University of Cambridge, Cambridge, United Kingdom.Department of Medicine, School of Clinical Medicine, Addenbrookes Hospital, University of Cambridge, Cambridge, United Kingdom.Department of Medicine, School of Clinical Medicine, Addenbrookes Hospital, University of Cambridge, Cambridge, United Kingdom.Unit 970, INSERM, Paris Cardiovascular Research Center, Paris, France.Department of Immunology, Royal Free Hospital, London, United Kingdom.Division of Cardiovascular Medicine, Department of Medicine, University of Cambridge, Cambridge, United Kingdom.Biopharmaceutical Research Division, AstraZeneca, Cambridge, United Kingdom.Department of Surgery, Center for Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States.Department of Medicine, School of Clinical Medicine, Addenbrookes Hospital, University of Cambridge, Cambridge, United Kingdom.Department of Medicine, School of Clinical Medicine, Addenbrookes Hospital, University of Cambridge, Cambridge, United Kingdom.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31139177

Citation

Elder, Matthew J., et al. "Dendritic Cell-Derived TSLP Negatively Regulates HIF-1α and IL-1β During Dectin-1 Signaling." Frontiers in Immunology, vol. 10, 2019, p. 921.
Elder MJ, Webster SJ, Fitzmaurice TJ, et al. Dendritic Cell-Derived TSLP Negatively Regulates HIF-1α and IL-1β During Dectin-1 Signaling. Front Immunol. 2019;10:921.
Elder, M. J., Webster, S. J., Fitzmaurice, T. J., Shaunak, A. S. D., Steinmetz, M., Chee, R., ... Goodall, J. C. (2019). Dendritic Cell-Derived TSLP Negatively Regulates HIF-1α and IL-1β During Dectin-1 Signaling. Frontiers in Immunology, 10, p. 921. doi:10.3389/fimmu.2019.00921.
Elder MJ, et al. Dendritic Cell-Derived TSLP Negatively Regulates HIF-1α and IL-1β During Dectin-1 Signaling. Front Immunol. 2019;10:921. PubMed PMID: 31139177.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Dendritic Cell-Derived TSLP Negatively Regulates HIF-1α and IL-1β During Dectin-1 Signaling. AU - Elder,Matthew J, AU - Webster,Steve J, AU - Fitzmaurice,Timothy J, AU - Shaunak,Aran S D, AU - Steinmetz,Martin, AU - Chee,Ronnie, AU - Mallat,Ziad, AU - Cohen,E Suzanne, AU - Williams,David L, AU - Gaston,J S Hill, AU - Goodall,Jane C, Y1 - 2019/05/08/ PY - 2018/11/22/received PY - 2019/04/10/accepted PY - 2019/5/30/entrez PY - 2019/5/30/pubmed PY - 2019/5/30/medline KW - HIF-1α KW - IL-1β KW - ROS KW - Syk KW - TSLP KW - dectin-1 KW - hypoxia SP - 921 EP - 921 JF - Frontiers in immunology JO - Front Immunol VL - 10 N2 - Thymic stromal lymphopoietin (TSLP) is a functionally pleotropic cytokine important in immune regulation, and TSLP dysregulation is associated with numerous diseases. TSLP is produced by many cell types, but has predominantly been characterized as a secreted factor from epithelial cells which activates dendritic cells (DC) that subsequently prime T helper (TH) 2 immunity. However, DC themselves make significant amounts of TSLP in response to microbial products, but the functional role of DC-derived TSLP remains unclear. We show that TSLPR signaling negatively regulates IL-1β production during dectin-1 stimulation of human DC. This regulatory mechanism functions by dampening Syk phosphorylation and is mediated via NADPH oxidase-derived ROS, HIF-1α and pro-IL-1β expression. Considering the profound effect TSLPR signaling has on the metabolic status and the secretome of dectin-1 stimulated DC, these data suggest that autocrine TSLPR signaling could have a fundamental role in modulating immunological effector responses at sites removed from epithelial cell production of TSLP. SN - 1664-3224 UR - https://www.unboundmedicine.com/medline/citation/31139177/Dendritic_Cell-Derived_TSLP_Negatively_Regulates_HIF-1α_and_IL-1β_During_Dectin-1_Signaling L2 - https://doi.org/10.3389/fimmu.2019.00921 DB - PRIME DP - Unbound Medicine ER -