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Asthma accounts for substantial morbidity and healthcare burden all over the world. Allergic asthma is characterized by recruitment of immune cells into the lung, mucus production and exaggerated narrowing of the conducting airways. B cells are critical upstream regulators of antibody-mediated immunity and inflammation, with several reports establishing their importance as producers of IgE, presenters of antigen and promoters of the Th2 response in asthma. However, the molecular regulators of the B cell asthma response remain poorly characterized. We have previously reported that Ezrin, a plasma membrane-actin cytoskeleton linker protein regulates B cell function. Here, we show that mice with B cell-specific deficiency of ezrin (Ez-def) display increased lung B cells and eosinophils, IgE production and inflammatory cytokines, and marked deterioration in respiratory function upon sensitization and challenge with house dust mite allergens, as compared to control Mb1cre/+ mice. On a mechanistic level, we observed that Ez-def B cells express higher levels of T cell activating proteins upon antigen stimulation and have enhanced chemotactic ability. Our data suggest that B cell intrinsic ezrin restricts allergic asthma, and may act as an important checkpoint regulator of allergic airway inflammation and hyperresponsiveness by regulating B cell recruitment, activation, antibody secretion and cytokine balance in the lungs.

Severe asthma affects 2.4 million Americans and 23.8 million people worldwide and accounts for the majority of total asthma hospital costs. Most severe asthma is mediated by Th17/neutrophilic responses, alone or combined with Th2 and/or Th1 responses. In contrast, Treg responses are deficient. Protein Arginine Methyl Transferase (PRMT) 5 catalyzes symmetric dimethylation (SDM) of arginine on histones and other proteins, thereby regulating gene expression. PRMT5 promotes murine Th1/Th17 responses in central nervous system autoimmunity. However, its impact on asthma has not been established. We evaluated the role of PRMT5 on mouse models of house dust mite (HDM) asthma. PRMT5 and its symmetric demethylation activity were increased in lung infiltrating cells during Th2/Th17-mediated HDM severe asthma, suggesting a role for PRMT5 in asthma pathogenesis. To determine the contribution of PRMT5 to HDM asthma pathogenesis, we used first-in-class PRMT5-specific inhibitors developed at The Ohio State University. PRMT5 inhibitor HLCL65 modulated Th1, Th2 and Th17 differentiation and suppressed airway hyperreactivity in Th2/Th17 models of house dust mite (HDM)-induced asthma. Overall, these results support a role for PRMT5 in severe asthma pathogenesis.

Asthma airway remodeling is linked to Th2 inflammation. Angiogenesis is a consistent feature of airway remodeling, but its contribution to pathophysiology remains unclear. We hypothesized that nascent endothelial cells in newly forming vessels are sufficient to initiate Th2-inflammation. Vascular endothelial (VE)-cadherin is a constitutively expressed endothelial cell adhesion molecule that is exposed in its monomer form on endothelial tip cells prior to adherens junction formation. Abs targeted to VE-cadherin monomers inhibit angiogenesis by blocking this adherens junction formation. In this study, VE-cadherin monomer Ab reduced angiogenesis in the lungs of the allergen-induced murine asthma model. Strikingly, Th2 responses including, IgE production, eosinophil infiltration of the airway, subepithelial fibrosis, mucus metaplasia, and airway-hyperreactivity were also attenuated by VE-cadherin blockade, via mechanisms that blunted endothelial IL-25 and proangiogenic progenitor cell thymic stromal lymphopoietin production. The results identify angiogenic responses in the origins of atopic inflammation.