Dendritic Cell-Derived TSLP Negatively Regulates HIF-1α and IL-1β During Dectin-1 Signaling

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.

[1]  J. Corren,et al.  Tezepelumab in Adults with Uncontrolled Asthma , 2017, The New England journal of medicine.

[2]  A. Gounni,et al.  Thymic Stromal Lymphopoietin Is Critical for Regulation of Proinflammatory Cytokine Response and Resistance to Experimental Trypanosoma congolense Infection , 2017, Front. Immunol..

[3]  David L. Williams,et al.  β-Glucan Size Controls Dectin-1-Mediated Immune Responses in Human Dendritic Cells by Regulating IL-1β Production , 2017, Front. Immunol..

[4]  G. Serre,et al.  Counterregulation between thymic stromal lymphopoietin- and IL-23-driven immune axes shapes skin inflammation in mice with epidermal barrier defects. , 2016, The Journal of allergy and clinical immunology.

[5]  C. Leclerc,et al.  Dectin-1 activation unlocks IL12A expression and reveals the TH1 potency of neonatal dendritic cells. , 2015, The Journal of allergy and clinical immunology.

[6]  X. Chen,et al.  TSLP Expression: Analysis with a ZsGreen TSLP Reporter Mouse , 2015, The Journal of Immunology.

[7]  R. Xavier,et al.  mTOR- and HIF-1α–mediated aerobic glycolysis as metabolic basis for trained immunity , 2014, Science.

[8]  D. Green,et al.  Caspase-8 Modulates Dectin-1 and Complement Receptor 3–Driven IL-1β Production in Response to β-Glucans and the Fungal Pathogen, Candida albicans , 2014, The Journal of Immunology.

[9]  S. Chimenti,et al.  Thymic stromal lymphopoietin links keratinocytes and dendritic cell-derived IL-23 in patients with psoriasis. , 2014, The Journal of allergy and clinical immunology.

[10]  M. Netea,et al.  Novel Structural Features in Candida albicans Hyphal Glucan Provide a Basis for Differential Innate Immune Recognition of Hyphae Versus Yeast* , 2013, The Journal of Biological Chemistry.

[11]  M. Pellegrino,et al.  The Epithelial Cell-Derived Atopic Dermatitis Cytokine TSLP Activates Neurons to Induce Itch , 2013, Cell.

[12]  G. Núñez,et al.  K⁺ efflux is the common trigger of NLRP3 inflammasome activation by bacterial toxins and particulate matter. , 2013, Immunity.

[13]  D. Foell,et al.  Treatment of Muckle-Wells syndrome: analysis of two IL-1-blocking regimens , 2013, Arthritis Research & Therapy.

[14]  E. Latz,et al.  Activation and regulation of the inflammasomes , 2013, Nature Reviews Immunology.

[15]  Liang Zheng,et al.  Succinate is an inflammatory signal that induces IL-1β through HIF-1α , 2013, Nature.

[16]  S. Ziegler,et al.  STAT5 is critical in Dendritic Cells for development of TH2- but not TH1-dependent Immunity , 2013, Nature Immunology.

[17]  Y. Taketani,et al.  Interleukin-1β stimulates the secretion of thymic stromal lymphopoietin (TSLP) from endometrioma stromal cells: possible involvement of TSLP in endometriosis. , 2012, Human reproduction.

[18]  D. Moody,et al.  Faculty Opinions recommendation of Pathogen-induced human TH17 cells produce IFN-γ or IL-10 and are regulated by IL-1β. , 2012 .

[19]  Xueping Zhou,et al.  DC‐derived TSLP promotes Th2 polarization in LPS‐primed allergic airway inflammation , 2012, European journal of immunology.

[20]  S. Gringhuis,et al.  Dectin-1 is an extracellular pathogen sensor for the induction and processing of IL-1β via a noncanonical caspase-8 inflammasome , 2012, Nature Immunology.

[21]  G. Rossi,et al.  Dendritic cells produce TSLP that limits the differentiation of Th17 cells, fosters Treg development, and protects against colitis , 2012, Mucosal Immunology.

[22]  W. Leonard,et al.  Thymic Stromal Lymphopoietin Is Produced by Dendritic Cells , 2011, Journal of Immunology.

[23]  S. Smeekens,et al.  The inflammasome drives protective Th1 and Th17 cellular responses in disseminated candidiasis , 2011, European journal of immunology.

[24]  W. Leonard,et al.  Thymic stromal lymphopoietin-mediated STAT5 phosphorylation via kinases JAK1 and JAK2 reveals a key difference from IL-7–induced signaling , 2010, Proceedings of the National Academy of Sciences.

[25]  V. Saudek,et al.  Endoplasmic reticulum stress-induced transcription factor, CHOP, is crucial for dendritic cell IL-23 expression , 2010, Proceedings of the National Academy of Sciences.

