Pathogenetic role of IL-4 and IL-13 in atopic dermatitis: The inhibitory pathways

The review article is devoted to the two key Th2 cytokines, IL-4 and IL-13, which are directly involved in the immunopathogenesis of atopic dermatitis (AD). The identification of IL-4 and IL-13 in AD was first reported by Q. Hamid et al. in 1994. Since then, a number of studies have appeared confirming the relationship of these Th2 cytokines with disruption of the skin epidermal barrier; a decrease in skin immune response due to inhibited expression of antimicrobial peptides against Staphylococcus aureus, etc. The convincing studies also confirm a relationship with IL-4/IL-13 to such clinical manifestations of ADs as skin infections, as well as inflammation, lichenification and itching of the skin. The role of IL-4 and IL-13 is also confirmed by clinical studies, which indicate a beneficial effect of drugs inhibiting these cytokines on the relief of skin symptoms in atopic dermatitis (itching, rashes). The IL-4 and IL-13 are shown to connect the JAK/STAT signaling pathway due to the common α-subunit of IL-4 receptor (IL-4Rα). Importantly, IL-4, IL-13 and other cytokines (including IL-31) are capable of activating the sensory neurons, thus being often considered potent pruritogens. The article also discusses issues related to the role of the JAK/STAT signaling pathway and, in particular, the JAK1 protein in development of atopic dermatitis. As based on pathogenetic significance of IL-4 and IL-13, drugs have recently been developed that block their activity and, thereby, affect important molecular pathways of the AD development. These drugs are classified as systemic medications which include, e.g., (1) biological therapy (dupilumab, the first monoclonal IgG4 antibody), which blocks IL-4Rα and, thereby, suppresses the IL-4/IL-13 axis, and (2). Janus kinase (JAK) inhibitors or small-molecule agents. Currently, some Janus kinase inhibitors, e.g., abrocitinib, upadacitinib, and barocitinib, are available in Russia. Clinical studies show that both biological therapy and small molecules have an immunomodulatory effect on the course of atopic dermatitis. The review briefly presents the main data of recent meta-analyses on the comparative characteristics of biotherapy and usage of Janus kinase inhibitors in this disorder.