scholarly journals Vehicular exhaust particles promote allergic airway inflammation through an aryl hydrocarbon receptor–notch signaling cascade

2015 ◽  
Vol 136 (2) ◽  
pp. 441-453 ◽  
Author(s):  
Mingcan Xia ◽  
Loida Viera-Hutchins ◽  
Maria Garcia-Lloret ◽  
Magali Noval Rivas ◽  
Petra Wise ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Aryl Hydrocarbon Receptor ◽  
Airway Inflammation ◽  
Allergic Airway Inflammation ◽  
Signaling Cascade ◽  
Aryl Hydrocarbon ◽  
Exhaust Particles ◽  
Vehicular Exhaust

scholarly journals Epithelial Aryl Hydrocarbon Receptor Protects From Mucus Production by Inhibiting ROS-Triggered NLRP3 Inflammasome in Asthma

2021 ◽  
Vol 12 ◽  
Author(s):  
Xinyue Hu ◽  
Yingchun Shen ◽  
Yilin Zhao ◽  
Ji Wang ◽  
Xin Zhang ◽  
...  
Keyword(s):  
Mouse Model ◽  
Aryl Hydrocarbon Receptor ◽  
Airway Inflammation ◽  
Nlrp3 Inflammasome ◽  
Allergic Airway Inflammation ◽  
Ros Generation ◽  
Inflammasome Activation ◽  
Mucus Production ◽  
Aryl Hydrocarbon ◽  
Cockroach Allergen

BackgroundDespite long-standing recognition in the significance of mucus overproduction in asthma, its etiology remains poorly understood. Muc5ac is a secretory mucin that has been associated with reduced pulmonary function and asthma exacerbations.ObjectivesWe sought to investigate the immunological pathway that controls Muc5ac expression and allergic airway inflammation in asthma.MethodsCockroach allergen-induced Muc5ac expression and aryl hydrocarbon receptor (AhR) signaling activation was examined in the human bronchial epithelial cells (HBECs) and mouse model of asthma. AhR regulation of Muc5ac expression, mitochondrial ROS (Mito-ROS) generation, and NLRP3 inflammasome was determined by AhR knockdown, the antagonist CH223191, and AhR-/- mice. The role of NLRP3 inflammasome in Muc5ac expression and airway inflammation was also investigated.ResultsCockroach allergen induced Muc5ac overexpression in HBECs and airways of asthma mouse model. Increased expression of AhR and its downstream genes CYP1A1 and CYP1B1 was also observed. Mice with AhR deletion showed increased allergic airway inflammation and MUC5AC expression. Moreover, cockroach allergen induced epithelial NLRP3 inflammasome activation (e.g., NLRP3, Caspase-1, and IL-1β), which was enhanced by AhR knockdown or the antagonist CH223191. Furthermore, AhR deletion in HBECs led to enhanced ROS generation, particularly Mito-ROS, and inhibition of ROS or Mito-ROS subsequently suppressed the inflammasome activation. Importantly, inhibition of the inflammasome with MCC950, a NLRP3-specifc inhibitor, attenuated allergic airway inflammation and Muc5ac expression. IL-1β generated by the activated inflammasomes mediated cockroach allergen-induced Muc5ac expression in HBECs.ConclusionsThese results reveal a previously unidentified functional axis of AhR-ROS-NLRP3 inflammasome in regulating Muc5ac expression and airway inflammation.

scholarly journals Lung epithelial CYP1 activity regulates aryl hydrocarbon receptor dependent allergic airway inflammation

2021 ◽  
Author(s):  
Francesca Alessandrini ◽  
Renske de Jong ◽  
Maria Wimmer ◽  
Ann-Marie Maier ◽  
Isis Fernandez ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Aryl Hydrocarbon Receptor ◽  
Airway Inflammation ◽  
Human Lung ◽  
Allergen Challenge ◽  
Allergic Airway Inflammation ◽  
Lung Epithelial Cells ◽  
Aryl Hydrocarbon ◽  
Lung Epithelial ◽  
Cyp1 Family

