Amplification of cytokine production through synergistic activation of NFAT and AP‐1 following stimulation of mast cells with antigen and IL‐33

Andrade, Marcus V.; Iwaki, Shoko; Ropert, Catherine; Gazzinelli, Ricardo T.; Cunha-Melo, José Renan; Beaven, Michael A.

doi:10.1002/eji.201040718

Cited by 89 publications

(134 citation statements)

References 57 publications

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“…In mast cells, activation of IL-33R, either alone or simultaneously with FcεRI, leads to, or enhances, the production of TNF-α, IL-6, IL-13, MCP-1, MCP-3, and MIP-1α via the Src and MAPK cascade [49]. This activation mirrors enhanced in vivo mast cell response in a mast cell dependent model of psoriasis [50] and airway inflammation [51].…”

Section: Il-33r Signaling and Modulation Of Fcr Activationmentioning

confidence: 94%

Mast cell activation: A complex interplay of positive and negative signaling pathways

Sibilano¹,

2014

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Mast cells regulate the immunological responses causing allergy and autoimmunity, and contribute to the tumor microenvironment through generation and secretion of a broad array of preformed, granule-stored and de novo synthesized bioactive compounds. The release and production of mast cell mediators is the result of a coordinated signaling machinery, followed by the FcεRI and FcγR antigen ligation. In this review, we present the latest understanding of FcεRI and FcγR signaling, required for the canonical mast cell activation during allergic responses and anaphylaxis. We then describe the cooperation between the signaling of FcR and other recently characterized membrane-bound receptors (i.e., IL-33R and thymic stromal lymphopoietin receptor) and their role in the chronic settings, where mast cell activation is crucial for the development and the sustainment of chronic diseases, such as asthma or airway inflammation. Finally, we report how the FcR activation could be used as a therapeutic approach to treat allergic and atopic diseases by mast cell inactivation. Understanding the magnitude and the complexity of mast cell signaling is necessary to identify the mechanisms underlying the potential effector and regulatory roles of mast cells in the biology and pathology of those disease settings in which mast cells are activated.Keywords: FcεRI r FcγR r IL-33 r mast cells r TSLP IntroductionMast cells originate in the BM from a lineage-specific multipotent hematopoietic progenitor, circulate as CD34 + precursors until they migrate to tissues and mature into effector cells in the proximity of organs and blood vessels. Mast cells respond to antigenic stimulation through the cross-linking of immunoglobulin E (IgE) bound to high-affinity receptors for IgE (FcεRI) and the activation of the FcγR after IgG binding (reviewed in [1,2]). Upon activation, mast cells release either preformed, granule-stored mediators, such as histamine and proteases, or newly generated mediators, such as eicosanoids, cytokines, and chemokines [3]. Although the basic molecular mechanisms of Ig:Fc activation have been extensively studied in the past 15 years [4][5][6], new molecules regulating the Correspondence: Dr. Barbara Frossi e-mail: barbara.frossi@uniud.it FcR-signaling cascades have recently been characterized, suggesting not only a still vivid interest in the field of mast cell activation and signaling, but also in identifying putative new therapeutic targets for intervention in mast cell dependent disorders. This review will focus on three aspects of mast cell activation/function. First, we give an essential but complete overview of the FcR-mediated activation in mast cells and report on recent advances in IgE-and IgG-mediated signaling. For clarity, we will dissect and analyze the signals derived from each pathway, with particular attention to the newly identified positive or negative molecular players describing -when possible -their implication toward degranulation and cytokine production. Second, we highlight the growing interest aroun...

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Section: Il-33r Signaling and Modulation Of Fcr Activationmentioning

confidence: 94%

Mast cell activation: A complex interplay of positive and negative signaling pathways

Sibilano¹,

2014

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“…These findings suggest that GRK2 interacts with multiple components of Fc⑀RI signaling pathway. It is well documented that activation of p38 and Akt pathways play important roles in antigen-induced cytokine production in mast cells (36,37). The data that loss of cytokine generation in GRK2-deleted mast cells is associated with deceases in antigen-induced p38 and Akt phosphorylation suggests that GRK2 modulates these signaling pathways to promote cytokine generation.…”

Section: Journal Of Biological Chemistrymentioning

confidence: 99%

“…Effects of GRK2 on Antigen-induced p38 and Akt Phosphorylation-Protein kinase B (Akt) and p38 are known to be involved in antigen-induced cytokine generation in mast cells (36,37). We therefore sought to determine the effect of GRK2 deletion on these signaling pathways.…”

Section: Effect Of Grk2 On Antigen-induced Cytokine Production Is Indmentioning

confidence: 99%

Regulation of FcϵRI Signaling in Mast Cells by G Protein-coupled Receptor Kinase 2 and Its RH Domain

Subramanian

Gupta

Parameswaran

et al. 2014

Journal of Biological Chemistry

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Background: Aggregation of high affinity IgE receptors (Fc⑀RI) on mast cells by antigen triggers allergic diseases. Results: Deletion of GRK2 inhibited antigen-induced mast cell degranulation and abolished cytokine generation. Overexpression of GRK2 or its RH domain in mast cells enhanced antigen-induced responses. Conclusion: GRK2 is a novel regulator of Fc⑀RI signaling in mast cells. Significance: Targeting GRK2 may provide a novel therapeutic approach for allergic diseases.

