Dynamic control of Th2 cell responses by STAT3 during allergic lung inflammation in mice

Lim, Hye‐Sun; Cho, Minkyoung; Choi, Garam; Na, Hyeongjin; Chung, Yeonseok

doi:10.1016/j.intimp.2015.03.051

Cited by 22 publications

(19 citation statements)

References 59 publications

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“…Intranasal PAO/OVA is known to induce allergen-specific T H 2 cells, as well as T H 17 cells, in the airway, offering an ideal model to study the potential mutual regulation between the 2 T H cell subsets. 24–26 As expected, wild-type mice expressed increased levels of IL-17A and IL-17F producers among CD4 + T cells in the lungs, which were absent in dKO mice (Fig 1, A–C ). Of note, frequencies and numbers of T H 2 cells were also significantly diminished in the lungs of dKO mice, and frequencies and numbers of T H 1 cells were increased compared with those in wild-type mice (Fig 1, A–C .)…”

Section: Resultssupporting

confidence: 75%

“…37 Although STAT3-deficient T cells exhibited reduced T H 2 and T H 17 cell differentiation in the bronchial lymph nodes, they showed more robust T H 2 cell responses in the airway compared with STAT3-sufficient T cells, suggesting that STAT3 blockade might increase T H 2 cell responses in the airway. 26 Unlike STAT3-deficient T cells, we observed a consistent reduction of T H 2 cell responses in airways of mice with RORγt–deficient T cells, as well as in mice treated with an RORγt inhibitor. Based on these observations, we propose that blockade of RORγt would offer a promising approach for the treatment of allergic asthma in human subjects.…”

Section: Discussionmentioning

confidence: 53%

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Concomitant suppression of TH2 and TH17 cell responses in allergic asthma by targeting retinoic acid receptor–related orphan receptor γt

Lim

Choi

et al. 2018

Journal of Allergy and Clinical Immunology

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Background Allergic asthma is a heterogeneous chronic inflammatory disease of the airways with a massive infiltration of eosinophils or neutrophils mediated by allergen-specific TH2 and TH17 cells, respectively. Therefore successful treatment of allergic asthma will require suppression of both TH2 and TH17 cells. Objective We sought to investigate the role of the TH17 cell pathway in regulating TH2 cell responses in allergic asthma. Methods Allergic asthma was induced by intranasal challenge with proteinase allergens in C57BL/6, Il17a−/−Il17f−/−, and retinoic acid receptor–related orphan receptor γt (RORγt)gfp/gfp mice. A pharmacologic RORγt inhibitor was used to evaluate its preventive and therapeutic effects in allergic asthma. Characteristics of allergic airway inflammation were analyzed by using flow cytometry, histology, quantitative real-time PCR, and ELISA. Mixed bone marrow chimeric mice, fate mapping analysis, short hairpin RNA transduction, and in vitro T-cell differentiation were used for mechanistic studies. Results Mice deficient in IL-17A and IL-17F, as well as RORγt, exhibited a significant reduction not only in TH17 cell responses but also in TH2 cell responses in an animal model of allergic asthma. Similarly, mice treated with an RORγt inhibitor had significantly diminished TH17 and TH2 cell responses, leading to reduced neutrophil and eosinophil numbers in the airway. RORγt-deficient T cells were intrinsically defective in differentiating into TH2 cells and expressed increased levels of B-cell lymphoma 6 (Bcl6). Bcl6 knockdown resulted in a remarkable restoration of TH2 cell differentiation in RORγt- deficient T cells. Blockade of RORγt also significantly hampered the differentiation of human TH2 and TH17 cells from naive CD4+ T cells. Conclusion RORγt in T cells is required for optimal TH2 cell differentiation by suppressing Bcl6 expression; this finding suggests that targeting RORγt might be a promising approach for the treatment of allergic asthma by concomitantly suppressing TH17 and TH2 cell responses in the airway.

