Unveiling Interleukin-40: A Novel Regulator of Macrophage and B Cell Function in Allergic Asthma

Allergic asthma is characterized by chronic airway inflammation and heightened type 2 immune responses. Although inhaled corticosteroids are the mainstay of therapy, a subset of patients exhibits suboptimal responses, underscoring the need for new therapeutic targets. In this study, we investigated the role of novel B cell-related interleukin-40 (IL-40) in allergic asthma using patient samples and a house dust mite (HDM)-induced mouse model. Through transcriptomic and immunological profiling, our findings revealed that IL-40 expression was significantly upregulated in both patients with allergic asthma and murine model. Elevated IL-40 levels exacerbated airway hyperresponsiveness (AHR), promoted inflammatory cell infiltration, and increased the production of type 2 cytokines, indicating a key role in amplifying allergic airway inflammation. Importantly, treatment with a neutralizing antibody against IL-40 or genetic deletion of IL-40 significantly alleviated airway inflammation, suggesting its therapeutic potential. Mechanistically, these pro-inflammatory effects of IL-40 were closely associated with alterations in macrophage polarization and B cell development. Macrophages exhibited the highest induction of IL-40 secretion following allergen exposure and responded most strongly to IL-40 stimulation. This response involved the activation of the JAK/STAT1 and p38-MAPK signaling pathways, driving their polarization toward a pro-inflammatory phenotype while inhibiting the differentiation of a specific Arg1⁺ macrophage subset. Although T cells did not display a direct response to IL-40 stimulation, IL-40 was found to be essential for normal B cell development. IL-40^-/- mice showed a marked reduction in pre-B cells in the bone marrow and impaired B cell maturation in the spleen, characterized by decreased follicular B cell populations. Genes involved in B cell receptor synthesis and complement activation were notably downregulated in IL-40^-/- mice. These findings position IL-40 as a key regulator of allergic asthma pathogenesis and suggest its potential as a novel biomarker and therapeutic target for airway inflammation.