IL-33 dysregulates regulatory T cells and impairs established immunologic tolerance in the lungs

Chen, Chien‐Chang; Kobayashi, Takao; Izutsu, Koji; Hsu, Fan Chi; Kita, Hirohito

doi:10.1016/j.jaci.2017.01.015

Cited by 90 publications

(105 citation statements)

References 65 publications

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“…Although IL‐33 is well recognized as a permissive influence in the development of autoimmune diseases involving the airways, the mechanisms by which it does this remain unclear. IL‐33 is able to promote the activity of immune cells while disabling regulatory T‐cells, activities that might sever immunological tolerance . IL‐33 is known to be produced principally by alveolar type II epithelial cells, and is rapidly released following activation or damage of the cells by viruses, allergens and other environmental insults impacting on the airways .…”

Section: Discussionmentioning

confidence: 99%

IL‐33 induces production of autoantibody against autologous respiratory epithelial cells: a potential mechanism for the pathogenesis of COPD

Chen

et al. 2019

Immunology

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Summary The mechanisms underlying the chronic, progressive airways inflammation, remodelling and alveolar structural damage characteristic of human chronic obstructive pulmonary disease (COPD) remain unclear. In the present study, we address the hypothesis that these changes are at least in part mediated by respiratory epithelial alarmin (IL‐33)‐induced production of autoantibodies against airways epithelial cells. Mice immunized with homologous, syngeneic lung tissue lysate along with IL‐33 administered directly to the respiratory tract or systemically produced IgG autoantibodies binding predominantly to their own alveolar type II epithelial cells, along with increased percentages of Tfh cells and B2 B‐cells in their local, mediastinal lymph nodes. Consistent with its specificity for respiratory epithelial cells, this autoimmune inflammation was confined principally to the lung and not other organs such as the liver and kidney. Furthermore, the serum autoantibodies produced by the mice bound not only to murine, but also to human alveolar type II epithelial cells, suggesting specificity for common, cross‐species determinants. Finally, concentrations of antibodies against both human and murine alveolar epithelial cells were significantly elevated in the serum of patients with COPD compared with those of control subjects. These data are consistent with the hypothesis that IL‐33 contributes to the chronic, progressive airways obstruction, inflammation and alveolar destruction characteristic of phenotypes of COPD/emphysema through induction of autoantibodies against lung tissue, and particularly alveolar type II epithelial cells.

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Section: Discussionmentioning

confidence: 99%

IL‐33 induces production of autoantibody against autologous respiratory epithelial cells: a potential mechanism for the pathogenesis of COPD

Chen

et al. 2019

Immunology

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“…When exposed to IL‐33, ST2 + Treg cells proliferated and upregulated GATA3 and ST2 expression . IL‐33‐stimulated GATA3 + Treg cells, but not GATA3 − Treg cells, expressed Il5 and Il13 mRNA, and were capable of producing IL‐5 and IL‐13 proteins . Furthermore, using an in vitro co‐culture assay, IL‐33 was shown to impair the ability of Foxp3 + Treg cells to suppress the proliferation of effector CD4 + T cells.…”

Section: Il‐33 In Adaptive Immunitymentioning

confidence: 98%

“…Treg cells are critically involved in immune homeostasis and tolerance to innocuous antigens . Under basal conditions, constitutive ST2 expression was observed in subsets of CD4 + Foxp3 + Treg cells in various tissues, including those in the lung and gastrointestinal tract . Interestingly, these ST2 + Treg cells also expressed the canonical Th2 transcription factor GATA3.…”

Section: Il‐33 In Adaptive Immunitymentioning

confidence: 99%

“…Interestingly, these ST2 + Treg cells also expressed the canonical Th2 transcription factor GATA3. When exposed to IL‐33, ST2 + Treg cells proliferated and upregulated GATA3 and ST2 expression . IL‐33‐stimulated GATA3 + Treg cells, but not GATA3 − Treg cells, expressed Il5 and Il13 mRNA, and were capable of producing IL‐5 and IL‐13 proteins .…”

Section: Il‐33 In Adaptive Immunitymentioning

confidence: 99%

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IL‐33: biological properties, functions, and roles in airway disease

