Targeting cell signaling in allergic asthma

Signal Transduction and Targeted Therapy REVIEW ARTICLE www.nature.com/sigtrans OPEN Targeting cell signaling in allergic asthma Seyyed Shamsadin Athari 1 Asthma is chronic inflammation of the airways characterized by airway hyper-responsiveness, wheezing, cough, and dyspnea. Asthma affects >350 million people worldwide. The Th2 immune response is a major contributor to the pathophysiology of asthma. Targeted therapy modulating cell signaling pathways can be a powerful strategy to design new drugs to treat asthma. The potential molecular pathways that can be targeted include IL-4-IL-13-JAK-STAT-MAP kinases, adiponectin-iNOS-NF-κB, PGD2-CRTH2, IFNs-RIG, Wnt/β-catenin-FAM13A, FOXC1-miR-PI3K/AKT, JNK-Gal-7, Nrf2-ROS, Foxp3-RORγt, CysLTR, AMP, Fas-FasL, PTHrP/PPARγ, PAI-1, FcɛRILAT-SLP-76, Tim-3-Gal-9, TLRs-MyD88, PAR2, and Keap1/Nrf2/ARE. Therapeutic drugs can be designed to target one or more of these pathways to treat asthma. 1234567890();,: Signal Transduction and Targeted Therapy (2019)4:45 INTRODUCTION Asthma is a complex and chronic inflammatory disease of the airways characterized by airway hyper-responsiveness (AHR), eosinophilic infiltration, reversible airflow obstruction, airway remodeling, mucus hypersecretion, and goblet cell hyperplasia. The disease usually presents with wheezing, cough, and dyspnea. Allergy and atopy comprise the main causes of asthma. Genetic and environmental triggers modulating the activation and regulation of the immune system (i.e., Th2 immune response) are the main orchestrators in the pathophysiology of asthma.1,2 Asthma affects >350 million people worldwide. Owing to the heterogeneous nature of the disease, these patients usually encounter difficulties in their treatment course.3,4 Bronchial inflammation, smooth muscle spasm, and mucus production in allergic asthma are triggered by IL-4, IL-5, and IL-13, which are released by Th2 cells. IL-13 plays the main role in the excessive secretion of mucus and AHR. IL-5 participates in the activation and migration of eosinophils to airways triggering bronchial inflammation. IL-4 induces IgE isotype switching in B cells and upregulates high-affinity IgE receptor (FcεRI) on the surface of target cells. Mast cells are activated upon allergeninduced cross-linking of FcεRI-bound IgE on their plasma membrane surface. Subsequently, mast cells release histamine and other mediators that lead to allergic symptoms. The levels of IL-4, IL-5, and IL-13 are increased in the bronchoalveolar lavage (BAL) of asthmatic patients (Fig. 1).5–8 In recent years, targeted therapy aimed at small signaling molecules has shown promise as a novel strategy to treat diseases. Here, we reviewed cell signaling pathways and molecules that are involved in the pathogenesis of asthma and can be potential targets for developing new drugs to treat this disease. These pathways have main roles in immunomodulatory processes in asthma and are involved in the pathogenesis of all asthma clinical subtypes (i.e., intermittent, mild, moderate, and severe persistent). Acute and chronic asthma attacks can be managed by precisely identifying the regulators of these pathogenic pathways and targeting their molecular mediators. ; https://doi.org/10.1038/s41392-019-0079-0 TARGETED THERAPY Asthma is a multifactorial disease influenced by genetic and environmental factors. Because of its complicated nature, asthma treatment is a very difficult and exhausting process. Asthma can be categorized based on either phenotype (i.e., functional and physiopathological), severity (intermittent, mild, moderate, or severe), etiology (allergic and nonallergic or extrinsic and intrinsic), and clinical presentation (acute and chronic). Recently, there has been a focus on phenotype- and endotype-based classification approaches.9 Asthma can also be classified based on the types of inflammatory and immune cells involved. Two subtypes of inflammatory processes caused by T helper cells have recently been defined (i.e., Th2-high and Th2-low). The Th2-high subtype is characterized by marked eosinophilic infiltration of the airways, whereas the Th2-low subtype is characterized by neutrophilic infiltration.10,11 The Th2-high subtype is further associated with the predominance of type 2 cytokines (i.e., IL-4, IL-5, and IL-13). Accordingly, agents targeting the molecular participants in the Th2-high subtype (e.g., anti-IL-4, anti-IL-5, anti-IL-13, IgE blockers, and inhibitors of prostaglandin D2 (CRTH2) receptor) have recently been presented as potential drugs to treat asthma.11 Some of these targets are shown in Table 1. The Th2-low (i.e., non-Th2-driven) inflammation includes either Th1 (IFN-γ, TNF, IL-1, and IL-6) or Th17 (IL-17A, IL-17E, IL-17F, and IL-22) responses. In addition to the aforementioned molecular targets, antagonists of C-X-C-chemokine receptor (CXCR2), suppressors of IFN-γ and IL-17, as well as peroxisome proliferator-activated receptorγ and IL-8 can be applied as novel targeting adaptors.12–16 Therefore, either allergic (i.e., Th2 high or extrinsic) or nonallergic (i.e., Th2 low or intrinsic) asthma can be treated by targeting these cell signaling mediators. The following sections briefly introduce these signaling pathways and their molecular drivers. IL-4/IL-13 SIGNALING PATHWAY The receptors of allergic cytokines, including IL-4, IL-5, IL-13, IL-31, and thymic stromal lymphopoietin (TSLP), trigger the JAK/STAT 1 Department of Immunology, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran Correspondence: Seyyed Shamsadin Athari () Received: 14 May 2019 Revised: 3 September 2019 Accepted: 15 September 2019 © The Author(s) 2019 Targeting cell signaling in allergic asthma Athari 2 Fig. 1 Asthma, a chronic inflammatory airway disease, is characterized by eosinophilic inflammation, mucus hypersecretion, goblet cell hyperplasia, airway hyper-responsiveness, and breathlessness. Th2 cell immune responses are dominant in the pathophysiology of asthma. IL-4, IL-5, and IL-13 are released by Th2 cells. IL-4 has a role in B-cell IgE isotype switching and upregulation of FcεRI on mast cells, which release histamine and other mediators that lead to allergic symptoms and smooth muscle spasm. IL-5 leads to activation, migration, and accumulation of eosinophils to the airway and initiates bronchial inflammation. IL-13 has a main role in mucus hypersecretion and goblet cell hyperplasia and promotes AHR. Therefore, a focus on the mechanisms of cell signaling that are related to asthma for designing new drugs and targeted molecules can be continued with the aforementioned parameters Table 1. Some of targeted therapies in control and treatment of asthma Cell surface protein Transcription factor Target Effects Th2high/low References Siglec-8 Apoptosis of eosinophils High 294,295 CD300a Activation of inhibitory receptor High 296 α4β1, α4β7 Increase blood eosinophils and inhibits their tissue accumulation High 297 CCR3 Block chemokine-ind (...truncated)