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“…Both cytokines act as amplifiers of the allergic inflammatory immune response [23,24] via the membrane receptors IL-33R and IL-17RA/IL-17RB, respectively, which are highly expressed in various immune cells, including ILC2s, MCs, basophils, DCs and macrophages [25][26][27][28][29]. In particular, IL-33 can stimulate MC degranulation [30] and release of IL-8 [31], IL-1B, IL-6, tumor necrosis factor-alpha (TNF-α), and chemokine (C-C motif) ligand (CCL) 2 [32], which lead to formation of leukotrienes and prostaglandins and can enhance the inflammatory environment in the lungs [33]. In addition, IL-33 also induces expression of IL-9 in freshly isolated basophils and CD4 + T cells [34].…”

Section: Airway Epithelium As a Key Player In Orchestrating The Allermentioning

confidence: 99%

Airway Epithelium Plays a Leading Role in the Complex Framework Underlying Respiratory Allergy

López-Rodríguez

Benedé

Barderas

et al. 2017

J Investig Allergol Clin Immunol

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Airway epithelium is the cellular structure with the greatest surface exposed to a plethora of environmental airborne substances, including microorganisms, respiratory viruses, air pollutants, and allergens. In addition to being a protective physical barrier at the air-liquid interface, the airway epithelium acts as an effective chemical and immunological barrier that plays a crucial role in orchestrating the immune response in the lungs, by supporting the activation, recruitment, and mobilization of immune cells. Airway epithelium dysfunction has been clearly associated with various airway inflammatory diseases, such as allergic asthma. Although it is not fully understood why a person develops respiratory allergy, a growing body of evidence shows that the nature of the host's immune response is strongly determined by the state of the airway epithelium at the time of contact with the inhaled allergen. Our review highlights the physiological state of airway epithelium as a key element in the development of allergy and, particularly, in exacerbation of asthma. We review the role of physiological oxidants as signaling molecules in lung biology and allergic diseases and examine how high exposure to air pollutants (eg, cigarette smoke and diesel particles) can contribute to the increased incidence of respiratory allergy and exacerbation of the disease. Key words: Airway epithelium. Barrier dysfunction. Respiratory allergy. Redox biology. Air pollutants. ResumenEl epitelio pulmonar constituye la barrera celular más susceptible a la acción deletérea de la multitud de agentes que se encuentran en el ambiente, incluidos los alérgenos. Además de prevenir su acceso al organismo, la barrera epitelial de las vías respiratorias juega un papel inmunomodulador crucial, regulando de forma local la acción de las células del sistema inmune subyacentes. Una disfunción epitelial, provocada tanto directa como indirectamente por la acción de los aeroalérgenos, parece ser una de las causas principales de desregulación de la homeostasis pulmonar, causando una respuesta proinflamatoria descontrolada que cada vez más autores atribuyen al origen de las reacciones alérgicas. En esta revisión se quiere destacar el papel de la barrera epitelial pulmonar como regulador de la respuesta inmune en el contexto de la alergia. Las enfermedades crónicas que afectan a las vías respiratorias, tales como el asma alérgica, muestran frecuentemente una función epitelial defectuosa, apoyando así la hipótesis antes mencionada que subyace al origen de la alergia. El impacto de otros contaminantes ambientales -como virus respiratorios, bacterias, humo del tabaco y partículas diésel-sobre la integridad epitelial, así como su influencia en la biología redox pulmonar relacionada con el desarrollo de la respuesta alérgica, también se abordarán en la presente revisión.

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Amplification of cytokine production through synergistic activation of NFAT and AP‐1 following stimulation of mast cells with antigen and IL‐33

Cited by 89 publications

References 57 publications

Mast cell activation: A complex interplay of positive and negative signaling pathways

Mast cell activation: A complex interplay of positive and negative signaling pathways

Regulation of FcϵRI Signaling in Mast Cells by G Protein-coupled Receptor Kinase 2 and Its RH Domain

Airway Epithelium Plays a Leading Role in the Complex Framework Underlying Respiratory Allergy

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