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

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.

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Roles of IL-22 in Allergic Airway Inflammation

Journal of Allergy ◽

10.1155/2013/260518 ◽

2013 ◽

Vol 2013 ◽

pp. 1-5 ◽

Cited By ~ 1

Author(s):

Koichi Hirose ◽

Kentaro Takahashi ◽

Hiroshi Nakajima

Keyword(s):

Epithelial Cells ◽

Airway Inflammation ◽

Th17 Cells ◽

Therapeutic Potential ◽

Allergen Challenge ◽

Allergic Airway Inflammation ◽

Lymphoid Cells ◽

Lung Epithelial Cells ◽

Chemokine Production ◽

Lung Epithelial

IL-23- and IL-17A-producing CD4+ T cell (Th17 cell) axis plays a crucial role in the development of chronic inflammatory diseases. In addition, it has been demonstrated that Th17 cells and their cytokines such as IL-17A and IL-17F are involved in the pathogenesis of severe asthma. Recently, IL-22, an IL-10 family cytokine that is produced by Th17 cells, has been shown to be expressed at the site of allergic airway inflammation and to inhibit allergic inflammation in mice. In addition to Th17 cells, innate lymphoid cells also produce IL-22 in response to allergen challenge. Functional IL-22 receptor complex is expressed on lung epithelial cells, and IL-22 inhibits cytokine and chemokine production from lung epithelial cells. In this paper, we summarize the recent progress on the roles of IL-22 in the regulation of allergic airway inflammation and discuss its therapeutic potential in asthma.

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IL-22 induces Reg3γ and inhibits allergic inflammation in house dust mite–induced asthma models

Journal of Experimental Medicine ◽

10.1084/jem.20162108 ◽

2017 ◽

Vol 214 (10) ◽

pp. 3037-3050 ◽

Cited By ~ 14

Author(s):

Takashi Ito ◽

Koichi Hirose ◽

Aiko Saku ◽

Kenta Kono ◽

Hiroaki Takatori ◽

...

Keyword(s):

Epithelial Cells ◽

Airway Inflammation ◽

House Dust ◽

House Dust Mite ◽

Cytokine Production ◽

Allergic Airway Inflammation ◽

Lung Epithelial Cells ◽

Intratracheal Administration ◽

Lung Epithelial ◽

Dust Mite

Previous studies have shown that IL-22, one of the Th17 cell–related cytokines, plays multiple roles in regulating allergic airway inflammation caused by antigen-specific Th2 cells; however, the underlying mechanism remains unclear. Here, we show that allergic airway inflammation and Th2 and Th17 cytokine production upon intratracheal administration of house dust mite (HDM) extract, a representative allergen, were exacerbated in IL-22-deficient mice. We also found that IL-22 induces Reg3γ production from lung epithelial cells through STAT3 activation and that neutralization of Reg3γ significantly exacerbates HDM-induced eosinophilic airway inflammation and Th2 cytokine induction. Moreover, exostatin-like 3 (EXTL3), a functional Reg3γ binding protein, is expressed in lung epithelial cells, and intratracheal administration of recombinant Reg3γ suppresses HDM-induced thymic stromal lymphopoietin and IL-33 expression and accumulation of type 2 innate lymphoid cells in the lung. Collectively, these results suggest that IL-22 induces Reg3γ production from lung epithelial cells and inhibits the development of HDM-induced allergic airway inflammation, possibly by inhibiting cytokine production from lung epithelial cells.

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Down-Regulation of p23 in Normal Lung Epithelial Cells Reduces Toxicities From Exposure to Benzo[a]pyrene and Cigarette Smoke Condensate via an Aryl Hydrocarbon Receptor-Dependent Mechanism

Toxicological Sciences ◽

10.1093/toxsci/kfy234 ◽

2018 ◽

Vol 167 (1) ◽

pp. 239-248 ◽

Cited By ~ 3

Author(s):

Jinyun Chen ◽

Poonam Yakkundi ◽

William K Chan

Keyword(s):

