Inhibition of JAK/STAT pathway restrains TSLP-activated dendritic cells mediated inflammatory T helper type 2 cell response in allergic rhinitis

Shi, Zhongqi; Jiang, Weihong; Wang, Min; Wang, Xiaocheng; Li, Xiaoyuan; Chen, Xiao; Qiao, Li

doi:10.1007/s11010-017-2963-7

Cited by 34 publications

(19 citation statements)

References 41 publications

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“…Different STATs have been shown to be expressed during Mo-DC differentiation and maturation, with STAT1-3-5 and 6 phosphorylated during Mo-DC differentiation, and STAT1 and STAT3 being further activated during TLR maturation ( 61 ). Furthermore, the JAK1/2 inhibitor CYT387, has been shown repress DC differentiation and maturation, reducing their capacity to promote T cell differentiation ( 62 ), similarly the JAK2 inhibitor AG490 has also been shown to be involved in mediating DC maturation ( 63 ). In addition, our group has previously shown that the JAK/STAT pathway is one of the pathway involved in Mo-DC differentiation ( 8 ), and STAT3 inhibition has been shown to repress endothelial cells differentiation from DC ( 64 ).…”

Section: Discussionmentioning

confidence: 99%

Monocyte-Derived Dendritic Cell Differentiation in Inflammatory Arthritis Is Regulated by the JAK/STAT Axis via NADPH Oxidase Regulation

et al. 2020

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Monocyte-derived Dendritic cells (Mo-DC) are a distinct DC subset, involved in inflammation and infection, they originate from monocytes upon stimulation in the circulation and their activation and function may vary in autoimmune diseases. In this study we investigate the differences in Mo-DC differentiation and function in patients with Rheumatoid (RA) compared to Psoriatic arthritis (PsA). A significant increase in the Mo-DC differentiation marker CD209, paralleled by a corresponding decrease in the monocytic marker CD14, was demonstrated in RA compared to PsA, as early as 1 day post Mo-DC differentiation. RA monocytes ex-vivo were phenotypically different to PsA, displaying a more mature phenotype associated with altered cellular-morphology, early dendrite formation, and a significant increase in the CD40 marker. In addition, SPICE algorithm flow cytometric analysis showed distinct differences in chemokine receptors distribution in HC compared to PsA and RA CD14 + cells in the blood, with increased expression of the chemokine receptors CCR7 and CXCR4 observed in PsA and RA. In addition CD14 + cells at the site of inflammation showed a different chemokine receptor pattern between PsA and RA patients, with higher expression of CXCR3 and CXCR5 in RA when compared to PsA. The early priming observed in RA resulted in monocyte-endocytosis and antigen-uptake mechanisms to be impaired, effects that were not observed in PsA where phagocytosis capacity remained highly functional. Tofacitinib inhibited early Mo-DC differentiation, decreasing both CD209 and CD40 activation markers in RA. Inhibition of Mo-DC differentiation in response to Tofacitinib was mediated via an imbalance in the activation of NADPH-oxidases NOX5 and NOX2. This effect was reversed by NOX5 inhibition, but not NOX2, resulting in suppression of NOX5-dependent ROS production. In conclusion, RA monocytes are already primed ex vivo to become DC, evident by increased expression of activation markers, morphological appearance and impaired endocytosis capacity. Furthermore, we demonstrated for the first time that NOX5 mediates Mo-DC differentiation and function in response to Tofacitinib, which may alter DC functions.

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Section: Discussionmentioning

confidence: 99%

Monocyte-Derived Dendritic Cell Differentiation in Inflammatory Arthritis Is Regulated by the JAK/STAT Axis via NADPH Oxidase Regulation

et al. 2020

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“…A recent study supported our findings showing that the expression of OX40L was dramatically downregulated in TSLP-primed DCs by inhibiting the JAK/STAT pathway following CYT387 treatment in an asthmatic cell model. 11 In addition, the expression levels of the classic Th2 cytokines, namely IL-5 and IL-13 were markedly increased in the AC group. This alteration was diminished in the AC + miR-19b group and in the AC + CYT387 group.…”

Section: Discussionmentioning

confidence: 93%

“…9 In addition, TSLPR ligation has been found to phosphorylate STAT3 in human subjects. 10 Previous reports indicated that DC maturation was significantly inhibited by the JAK/STAT pathway inhibitor (CYT387) in allergic diseases 11 and that STAT3 was required for Th2 cell development and cytokine production following activation. 12 In the present study, we speculated that the JAK/STAT pathway in DCs was important in regulating AC downstream of TSLP.…”

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confidence: 99%

The Potential Inhibitory Effects of miR-19b on Ocular Inflammation are Mediated Upstream of the JAK/STAT Pathway in a Murine Model of Allergic Conjunctivitis

