Targeting cell signaling in allergic asthma

Abstract

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, FcɛRI-LAT-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.

Keywords: Diseases; Immunology; Molecular biology.

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

Fig. 2

The functions of PGs and their subtypes. The subtypes of PGs have main roles in the pathophysiology of asthma. New drugs have been designed to target the PG pathway. DP2 receptor activation induces the production of proinflammatory cytokines, as well as the migration of eosinophils to the airways

Fig. 3

The cAMP signaling pathway and its relationships with β2-AR, GPCR, and potassium channels. cAMP is a negative regulator of T-cell activation. Along with PDE4 inhibitors, cAMP can suppress cytokine production

Fig. 4

The Fas-FasL pathway and its roles in cell death and cell survival. Fas signaling via the FADD adaptor triggers the MAPK signaling cascade, leading to NF-kB activation and cellular proliferation. Th2 cells are resistant to Fas-mediated apoptosis, as well as to the activation of NF-kB following attachment of FasL. Fas signaling is necessary for the resolution of type 2 inflammation. Nonapoptotic Fas signaling in Th2 cells further contributes to lung inflammation

Fig. 5

Allergen-IgE-mediated signaling via FcɛRI during allergic attacks of asthma. The activation of FcεRI recruits Lyn, Fyn, and Syk kinases, which subsequently phosphorylate LAT, SLP-76, and PLC-γ1, leading to mast cell degranulation. Following the aggregation of FcεRI by IgE-allergen complexes, Src family kinases are activated that subsequently phosphorylate LAT and SLP-76. LAT binds to Grb2, Gads, and PLC-γ1, as well as VAV and SOS, the guanine exchange factors. This event then induces PI3K and MAPK-dependent pathways and cytokine production

Fig. 6

The Ca²⁺ signaling pathway and the roles of CD38, Ca²⁺ channels, and G-protein-coupled receptors. In the Ca²⁺-dependent signaling pathway, PLCb generates IP3 that binds to its receptor on the sarcoplasmic reticulum (SR) membrane and induces Ca²⁺ⁱ release. Ca²⁺ⁱ activates calmodulin and myosin light chain kinase (MLCK) to induce actin-myosin cross-bridge cycling and subsequently smooth muscle spasm. CD38 expression evokes the generation of cyclic ADP-ribose, which binds to the ryanodine receptor and stimulates the SR to release Ca²⁺ⁱ. SERCA refills the SR with cytosolic Ca²⁺ⁱ and inhibits smooth muscle spasm. The Ca²⁺-independent pathway is mediated by RhoA and ROCK, which phosphorylate and inactivate MYTP1, leading to airway smooth muscle spasm

Fig. 7

Signaling pathways contributing to mucus production. The CLCA1 (a Serpin) and 15-lipoxygenase-1-dependent pathways are triggered following the binding of IL-13 to its receptor. These pathways lead to the phosphorylation of STAT-6, leading to MUC5AC gene expression and mucus production. EGFR signaling is initiated following the activation of the PKC δ and PKC θ isoforms. The activation of EGFR kinase induces the Ras–Raf–MEK1/2–ERK1/2 pathway and the transcription of MUC5AC gene in airways via binding of the Sp1 transcription factor to specific binding sites within the gene promoter. Notch activates γ-secretase-mediated proteolytic processes, and Hes1 inhibits MUC5AC expression and mucus production