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

Abstract

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...

New insights into the pathogenesis of giant cell arteritis

“…Mast cells (MCs) regulate different immunological responses causing allergy and autoimmunity and participating in tissue neovascularization through the secretion of a broad array of bioactive compounds [97]. In particular, it has been demonstrated that mast cells direct inhibit the functionality of Treg suppression thus actively participating in the establishment of Th17-mediated inflammatory responses.…”

Protein Tyrosine Kinase Fyn Regulates TLR4-Elicited Responses on Mast Cells Controlling the Function of a PP2A-PKCα/β Signaling Node Leading to TNF Secretion

“…Other downstream events that lead to anaphylactic degranulation include the activation of different isoforms of protein kinase C (PKC) (5) and protein phosphatases, such as SHP1, PTP, and protein phosphatase 2A (PP2A) (12,13). Altogether, the production of preformed and de novosynthesized inflammatory mediators triggered by FcεRI is controlled by a complex network of positive and negative signals orchestrated by Src family kinases (14) MCs also express TLRs in their plasma membrane (15,16). In particular, activation of TLR4 with bacterial LPS leads to cytokine production but not to anaphylactic degranulation (17).…”

Sinyal Intrasel Pemicu Reorganisasi Sitoskeleton Sel Mast Pada Reaksi Hipersensitivitas Tipe I

“…Selain memicu fosforilasi ITAM, Fyn yang aktif juga mengaktifk an protein Syk dan Gab2 (Grb-2 Associated binding protein 2) sedangkan Lyn mengaktifk an Syk Raet al, 2012;Sibilano et al, 2014). Selanjutnya Syk memicu fosforilasi NTAL (Non T Cell Activation Linker), LAT (Linker for Activation of T Cells), dan mendorong terjadinya reorganisasi sitoskeleton (Polakovicova et al, 2014;Draber et al, 2012;Tumova´et al, 2010).…”