SIGNAL transducer and activator of transcription 6 (STAT6) plays a central role in Type 2 (T2) inflammation, primarily through its involvement in IL-4 and IL-13 signalling pathways. These pathways are crucial in the pathogenesis of asthma and allergic diseases. Upon stimulation, STAT6 is phosphorylated by Janus kinases, enabling its dimerisation and nuclear translocation, where it activates transcriptional responses. This process promotes TH2 differentiation of CD4+ T cells and IgE class switching in B cells, mechanisms central to allergic inflammation. STAT6 is strongly associated with asthma risk, with common noncoding variants linked to elevated serum IgE levels and asthma susceptibility. Additionally, gain-of-function mutations in STAT6 have been associated with severe atopic diseases, eosinophilia, and heightened IgE production.
Recent findings highlight a rare partial loss-of-function (LOF) missense variant in STAT6, p.L406P, which reduces T2 inflammatory responses and protects against severe T2-high asthma. This variant results in reduced STAT6 protein levels, dampened IL-4 responses, and lower IgE and eosinophil counts in the blood. Functional assays demonstrated that p.L406P leads to weaker IL-4-induced activation in cell lines, and carriers of this variant exhibited attenuated gene expression responses to IL-4 in CD4+ T cells. These findings highlight the role of STAT6 in asthma pathogenesis and suggest that downregulating STAT6 activity could provide therapeutic benefits.
The STAT6 pathway is already a target for several asthma biologics. Tezepelumab inhibits thymic stromal lymphopoietin, which acts upstream of STAT6, while dupilumab blocks IL-4 and IL-13 signalling. Janus kinase inhibitors are under development for similar purposes. Downstream targets include omalizumab, which blocks IgE, and IL-5 pathway inhibitors such as mepolizumab, reslizumab, and benralizumab. Modulating STAT6 directly may offer a unified approach, combining the effects of these drugs and representing an innovative strategy for managing severe, uncontrolled T2-high asthma. Thus, targeting STAT6 could transform asthma treatment, providing an opportunity to address a broad range of inflammatory mechanisms with a single therapeutic approach.
Reference
Kristjansdottir K et al. A partial loss-of-function variant in STAT6 protects against type 2 asthma. J Allergy Clin Immunol. 2024;DOI:10.1016/j.jaci.2024.10.002.
