Role of Growth Arrest–Specific Gene 6 in the Development of Fungal Allergic Airway Disease in Mice

Shibata, Takehiko; Ismailoglu, Ugur B.; Kittan, Nicolai A.; Moreira, Ana Paula; Coelho, Ana Lúcia; Chupp, Geoffrey; Kunkel, Steven L.; Lukacs, Nicholas W.; Hogaboam, Cory M.

doi:10.1165/rcmb.2014-0049oc

Cited by 17 publications

(19 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Gas6/Axl signaling in this model was found to regulate adaptive Th2-mediated immune responses, including Th2 cytokine production, airway hyperresponsiveness with airway inflammation, goblet cell metaplasia, and increased IgE production (8,33). Similar to the fungal allergic airway model, Axl mAb treatment in mice with IPA was protective via demonstrable effects on cells of myeloid origin.…”

Section: Discussionmentioning

confidence: 74%

“…We recently reported on the role of Gas6/TAM signaling in a well-established fungal allergic model (8,33). Gas6/Axl signaling in this model was found to regulate adaptive Th2-mediated immune responses, including Th2 cytokine production, airway hyperresponsiveness with airway inflammation, goblet cell metaplasia, and increased IgE production (8,33).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Axl Receptor Blockade Protects from Invasive Pulmonary Aspergillosis in Mice

Shibata

Habiel

Coelho

et al. 2014

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

Aspergillus fumigatus is a sporulating fungus found ubiquitously in the environment, which is quickly contained in the immunocompetent host but can cause lethal invasive aspergillosis in the immunocompromised host. We have recently demonstrated that Axl (one member of the Tyro3, Axl, Mertk receptor family) is a key regulator of antiviral immune responses in the lung. In this study, we investigated the role of Axl in antifungal immunity in a model of invasive pulmonary aspergillosis (IPA). In this model, Aspergillus fumigatus conidia were administered into the lungs of neutrophil-depleted mice, and the mice were monitored for survival, lung inflammatory response, and fungal clearance. The lethal effect of IPA was significantly reduced in anti-Axl mAb–treated mice compared with IgG control–treated mice. Targeting Axl significantly inhibited pulmonary inflammation, including the expression of IL-1β, IL-6, TNF-α, and chitinase-like proteins in whole lung. Further, anti-Axl mAb treatment significantly increased M1 macrophages that highly expressed inducible NO synthase and decreased M2 macrophages that expressed Arginase 1 and were found in inflammatory zone protein (Fizz1). More importantly, anti-Axl mAb treatment significantly increased the number of IFN-γ–producing T cells and NK cells compared with the IgG control group during IPA. Together, our results demonstrate that the Axl mAb treatment is protective during invasive aspergillosis in neutropenic mice. Collectively, these data suggest a potential deleterious role for Axl during primary immune responses directed against A. fumigatus and novel therapeutic strategy for IPA.

show abstract

Section: Discussionmentioning

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Axl Receptor Blockade Protects from Invasive Pulmonary Aspergillosis in Mice

Shibata

Habiel

Coelho

et al. 2014

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

show abstract

“…These results suggest that Gas6 regulates the differentiation of Th1 and Th2 cells via DCs during immunization with FI‐RSV (Figure 4c). In line with this, we previously found that DCs and macrophages, but not T cells, produce high levels of Gas6, which facilitates the allergic response, and express TAM receptors—Axl in particular—in a fungal asthma model 30 . Therefore, we again focused on DCs as the key cell subset driving subsequent immune responses.…”

Section: Resultsmentioning

confidence: 54%

“…Allergic airway responses are associated with Th2 immunity, and IL‐25, IL‐33 and TSLP have been identified as triggers in various allergic models 37 , 38 , 39 . In contrast, our previous study showed that signaling from Gas6 and its receptor, Axl, is a novel inducer of allergic airway responses in a model of fungal asthma 28 , 30 . In this study, we also observed that Gas6/Axl signaling leads to allergic airway responses in RSV infection after immunization with FI‐RSV (that is, FI‐RSV VED); this mechanism was previously unknown.…”