Guo

Liu

Peng

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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Citation: Guo C, Liu J, Hao P, et al. The potential inhibitory effects of miR-19b on ocular inflammation are mediated upstream of the JAK/STAT pathway in a murine model of allergic conjunctivitis. Invest Ophthalmol Vis Sci. 2020;61(3):8. https://doi.org/10.1167/iovs.61.3.8 PURPOSE.Thymic stromal lymphopoietin (TSLP) is a pro-allergic cytokine that initiates allergic inflammatory reaction between epithelial and dendritic cells (DCs). miR-19b was reported to suppress TSLP expression. The present study aimed to examine miR-19b expression, regulation, and function in allergic conjunctivitis (AC). METHODS.A murine model of experimental AC was induced in BALB/c mice by short ragweed pollen. The serum, eye balls, conjunctiva, and cervical lymph nodes (CLN) were used for the study. Gene expression was determined by RT-PCR, whereas protein production and activation were evaluated by immunostaining, ELISA, and Western blotting. RESULTS.In the murine AC model, miR-19b was aberrantly downregulated, whereas the levels of TSLP and p-STAT3, as well as the number of CD11c+ pSTAT3+ DCs were increased. Moreover, Th2 inflammatory cytokine expression was significantly increased. These severe phenotypes could be counteracted by either applying exogenous miR-19b mimic microRNAs or the JAK/STAT inhibitor CYT387. Moreover, overexpression of miR-19b repressed p-STAT3 expression and the number of CD11c+ cells in AC eye and CLN tissues.CONCLUSIONS. These findings suggested that miR-19b reduced ocular surface inflammation by inhibiting Stat3 signaling via TSLP downregulation in a murine AC model. Moreover, the present study further demonstrated the clinical potential of applying miR-19b and anti-JAK/STAT therapies in the treatment of AC.

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“…Serum total and OVA-specific IgE levels were significantly increased in OVA-stimulated mice. As an exogenous antigen, OVA stimulates B cells to produce IgE and activate mast cells [ 17 ]. Intranasal instillation of EOCO suppressed the serum OVA-specific IgE level, but did not influence the total serum IgE level.…”

Section: Discussionmentioning

confidence: 99%

Immunomodulative Effects of Chamaecyparis obtusa Essential Oil in Mouse Model of Allergic Rhinitis

Shin

Lee

et al. 2020

Molecules

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The present study aims to investigate the immunomodulatory effects of essential oil from Chamaecyparis obtusa (EOCO) in an ovalbumin (OVA)-induced allergic rhinitis (AR) mouse model. BALB/c mice were intraperitoneally sensitized and stimulated with OVA. From day 22 to 35, 0.01% and 0.1% ECOC was intranasally administered 1 h before OVA stimulation. Nasal symptoms, as well as serum total and OVA-specific immunoglobulin (Ig) E levels, were measured. Interleukin (IL)-4, IL-10, interferon (IFN)-γ, and tumor necrosis factor (TNF)-α levels in nasal lavage fluid (NLF) and their production by activated splenocytes were measured. Histological changes in the sinonasal mucosa were evaluated through hematoxylin and eosin and periodic acid-Schiff staining procedure. Th cytokines and their transcription factor mRNA expressions were determined using reverse-transcription polymerase chain reaction. Intranasal EOCO administration significantly suppressed allergic symptoms, OVA-specific IgE level, sinonasal mucosal inflammatory cell infiltration, and mucus-producing periodic acid-Schiff (PAS) positive cell count. EOCO also significantly inhibited IL-4, IL-10, and TNF-α levels in NLF and activated splenocytes. Th2 and Treg related cytokines and their transcription factors in sinonasal mucosa were significantly suppressed through intransal EOCO instillation. In conclusion, repetitive EOCO intranasal instillation showed anti-inflammatory and anti-allergic effects by suppressing nasal symptoms and inhibiting the production and expression of inflammatory mediators in the OVA-induced AR mouse model.

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Inhibition of JAK/STAT pathway restrains TSLP-activated dendritic cells mediated inflammatory T helper type 2 cell response in allergic rhinitis

Cited by 34 publications

References 41 publications

Monocyte-Derived Dendritic Cell Differentiation in Inflammatory Arthritis Is Regulated by the JAK/STAT Axis via NADPH Oxidase Regulation

Monocyte-Derived Dendritic Cell Differentiation in Inflammatory Arthritis Is Regulated by the JAK/STAT Axis via NADPH Oxidase Regulation

The Potential Inhibitory Effects of miR-19b on Ocular Inflammation are Mediated Upstream of the JAK/STAT Pathway in a Murine Model of Allergic Conjunctivitis

Immunomodulative Effects of Chamaecyparis obtusa Essential Oil in Mouse Model of Allergic Rhinitis

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