MARCH1 plays an indispensable role for the development of airway allergic immunity and asthma

Abstract Membrane associated RING-CH-1 (MARCH1) is an E3 ubiquitin ligase expressed mostly by antigen presenting cells (APCs) of the hematopoietic lineage. MARCH1 ubiquitinates surface MHCII and CD86 targeting these molecules for lysosomal degradation. MARCH1-mediated MHCII ubiquitination is crucial for thymic regulatory T cell generation. Whether MARCH1 plays a role in airway allergic inflammation remains unknown. We interrogated the function of MARCH1 in a well-established house dust mite (HDM) driven allergic inflammation mouse model of asthma. Despite displaying higher levels of MHCII and CD86 in APCs, MARCH1-deficient mice were incapable of developing allergic airway inflammation comprising of lung eosinophil accumulation, Th2 cell production of IL-4 and IL-13 cytokines, serum IgE responses, airway hyper-reactivity and mucus production. MARCH1-deficient mice failed to elicit IL-4 production from naïve CD4+ T cells in the lung draining lymph node during HDM sensitization. In addition, MARCH1-deficient mice did not effectively expand effector Th2 cells in the lungs after HDM challenge. Importantly, ablation of MARCH1 expression protected HDM sensitized mice from developing airway inflammation and hyper-production of IgE following re-exposure to HDM. These findings indicate that MARCH1 plays a crucial role in the initiation and progression of allergic airway inflammation, raising the possibility that modulating MARCH1 function might be therapeutically beneficial in asthma treatment.