Drake

Kita

2017

Immunological Reviews

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214

203

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Summary Interleukin (IL)-33 is a key cytokine involved in type 2 immunity and allergic airway diseases. Abundantly expressed in lung epithelial cells, IL-33 plays critical roles in both innate and adaptive immune responses in mucosal organs. In innate immunity, IL-33 and group 2 innate lymphoid cells (ILC2s) provide an essential axis for rapid immune responses and tissue homeostasis. In adaptive immunity, IL-33 interacts with dendritic cells, Th2 cells, follicular T cells, and regulatory T cells, where IL-33 influences the development of chronic airway inflammation and tissue remodeling. The clinical findings that both the IL-33 and ILC2 levels are elevated in patients with allergic airway diseases suggest that IL-33 plays an important role in the pathogenesis of these diseases. IL-33 and ILC2 may also serve as biomarkers for disease classification and to monitor the progression of diseases. In this article, we reviewed the current knowledge of the biology of IL-33 and discussed the roles of the IL-33 in regulating airway immune responses and allergic airway diseases.

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“…RSV infection impaired immune tolerance by inducing phenotypic changes in Foxp3 + Treg cells, including GATA-3 expression, Th2 cytokine production, and loss of suppressive functions, in an IL-4-dependent pathway [19]. The potential of IL-33 in overcoming acquired immune tolerance was confirmed recently [54]. It was revealed that Foxp3 + Treg cells express the IL-33 receptor ST2, the expression of which was enhanced by the ligand, that IL-33 evoked Th2-like properties in those cells by inducing GATA-3 expression and the synthesis of Th2 cytokines associated with the loss of suppressive function, and that intranasal IL-33 administration to tolerized mice (during or after sensitization) caused allergen-induced airway inflammation.…”

Section: Discussionmentioning

confidence: 99%

Increased Susceptibility to Allergic Asthma with the Impairment of Respiratory Tolerance Caused by Psychological Stress

Kawano

Ouchi

Ishigaki

et al. 2018

Int Arch Allergy Immunol

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Background: Bronchial asthma is characterized by type 2 T helper (Th2) cell inflammation, essentially due to a breakdown of immune tolerance to harmless environmental allergens. Etiologically, experiences of psychological stress can be associated with a heightened prevalence of asthma. However, the mechanisms underlying stress-related asthma development are unclear. In this study, we examined whether psychological stress increases susceptibility to allergic asthma by downregulating immune tolerance. Methods: Female BALB/c mice were sensitized with ovalbumin/alum, followed by ovalbumin inhalation. Ovalbumin inhalation induced immune tolerance before sensitization occurred. Some mice were exposed to restraint stress during tolerance induction or sensitization. Asthma development was evaluated by airway responsiveness, inflammation, cytokine expression, and IgE synthesis. Sensitization was evaluated by measuring proliferation and cytokine production by splenocytes. The effects of stress exposure on the numbers and functions of dendritic cells and regulatory T (Treg) cells in bronchial lymph nodes and spleens were evaluated. To investigate the role of endogenous glucocorticoid in inhibiting immune tolerance after stress exposure, we examined the effects of (i) a glucocorticoid-receptor antagonist administered prior to stress exposure, and (ii) exogenous glucocorticoid (instead of stress exposure). Results: Asthmatic responses and Th2-biased sensitization, which were suppressed in tolerized mice, re-emerged in tolerized mice stressed during tolerance induction in association with decreased tolerogenic dendritic and Treg cell numbers. The effects of stress exposure on tolerized mice were abolished by administering a glucocorticoid-receptor antagonist and reproduced by administering exogenous glucocorticoid without stress. Conclusions: Our findings suggested that psychological stress can potentially increase allergic asthma susceptibility by inhibiting immune tolerance.

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IL-33 dysregulates regulatory T cells and impairs established immunologic tolerance in the lungs

Cited by 90 publications

References 65 publications

IL‐33 induces production of autoantibody against autologous respiratory epithelial cells: a potential mechanism for the pathogenesis of COPD

IL‐33 induces production of autoantibody against autologous respiratory epithelial cells: a potential mechanism for the pathogenesis of COPD

IL‐33: biological properties, functions, and roles in airway disease

Increased Susceptibility to Allergic Asthma with the Impairment of Respiratory Tolerance Caused by Psychological Stress

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