IL‐33 induces skin inflammation with mast cell and neutrophil activation

Hueber, Axel J.; Alves‐Filho, José C.; Asquith, Darren L.; Michels, Chesney; Millar, Neal L.; Reilly, James; Graham, Gerry; Liew, Foo Y.; Miller, Ashley M.; McInnes, Iain B.

doi:10.1002/eji.201041360

Cited by 151 publications

(142 citation statements)

References 40 publications

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“…These reports indicated that accumulated neutrophils in liver were significantly associated with PBC progression. In addition, IL-33 has been shown to induce neutrophil migration to the inflammatory tissues Verri et al 2010;Hueber et al 2011), a finding consistent with our current data which suggested that serum from PBC patients induced more neutrophils to migrate compared to HC. These results indicated that the overexpression of IL-33 in the liver, at least in part, contributes to the accumulation of neutrophils.…”

Section: Discussionsupporting

confidence: 92%

Interleukin-33 Promotes Disease Progression in Patients with Primary Biliary Cirrhosis

Sun

Zhang

et al. 2014

Tohoku J. Exp. Med.

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Primary biliary cirrhosis (PBC) is a progressive autoimmune liver disease that can cause a series of complications, including cirrhosis, liver failure and hepatocellular carcinoma. Interleukin-33 (IL-33) is expressed in various non-hematopoietic cells and a certain population of immune cells, and exerts its biological effects by binding to the specific receptor, suppression of tumorigenicity 2 (ST2). A soluble form of ST2 (sST2) has been postulated to act as a decoy receptor for IL-33. In this study, we aimed to investigate the role of IL-33 in the pathogenesis of PBC. The study included 20 healthy controls and 68 patients with PBC. We thus found the increased serum IL-33 levels in PBC patients. Its elevated levels were positively correlated with serum alkaline phosphatase levels (a key parameter for the definition of PBC) and with Child-Pugh scores, which were used to determine the prognosis of liver cirrhosis. Moreover, the serum concentrations of sST2 were significantly higher in PBC patients compared with healthy subjects, irrespective of the disease severity. Importantly, the cells that express IL-33 and/or myeloperoxidase (a marker for neutrophils) were accumulated in the livers of PBC patients, and their number increased with the severity of liver lesions. Lastly, in vitro chemotaxis assays revealed that IL-33 enhanced the migration of neutrophils. These data suggest that IL-33 may affect the progress of PBC by recruiting neutrophils to the liver. This expanded knowledge of IL-33 in PBC patients is important for developing therapeutic strategies (e.g., neutralization of IL-33), selecting optimal clinical management, and predicting prognosis.

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Section: Discussionsupporting

confidence: 92%

Interleukin-33 Promotes Disease Progression in Patients with Primary Biliary Cirrhosis

Sun

Zhang

et al. 2014

Tohoku J. Exp. Med.

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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]. Indeed, IL-33 is highly expressed in asthmatics [52] …”

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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“…Moreover, IL-33 production of IL-13 independently of Fc«RI stimulation (Ho et al, 2007) stimulated prostaglandin D 2 , but not tryptase, release from activated human MCs . IL-33 was also able to prime murine MCs for enhanced activation by IgG immune complexes (Drube et al, 2010;Kaieda et al, 2012), and stimulated MC-dependent neutrophil influx (Hueber et al, 2011;Enoksson et al, 2013). In addition to activation through cross-linking of the highaffinity IgE receptor (Fc«RI) (Blank and Rivera, 2004), MCs are also stimulated by a variety of other triggers (Theoharides et al, 2007), such as the neuropeptide neurotensin (Donelan et al, 2006) and substance P (Zhang et al, 2011a).…”

Section: Introductionmentioning

confidence: 99%