The lung epithelial barrier serves as a guardian towards environmental insults and responds to allergen encounter with a cascade of immune reactions that can possibly lead to inflammation. Whether the environmental sensor aryl hydrocarbon receptor (AhR) together with its downstream targets cytochrome P450 (CYP1) family members contribute to the regulation of allergic airway inflammation remains unexplored. By employing knockout mice for AhR and for single CYP1 family members, we found that AhR-/- and CYP1B1-/- but not CYP1A1-/- or CYP1A2-/- animals display enhanced allergic airway inflammation compared to WT. Expression analysis, immunofluorescence staining of murine and human lung sections and bone marrow chimeras suggest an important role of CYP1B1 in non-hematopoietic lung epithelial cells to prevent exacerbation of allergic airway inflammation. Transcriptional analysis of murine and human lung epithelial cells indicates a functional link of AhR to barrier protection/inflammatory mediator signaling upon allergen challenge. In contrast, CYP1B1 deficiency leads to enhanced expression and activity of CYP1A1 in lung epithelial cells and to an increased availability of the AhR ligand kynurenic acid following allergen challenge. Thus, differential CYP1 family member expression and signaling via the AhR in epithelial cells represents an immunoregulatory layer protecting the lung from exacerbation of allergic airway inflammation.

scholarly journals Interleukin 33 Expression Induced by Aryl Hydrocarbon Receptor in Macrophages

2019 ◽  
Vol 170 (2) ◽  
pp. 404-414 ◽  
Author(s):  
Yasuhiro Ishihara ◽  
Thomas Haarmann-Stemmann ◽  
Norman Y Kado ◽  
Christoph F A Vogel
Keyword(s):  
Particulate Matter ◽  
Aryl Hydrocarbon Receptor ◽  
Airway Inflammation ◽  
Airborne Particulate Matter ◽  
Response To Treatment ◽  
Luciferase Assay ◽  
Interleukin 33 ◽  
Aryl Hydrocarbon ◽  
Polycyclic Aromatic ◽  
Mrna And Protein Expression

Abstract Polycyclic aromatic hydrocarbons (PAHs) contained in airborne particulate matter have been identified as a contributing factor for inflammation in the respiratory tract. Recently, interleukin-33 (IL-33) is strongly suggested to be associated with airway inflammation. Aryl hydrocarbon receptor (AhR) is a receptor for PAHs to regulate several metabolic enzymes, but the relationships between AhR and airway inflammation are still unclear. In this study, we examined the role of AhR in the expression of IL-33 in macrophages. THP-1 macrophages mainly expressed IL-33 variant 5, which in turn was strongly induced by the AhR agonists 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) and kynurenine (KYN). AhR antagonist CH223191 suppressed the increase in IL-33 expression. Promoter analysis revealed that the IL-33 promoter has 2 dioxin response elements (DREs). AhR was recruited to both DREs after treatment with TCDD or KYN as assessed by gel shift and chromatin immunoprecipitation assays. A luciferase assay showed that one of the DREs was functional and involved in the expression of IL-33. Macrophages isolated from AhR-null mice expressed only low levels of IL-33 even in response to treatment with AhR ligands compared with wild-type cells. The treatment of THP-1 macrophages with diesel particulate matter and particle extracts increased the mRNA and protein expression of IL-33. Taken together, the results show that ligand-activated AhR mediates the induction of IL-33 in macrophages via a DRE located in the IL-33 promoter region. AhR-mediated IL-33 induction could be involved in the exacerbation and/or prolongation of airway inflammation elicited by toxic chemical substances.

scholarly journals Multi-Faceted Notch in Allergic Airway Inflammation

2019 ◽  
Vol 20 (14) ◽  
pp. 3508
Author(s):  
Miao-Tzu Huang ◽  
Chiao-Juno Chiu ◽  
Bor-Luen Chiang
Keyword(s):  
Embryonic Development ◽  
Notch Signaling ◽  
Airway Inflammation ◽  
Cell Activity ◽  
Adult Life ◽  
Allergic Airway Inflammation ◽  
T Cell Subsets ◽  
Cell Fate Decisions ◽  
Physiological Processes

Notch is an evolutionarily conserved signaling family which iteratively exerts pleiotropic functions in cell fate decisions and various physiological processes, not only during embryonic development but also throughout adult life. In the context of the respiratory system, Notch has been shown to regulate ciliated versus secretory lineage differentiation of epithelial progenitor cells and coordinate morphogenesis of the developing lung. Reminiscent of its role in development, the Notch signaling pathway also plays a role in repair of lung injuries by regulation of stem cell activity, cell differentiation, cell proliferation and apoptosis. In addition to functions in embryonic development, cell and tissue renewal and various physiological processes, including glucose and lipid metabolism, Notch signaling has been demonstrated to regulate differentiation of literally almost all T-cell subsets, and impact on elicitation of inflammatory response and its outcome. We have investigated the role of Notch in allergic airway inflammation in both acute and chronic settings. In this mini-review, we will summarize our own work and recent advances on the role of Notch signaling in allergic airway inflammation, and discuss potential applications of the Notch signaling family in therapy for allergic airway diseases.

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