Epithelial Cells ◽

Aryl Hydrocarbon Receptor ◽

Cigarette Smoke ◽

Lung Epithelial Cells ◽

Normal Lung ◽

Cigarette Smoke Condensate ◽

Down Regulation ◽

Protein Levels ◽

Aryl Hydrocarbon ◽

Lung Epithelial

Abstract The aryl hydrocarbon receptor (AHR) is a ligand-activated signaling molecule which controls tumor growth and metastasis, T cell differentiation, and liver development. Expression levels of this receptor protein is sensitive to the cellular p23 protein levels in immortalized cancer cell lines. As little as 30% reduction of the p23 cellular content can suppress the AHR function. Here we reported that down-regulation of the p23 protein content in normal, untransformed human bronchial/tracheal epithelial cells to 48% of its content also suppresses the AHR protein levels to 54% of its content. This p23-mediated suppression of AHR is responsible for the suppression of (1) the ligand-dependent induction of the cyp1a1 gene transcription; (2) the benzo[a]pyrene- or cigarette smoke condensate-induced CYP1A1 enzyme activity, and (3) the benzo[a]pyrene and cigarette smoke condensate-mediated production of reactive oxygen species. Reduction of the p23 content does not alter expression of oxidative stress genes and production of PGE2. Down regulation of p23 suppresses the AHR protein levels in two other untransformed cell types, namely human breast MCF-10A and mouse immune regulatory Tr1 cells. Collectively, down-regulation of p23 suppresses the AHR protein levels in normal and untransformed cells and can in principle protect our lung epithelial cells from AHR-dependent oxidative damage caused by exposure to agents from environment and cigarette smoking.

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Crispr/Cas9 Knockout of the Aryl Hydrocarbon Receptor (AhR) in Mouse Lung Epithelial Cells (MLE-15) Results in Changes in Epithelial Phenotype and Features of Epithelial-Mesenchymal Transition

10.1164/ajrccm-conference.2020.201.1_meetingabstracts.a5654 ◽

2020 ◽

Author(s):

A. Sturrock ◽

E. Zimmerman ◽

K.L. Burrell ◽

C.A. Reilly ◽

R. Paine

Keyword(s):

Epithelial Cells ◽

Aryl Hydrocarbon Receptor ◽

Epithelial Mesenchymal Transition ◽

Lung Epithelial Cells ◽

Mouse Lung ◽

Mesenchymal Transition ◽

Aryl Hydrocarbon ◽

Lung Epithelial ◽

Epithelial Phenotype

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Intelectin is required for IL-13-induced monocyte chemotactic protein-1 and -3 expression in lung epithelial cells and promotes allergic airway inflammation

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.90612.2008 ◽

2010 ◽

Vol 298 (3) ◽

pp. L290-L296 ◽

Cited By ~ 35

Author(s):

Naibing Gu ◽

Guannan Kang ◽

Chang'E Jin ◽

Yongjian Xu ◽

Zhenxiang Zhang ◽

...

Keyword(s):

Epithelial Cells ◽

Airway Inflammation ◽

Airway Epithelium ◽

Allergic Airway Inflammation ◽

Airway Epithelial Cells ◽

Lung Epithelial Cells ◽

Mouse Lung ◽

Airway Epithelial ◽

Chemotactic Protein ◽

Lung Epithelial

Asthma is characterized by airway inflammation, mucus overproduction, airway hyperreactivity, and peribronchial fibrosis. Intelectin has been shown to be increased in airway epithelium of asthmatics. However, the role of intelectin in the pathogenesis of asthma is unknown. Airway epithelial cells can secrete chemokines such as monocyte chemotactic protein (MCP)-1 and -3 that play crucial roles in asthmatic airway inflammation. We hypothesized that intelectin plays a role in allergic airway inflammation by regulating chemokine expression. In a mouse allergic asthma model, we found that mRNA expression of intelectin-2 as well as MCP-1 and -3 in mouse lung was increased very early (within 2 h) after allergen challenge. Expression of intelectin protein was localized to mucous cells in airway epithelium. Treatment of MLE12 mouse lung epithelial cells with interleukin IL-13, a critical mediator of allergic airway disease, induced expression of intelectin-1 and -2 as well as MCP-1 and -3. When IL-13-induced intelectin-1 and -2 expression was inhibited by RNA interference, IL-13-induced extracellular signal-regulated kinase 1/2 phosphorylation and MCP-1 and -3 production by MLE12 cells was inhibited. Furthermore, inhibition of intelectin expression by airway transfection with shRNA targeting intelectin-1 and -2 attenuated allergen-induced airway inflammation. We conclude that intelectin, a molecule expressed by airway epithelial cells and upregulated in asthma, is required for IL-13-induced MCP-1 and -3 production in mouse lung epithelial cells and contributes to allergic airway inflammation.

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