[26]  T. Holowka,et al.  Toll-like receptor-induced changes in glycolytic metabolism regulate dendritic cell activation. , 2010, Blood.

[27]  S. Ziegler,et al.  Sensing the outside world: TSLP regulates barrier immunity , 2010, Nature Immunology.

[28]  Shao-Cong Sun,et al.  Distinct Signal Codes Generate Dendritic Cell Functional Plasticity , 2010, Science Signaling.

[29]  D. Underhill,et al.  β‐glucan recognition by the innate immune system , 2009, Immunological reviews.

[30]  M. Rescigno,et al.  Human intestinal epithelial cells promote the differentiation of tolerogenic dendritic cells , 2009, Gut.

[31]  J. Tschopp,et al.  Syk kinase signalling couples to the Nlrp3 inflammasome for anti-fungal host defence , 2009, Nature.

[32]  K. Fitzgerald,et al.  An essential role for the NLRP3 inflammasome in host defense against the human fungal pathogen Candida albicans. , 2009, Cell host & microbe.

[33]  D. Artis,et al.  TSLP regulates intestinal immunity and inflammation in mouse models of helminth infection and colitis , 2009, The Journal of experimental medicine.

[34]  K. Rock,et al.  Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization , 2008, Nature Immunology.

[35]  Aleksander S. Popel,et al.  Reactive Oxygen Species Regulate Hypoxia-Inducible Factor 1α Differentially in Cancer and Ischemia , 2008, Molecular and Cellular Biology.

[36]  S. Ziegler,et al.  Inducible expression of the proallergic cytokine thymic stromal lymphopoietin in airway epithelial cells is controlled by NFκB , 2007, Proceedings of the National Academy of Sciences.

[37]  M. Netea,et al.  Endogenous Interleukin (IL)–1α and IL-1β Are Crucial for Host Defense against Disseminated Candidiasis , 2006 .

[38]  V. Dixit,et al.  Cryopyrin activates the inflammasome in response to toxins and ATP , 2006, Nature.

[39]  Yu Wang,et al.  TSLP-activated dendritic cells induce an inflammatory T helper type 2 cell response through OX40 ligand , 2005, The Journal of experimental medicine.

[40]  H. D. Liggitt,et al.  Thymic stromal lymphopoietin as a key initiator of allergic airway inflammation in mice , 2005, Nature Immunology.

[41]  D. Underhill,et al.  Dectin-1 activates Syk tyrosine kinase in a dynamic subset of macrophages for reactive oxygen production. , 2005, Blood.

[42]  S. Ho,et al.  Human thymic stromal lymphopoietin promotes dendritic cell–mediated CD4+ T cell homeostatic expansion , 2004, Nature Immunology.

[43]  L. Neckers,et al.  IL‐1β mediated up‐regulation of HIF‐lα via an NFkB/COX‐2 pathway identifies HIF‐1 as a critical link between inflammation and oncogenesis , 2003 .

[44]  Siamon Gordon,et al.  Dectin-1 Is A Major β-Glucan Receptor On Macrophages , 2002, The Journal of experimental medicine.

[45]  Kathleen M. Smith,et al.  Human epithelial cells trigger dendritic cell–mediated allergic inflammation by producing TSLP , 2002, Nature Immunology.

[46]  D. Largaespada,et al.  Cloning of the Murine Thymic Stromal Lymphopoietin (Tslp) Receptor , 2000, The Journal of experimental medicine.

[47]  J. Caro,et al.  Interleukin 1 induces hypoxia-inducible factor 1 in human gingival and synovial fibroblasts. , 2000, The Biochemical journal.

[48]  D. Williams,et al.  A thymic stromal cell line supports in vitro development of surface IgM+ B cells and produces a novel growth factor affecting B and T lineage cells. , 1994, Experimental hematology.

[49]  E. Jones,et al.  A method for the solubilization of a (1----3)-beta-D-glucan isolated from Saccharomyces cerevisiae. , 1991, Carbohydrate research.

[50]  C. Dinarello,et al.  Protection of neutropenic mice from lethal Candida albicans infection by recombinant interleukin 1 , 1988, European journal of immunology.

[51]  S. Gordon,et al.  Dectin-1 is required for β-glucan recognition and control of fungal infection , 2007, Nature Immunology.

[52]  W. Jelkmann,et al.  Interleukin-1beta and tumor necrosis factor-alpha stimulate DNA binding of hypoxia-inducible factor-1. , 1999, Blood.

[53]  W. Jelkmann,et al.  Interleukin-1β and Tumor Necrosis Factor- Stimulate DNA Binding of Hypoxia-Inducible Factor-1 , 1999 .