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Section: Resultssupporting

confidence: 75%

Section: Discussionmentioning

confidence: 53%

Concomitant suppression of TH2 and TH17 cell responses in allergic asthma by targeting retinoic acid receptor–related orphan receptor γt

Lim

Choi

et al. 2018

Journal of Allergy and Clinical Immunology

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“…However the mechanism behind the opposing role of STAT3 on Th2 cells remains to be investigated. Why previous studies had not shown similar effects with similar models is not clear, but the authors suggest that these discrepancies might be due to differences in the asthma induction protocols [16]. Together, these data demonstrate that STAT3 contributes to Th2-mediated allergic inflammation, but this contribution may be complex and varied.…”

Section: Stat3 and Asthmamentioning

confidence: 78%

“…For example, STAT3-deficient T cells resident in the bronchial lymph nodes produced significantly diminished levels of Th2 cytokines, whereas, in a different model that assessed STAT3-deficient T-cells located in the airways, these cells were found to produce elevated levels of Th2 cytokines. It has been determined that these differential effects were T cell-intrinsic rather than milieu dependent [16]. However the mechanism behind the opposing role of STAT3 on Th2 cells remains to be investigated.…”

Section: Stat3 and Asthmamentioning

confidence: 99%

Contribution of STAT3 to Inflammatory and Fibrotic Diseases and Prospects for its Targeting for Treatment

Kasembeli

Bharadwaj

Robinson

et al. 2018

IJMS

145

119

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Signal transducer and activator of transcription (STAT) 3 plays a central role in the host response to injury. It is activated rapidly within cells by many cytokines, most notably those in the IL-6 family, leading to pro-proliferative and pro-survival programs that assist the host in regaining homeostasis. With persistent activation, however, chronic inflammation and fibrosis ensue, leading to a number of debilitating diseases. This review summarizes advances in our understanding of the role of STAT3 and its targeting in diseases marked by chronic inflammation and/or fibrosis with a focus on those with the largest unmet medical need.

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“…1A) (15). Intranasal challenges with proteinase from Aspergillus oryzae in combination with ovalbumin (PAO/Ova) have been used to induce allergic airway inflammation in mice (181920). Total number of immune cells as well as the frequency of CD4 + T cells in the lung of unchallenged mice was comparable between Rorgt +/gfp and Rorgt gfp/gfp mice (Fig.…”

Section: Resultsmentioning

confidence: 99%

Clonal Expansion of Allergen-specific CD4⁺T Cell in the Lung in the Absence of Lymph Nodes

et al. 2017

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The expansion of allergen-specific CD4+ T cells is a critical step in inducing airway inflammation during allergic asthma. Such clonal expansion of T cells is initiated through the interaction between allergen-bearing dendritic cells and allergen-specific naïve T cells in the draining lymph nodes. Whether such T cell clonal expansion also occurs in the lung, the primary organ encountering inhaled allergens, remains unclear. Compared with wild-type mice, we found similar frequencies of CD4+ T cells in the lung of lymph node-deficient Rorgtgfp/gfp mice after repeated exposure to inhaled allergens. In addition, we observed an evident population of CD4+ T cells that underwent clonal expansion in the lung of allergen-challenged mice treated with an S1P antagonist FTY720 in an in vivo proliferation study with CFSE-labeled OT-II T cells. Moreover, the expansion of allergen-specific CD4+ T cells was significantly enhanced in the lungs of Rorgtgfp/gfp mice in comparison to that of wild-type mice. These results together demonstrate that the clonal expansion of allergen-specific CD4+ T cells occurs in the absence of the lymph nodes, indicating that the lung can act as a primary site of the clonal expansion of CD4+ T cells in response to inhaled allergens.

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Dynamic control of Th2 cell responses by STAT3 during allergic lung inflammation in mice

Cited by 22 publications

References 59 publications

Concomitant suppression of TH2 and TH17 cell responses in allergic asthma by targeting retinoic acid receptor–related orphan receptor γt

Concomitant suppression of TH2 and TH17 cell responses in allergic asthma by targeting retinoic acid receptor–related orphan receptor γt

Contribution of STAT3 to Inflammatory and Fibrotic Diseases and Prospects for its Targeting for Treatment

Clonal Expansion of Allergen-specific CD4⁺T Cell in the Lung in the Absence of Lymph Nodes

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Dynamic control of Th2 cell responses by STAT3 during allergic lung inflammation in mice

Cited by 22 publications

References 59 publications

Concomitant suppression of TH2 and TH17 cell responses in allergic asthma by targeting retinoic acid receptor–related orphan receptor γt

Concomitant suppression of TH2 and TH17 cell responses in allergic asthma by targeting retinoic acid receptor–related orphan receptor γt

Contribution of STAT3 to Inflammatory and Fibrotic Diseases and Prospects for its Targeting for Treatment

Clonal Expansion of Allergen-specific CD4+T Cell in the Lung in the Absence of Lymph Nodes

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About

Clonal Expansion of Allergen-specific CD4⁺T Cell in the Lung in the Absence of Lymph Nodes