The membrane-associated ubiquitin ligases MARCH2 and MARCH3 target IL-5 receptor alpha to negatively regulate eosinophilic airway inflammation

Interleukin 5 (IL-5) plays crucial roles in type 2-high asthma by mediating eosinophil maturation, activation, chemotaxis and survival. Inhibition of IL-5 signaling is considered a strategy for asthma treatment. Here, we identified MARCH2 and MARCH3 as critical negative regulators of IL-5-triggered signaling. MARCH2 and MARCH3 associate with the IL-5 Receptor α chain (IL-5Rα) and mediate its K27-linked polyubiquitination at K379 and K383, respectively, and its subsequent lysosomal degradation. Deficiency of MARCH2 or MARCH3 modestly increases the level of IL-5Rα and enhances IL-5-induced signaling, whereas double knockout of MARCH2/3 has a more dramatic effect. March2/3 double knockout markedly increases the proportions of eosinophils in the bone marrow and peripheral blood in mice. Double knockout of March2/3 aggravates ovalbumin (OVA)-induced eosinophilia and causes increased inflammatory cell infiltration, peribronchial mucus secretion and production of Th2 cytokines. Neutralization of IL-5 attenuates OVA-induced airway inflammation and the enhanced effects of March2/3 double deficiency. These findings suggest that MARCH2 and MARCH3 play redundant roles in targeting IL-5Rα for degradation and negatively regulating allergic airway inflammation.