Interleukins 4 and 13 in Asthma: Key Pathophysiologic Cytokines and Druggable Molecular Targets

Abstract

Interleukins (IL)-4 and -13 play a pivotal role in the pathobiology of type-2 asthma. Indeed, IL-4 is crucially involved in Th2 cell differentiation, immunoglobulin (Ig) class switching and eosinophil trafficking. IL-13 cooperates with IL-4 in promoting IgE synthesis, and also induces nitric oxide (NO) production, goblet cell metaplasia and fibroblast proliferation, as well as elicits contractile responses and hyperplasia of airway smooth muscle cells.IL-4 and IL-13 share common signaling pathways, activated by the binding of both cytokines to receptor complexes including the α-subunit of the IL-4 receptor (IL-4Rα). Therefore, the subsequent receptor dimerization is responsible for the pathophysiologic effects of IL-4 and IL-13. By selectively blocking IL-4Rα, the fully human IgG4 monoclonal antibody dupilumab behaves as a dual receptor antagonist of both IL-4 and IL-13. Through this mechanism of action, dupilumab exerts effective therapeutic actions in type-2 inflammation, thus decreasing asthma exacerbations, FeNO (fractional exhaled NO) levels, and the intake of oral corticosteroids (OCS). In addition to being approved for the add-on biological therapy of severe asthma, dupilumab has also been licensed for the treatment of nasal polyposis and atopic dermatitis.

Real-life effects of dupilumab in patients with severe type 2 asthma, according to atopic trait and presence of chronic rhinosinusitis with nasal polyps

“…The daily dose of prednisone decreased by -5.00 mg (from -12.50 to 0.00) in patients without CRSwNP and -12.5 mg (from -25.00 to 0.00) in subjects with CRSwNP, respectively (p < 0.05) (Figure 6B). The increase in ACT score was 7 points (4-10) and 7 points (4)(5)(6)(7)(8)(9)(10)(11) in patients without or with CRSwNP, respectively (p = 0.422) (Figure 6C). The mean increase in FEV 1 was 0.15 L (-0.01-0.49) in patients without CRSwNP, and 0.24 L (0.01-0.69) in subjects with CRSwNP; this difference was not statistically significant (p = 0.138) (Figure 6D).…”

Methyl P-Coumarate Ameliorates the Inflammatory Response in Activated-Airway Epithelial Cells and Mice with Allergic Asthma

“…The upregulation of various molecules, including cytokines, chemokines, and adhesion molecules, has been reported in the pathogenesis of asthma [ 36 , 51 , 52 ] and in experimental models of inflammatory lung diseases, including AA [ 53 , 54 , 55 ]. Accumulated evidence has indicated that the activation of NF-κB plays a pivotal role in the expression of inflammatory molecules in lung epithelial cells and macrophages [ 5 , 13 , 15 , 56 , 57 ].…”

Pericytes: The lung-forgotten cell type

“…Many cases of asthma are also eosinophilic, often with the extent of the eosinophilia determining disease severity ( Bakakos et al, 2019 ). The Th2 cytokines IL-5, IL-4 and IL-13 have all been linked to eosinophil trafficking or the activation of adjacent signalling pathways such as the IgE cascade responsible for Th2 lymphocyte production thus encouraging further migration of eosinophils ( Fulkerson and Rothenberg, 2013 ; Pelaia et al, 2022 ). In addition to increases in eosinophils, many other immune cells are also upregulated within inflamed airways including dendritic cells, basophils and mast cells which may also have antigen-presenting roles alongside their effector roles ( Kim et al, 2010 ).…”