Interleukin-40 (IL-40) exacerbates allergic asthma by polarizing macrophages and impairing B cell development

Allergic asthma is a chronic respiratory disease marked by persistent airway inflammation and exaggerated type 2 immune responses. Despite inhaled corticosteroids being the primary treatment, a significant subset of patients experiences suboptimal therapeutic outcomes, highlighting an urgent need for novel targets. Understanding the complex interplay of cytokines and immune cells is crucial to develop more effective interventions. This study investigates the role of a novel B cell-related cytokine, Interleukin-40 (IL-40), in driving allergic airway inflammation.

Researchers investigated IL-40's role in allergic asthma using patient samples and a house dust mite (HDM)-induced mouse model. They performed transcriptomic and immunological profiling to assess IL-40 expression and its effects. In the mouse model, they treated animals with a neutralizing antibody against IL-40 or utilized IL-40-/- mice (genetic deletion) to evaluate the impact on airway inflammation. Primary endpoints included airway hyperresponsiveness (AHR), inflammatory cell infiltration, type 2 cytokine production, macrophage polarization, and B cell development, comparing treated/deficient groups to untreated/wild-type controls.

IL-40 expression was significantly upregulated in both patients with allergic asthma and in the 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. Mechanistically, these pro-inflammatory effects were linked to alterations in macrophage polarization and B cell development. Macrophages showed the highest induction of IL-40 secretion after 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 macrophage polarization toward a pro-inflammatory phenotype while inhibiting the differentiation of a specific Arg1+ macrophage subset. Although T cells did not directly respond to IL-40, it was essential for normal B cell development. > IL-40-/- mice exhibited 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.