Systemic Pharmacological Smoothened Inhibition Reduces Lung T-Cell Infiltration and Ameliorates Th2 Inflammation in a Mouse Model of Allergic Airway Disease

Yánez, Diana C.; Papaioannou, Eleftheria; Chawda, Mira Manilal; Rowell, Jasmine; Ross, Scott R.; Lau, Ching‐In; Crompton, Tessa

doi:10.3389/fimmu.2021.737245

Cited by 14 publications

(15 citation statements)

References 50 publications

(79 reference statements)

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“…The results showed that the Hh signaling both promotes the γ-δ differentiation in the thymus and influences the T-cell pattern of distribution in the spleen. Consequently, the SMO inhibition causes the reduction of the γ-δ T-cells and γ-δ NKT cells both in the thymus and in the spleen, confirming a role for Hh pathway in the T-cell differentiation process ( 48 ).…”

Section: Effects Of Hedgehog Pathway Inhibitors On Systemic Immune Re...mentioning

confidence: 78%

“…Yanez et al reported a reduced inflammatory reaction in a mouse model of allergic airway disease. During systemic therapy, they observed not only a reduced percentage of basophils, eosinophils, mast cells and CD4+ T cell in the lungs, but also a decreased CD4+T cells infiltration in the mediastinal lymph nodes, as well as a reduced level of immunoglobulin E in the serum ( 48 ). Although not only local effects were observed, the systemic ones could be more likely correlated to the reduced local inflammation, so that the systemic effect should not be interpreted as primary, but as a consequence of SMO inhibition.…”

Section: Effects Of Hedgehog Pathway Inhibitors On Systemic Immune Re...mentioning

confidence: 99%

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Basal Cell Carcinoma and Hedgehog Pathway Inhibitors: Focus on Immune Response

et al. 2022

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Basal cell carcinoma (BCC) is the most common form of skin cancer, affecting more often elderly patients, but sometimes even younger ones, particularly if immunocompromised or genetically predisposed. Specifically, the Gorlin-Goltz syndrome, an autosomal dominant genodermatosis, also known as nevoid basal cell carcinoma syndrome, characterizes for multiple early onset BCCs. It is caused by a germline mutation in PTCH1, a tumor suppressor gene whose product is the key component of Hedgehog (Hh) signaling pathway, which also appears somatically mutated in more than 85% of sporadic BCCs. Hh pathway inhibitors vismodegib and sonidegib are currently indicated for BCC, in adults with advanced or recurred tumor following surgery or radiation therapy. The principal mechanism of action of these drugs is the inhibition of Smoothened (SMO), a transmembrane protein involved in Hh signal transduction, that plays a role in both cellular differentiation and cancer development. Some studies have reported effects of Hh pathway inhibitors at different levels of the immune response, from cytotoxic T cells to a modified local cytokines pattern. Given the specific relation between immune system and BCC development in some conditions, we will review BCC with focus on immune system changes mediated by Hh signaling pathway and induced by the inhibitors vismodegib and sonidegib in the treatment of BCC. Thus, we will give an overview of their effects on the local immune response, as well as a brief note on the supposed function of Hh pathway inhibition on the systemic one.

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Section: Effects Of Hedgehog Pathway Inhibitors On Systemic Immune Re...mentioning

confidence: 78%

Section: Effects Of Hedgehog Pathway Inhibitors On Systemic Immune Re...mentioning

confidence: 99%

Basal Cell Carcinoma and Hedgehog Pathway Inhibitors: Focus on Immune Response

et al. 2022

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“…Comparison between control populations showed that Foxa2 is ~6-fold more highly expressed in lung epithelial cells than in lung T-cells ( Figure S3A ). To induce AAD, we used papain as allergen, which induces allergic airway inflammation by initiating a Th2 immune response and is linked to occupational and non-occupational asthma and allergy in humans ( 29 , 35 , 39 – 45 ). We administered intranasal papain in PBS to Foxa2cKO (Foxa2f/fCD4Cre+) and control (Foxa2f/fCD4Cre neg ) mice on day 0 and day 7 and sacrificed mice on day 10, treating with PBS alone at the same time points as negative control ( Figure S1A ).…”