Section: Discussionmentioning

confidence: 93%

“…In addition, TAM receptor signaling in dendritic cells (DCs) controls the magnitude of the immune response by suppressing the activation of T cells in vivo 27 . More recently, our study showed that signaling through Gas6 and its highest affinity receptor Axl, but not Mertk and Tyro3, is a novel inducer of Th2 immune responses in fungus‐induced allergic airway inflammation 28 , 29 , 30 …”

mentioning

confidence: 91%

See 1 more Smart Citation

A critical role of Gas6/Axl signal in allergic airway responses during RSV vaccine‐enhanced disease

Shibata

Ato

2017

Immunol Cell Biol

Self Cite

View full text Add to dashboard Cite

Respiratory syncytial virus (RSV) is a common virus that causes lower respiratory infections across a wide range of ages. A licensed RSV vaccine is not available because vaccination with formalin-inactivated RSV (FI-RSV) and the subsequent RSV infection cause not only insufficient induction of neutralizing antibodies but also severe allergic airway responses, termed FI-RSV vaccine-enhanced disease (FI-RSV VED). However, the underlying mechanism has not been identified, although a Th2-biased immune response is known to be a hallmark of this disease. Our previous studies have shown that growth arrest-specific 6 (Gas6)/Axl signaling leads to Th2-biased immune responses during fungus-induced allergic airway inflammation. Here, we show that Gas6/Axl signaling also leads to FI-RSV VED and partially identify the mechanism in mice. Inhibiting Gas6/Axl signaling using Gas6-deficient mice, neutralizing antibodies, and a specific inhibitor of Axl attenuated allergic airway hyperresponsiveness, including airway inflammation, goblet cell hyperplasia, and Th2 cytokine production, in addition to increasing interferon-γ levels and the production of RSV-neutralizing IgG2a in FI-RSV VED. Gas6 was produced in lymph nodes during immunization with FI-RSV. Lymph node cells derived from immunized mice produced high levels of Gas6 and Th2 cytokines, but not IFN-γ, after restimulation with RSV. Finally, we found that dendritic cells stimulated with RSV-glycoprotein (G protein) produced Gas6 and that Axl signaling suppressed DC maturation and the induction of IL-12 production by the toll-like receptor 4 agonist RSV-fusion protein. Taken together, these results indicate that RSV-G protein-induced Gas6/Axl signaling causes allergic airway responses during FI-RSV VED.

show abstract

A scoping review: What are the cellular mechanisms that drive the allergic inflammatory response to fungal allergens in the lung epithelium?

Goode¹,

Marczylo²

2023

Clinical & Translational All

View full text Add to dashboard Cite

Allergic airway disease (AAD) is a collective term for respiratory disorders that can be exacerbated upon exposure to airborne allergens. The contribution of fungal allergens to AAD has become well established over recent years. We conducted a comprehensive review of the literature using Preferred Reporting Items for Systematic Reviews and Meta‐Analyses guidelines to better understand the mechanisms involved in the allergic response to fungi in airway epithelia, identify knowledge gaps and make recommendations for future research. The search resulted in 61 studies for final analysis. Despite heterogeneity in the models and methods used, we identified major pathways involved in fungal allergy. These included the activation of protease‐activated receptor 2, the EGFR pathway, adenosine triphosphate and purinergic receptor‐dependent release of IL33, and oxidative stress, which drove mucin expression and goblet cell metaplasia, Th2 cytokine production, reduced barrier integrity, eosinophil recruitment, and airway hyperresponsiveness. However, there were several knowledge gaps and therefore we recommend future research should focus on the use of more physiologically relevant methods to directly compare key allergenic fungal species, clarify specific mechanisms of fungal allergy, and assess the fungal allergy in disease models. This will inform disease management and future interventions, ultimately reducing the burden of disease.

show abstract

Role of Growth Arrest–Specific Gene 6 in the Development of Fungal Allergic Airway Disease in Mice

Cited by 17 publications

References 36 publications

Axl Receptor Blockade Protects from Invasive Pulmonary Aspergillosis in Mice

Axl Receptor Blockade Protects from Invasive Pulmonary Aspergillosis in Mice

A critical role of Gas6/Axl signal in allergic airway responses during RSV vaccine‐enhanced disease

A scoping review: What are the cellular mechanisms that drive the allergic inflammatory response to fungal allergens in the lung epithelium?

Contact Info

Product

Resources

About