Abstract
Group 2 innate lymphoid cells (ILC2s) promote the recruitment of eosinophils by secreting large amounts of type 2 cytokines (IL-5 and IL-13), thus triggering the main feature of asthma, pathological inflammation. Recent insights from mouse and human studies indicated a potential relationship between ILC2s and macrophages. However, the mechanism by which lung M2 macrophage-derived extracellular vesicles (M2 EVs) regulate ILC2s remains unclear. Here the size, morphology and specific markers of M2 EVs were successfully characterized in the lungs. Furthermore, we discovered that M2 EVs strongly promoted type 2 immune inflammation induced by papain. Mechanistically, M2 EVs were internalized by ILC2s, triggering ILC2s activation and inducing pro-inflammatory cytokine (IL-5 and IL-13) production. M2 EVs also indirectly enhanced the function of ILC2s through macrophages and CD4(+) T cells. Using RNA sequencing, we found that long non-coding RNA 4930474H06Rik participated in mediating these effects of M2 EVs. Further mechanistic studies have elucidated the underlying mechanism by which 4930474H06Rik influences the function of ILC2s. Inhibition of 4930474H06Rik significantly altered the intracellular metabolic status of activated ILC2s and effectively alleviated airway inflammation in a mouse model of asthma. Taken together, we demonstrated that M2 EVs promoted allergic airway inflammation at least partially through 4930474H06Rik, implying that 4930474H06Rik can be considered as a therapeutic target for ILC2s activation in allergic airway inflammation.