Section: Resultsmentioning

confidence: 99%

“…Many studies have shown that Shh upregulation in lung epithelial cells exacerbates allergic airway inflammation ( 22 – 28 ). Additionally, Shh signalling to naïve CD4 T-cells promotes their differentiation to Th2 in vitro and drives allergic airway disease (AAD) in lung in vivo ( 23 , 24 , 29 , 30 ).…”

Section: Introductionmentioning

confidence: 99%

The Pioneer Transcription Factor Foxa2 Modulates T Helper Differentiation to Reduce Mouse Allergic Airway Disease

et al. 2022

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Foxa2, a member of the Forkhead box (Fox) family of transcription factors, plays an important role in the regulation of lung function and lung tissue homeostasis. FOXA2 expression is reduced in the lung and airways epithelium of asthmatic patients and in mice absence of Foxa2 from the lung epithelium contributes to airway inflammation and goblet cell hyperplasia. Here we demonstrate a novel role for Foxa2 in the regulation of T helper differentiation and investigate its impact on lung inflammation. Conditional deletion of Foxa2 from T-cells led to increased Th2 cytokine secretion and differentiation, but decreased Th1 differentiation and IFN-γ expression in vitro. Induction of mouse allergic airway inflammation resulted in more severe disease in the conditional Foxa2 knockout than in control mice, with increased cellular infiltration to the lung, characterized by the recruitment of eosinophils and basophils, increased mucus production and increased production of Th2 cytokines and serum IgE. Thus, these experiments suggest that Foxa2 expression in T-cells is required to protect against the Th2 inflammatory response in allergic airway inflammation and that Foxa2 is important in T-cells to maintain the balance of effector cell differentiation and function in the lung.

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“…Thus, systemic pharmacological smoothened inhibition in a mouse model of allergic airway illness reduced the infiltration of T-cells and differentiation of Th2 cells in the lung. Moreover, it attenuated the inflammation, disease severity, Mucin gene Muc 5ac expression, andserum IgE, and it seemed to be defensive against lung diseases [ 145 ].…”

Section: Potentially Therapeutic Significancementioning

confidence: 99%

Hedgehog Signaling: Linking Embryonic Lung Development and Asthmatic Airway Remodeling

Zeng

Barkat

Syed

et al. 2022

Cells

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The development of the embryonic lung demands complex endodermal–mesodermal interactions, which are regulated by a variety of signaling proteins. Hedgehog (Hh) signaling is vital for lung development. It plays a key regulatory role during several morphogenic mechanisms, such as cell growth, differentiation, migration, and persistence of cells. On the other hand, abnormal expression or loss of regulation of Hh signaling leads to airway asthmatic remodeling, which is characterized by cellular matrix modification in the respiratory system, goblet cell hyperplasia, deposition of collagen, epithelial cell apoptosis, proliferation, and activation of fibroblasts. Hh also targets some of the pathogens and seems to have a significant function in tissue repairment and immune-related disorders. Similarly, aberrant Hh signaling expression is critically associated with the etiology of a variety of other airway lung diseases, mainly, bronchial or tissue fibrosis, lung cancer, and pulmonary arterial hypertension, suggesting that controlled regulation of Hh signaling is crucial to retain healthy lung functioning. Moreover, shreds of evidence imply that the Hh signaling pathway links to lung organogenesis and asthmatic airway remodeling. Here, we compiled all up-to-date investigations linked with the role of Hh signaling in the development of lungs as well as the attribution of Hh signaling in impairment of lung expansion, airway remodeling, and immune response. In addition, we included all current investigational and therapeutic approaches to treat airway asthmatic remodeling and immune system pathway diseases.

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Systemic Pharmacological Smoothened Inhibition Reduces Lung T-Cell Infiltration and Ameliorates Th2 Inflammation in a Mouse Model of Allergic Airway Disease

Cited by 14 publications

References 50 publications

Basal Cell Carcinoma and Hedgehog Pathway Inhibitors: Focus on Immune Response

Basal Cell Carcinoma and Hedgehog Pathway Inhibitors: Focus on Immune Response

The Pioneer Transcription Factor Foxa2 Modulates T Helper Differentiation to Reduce Mouse Allergic Airway Disease

Hedgehog Signaling: Linking Embryonic Lung Development and Asthmatic Airway Remodeling

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