**2. MicroRNAs and ILC2s**

Derived from typical lymph-like progenitor cells in the bone marrow and expressed in tissues, such as the lung, ILC2s are considered the innate counterpart of Th2 cells and have a collaborative role in the pathogenesis of allergic diseases. Belonging to the innate immune system, ILC2s do not articulate rearranged specific antigen receptors, but their activation is mainly controlled by epithelial cytokines, such as TSLP, IL-25, and IL-33. Among these, IL-33 and IL-25 are potent activators of ILC2. ILC2s can be characterized by the generation of type 2 cytokines (IL-13, IL-4, and IL-5) and the expression of GATA-3 transcription factors. Located strategically in the airway mucosa, ILC2 can be critical for patrolling the airway, enrolling other immune system cells, and activating resident cells in response to pathogenic injury or tissue damage [50]. Consequently, ILC2s have been studied for their development, proliferation, and expression. The study of the underlying mechanisms of ILC2 is of current interest; however, extensive research on ILC2s has in recent years yielded the conclusion that it is ILC2s that act as the significant secretory drivers of allergic inflammation and contribute significantly to airway disease models [51]. Therefore, the following section will describe the effects of various miRNAs, including miR-155, miR-1146, and miR-206, on ILC2s, as an increasing amount of research has been devoted to ILC2s.

### **2.1 MiR-155**

There is no doubt that the development of the immune system, the maturation and differentiation of immune cells, and the stability of their function are inseparable from the involvement of miR-155, which participates in the modulation of the Th2 immune response in eosinophilic airway inflammation. Analyzing the nasal mucosa and peripheral blood collected from allergic rhinitis (AR) patients, Zhu revealed that the miR-155, IL-25, and IL-33 in nasal mucosa exceeded those in controls, as did ILC2s in blood, all of which had statistical significance. Later, a mouse model of LAR was built to validate this idea and concluded that miR-155 was indispensable in the proliferation and activation of ILC2s induced by IL-33 [52]. In other words, overexpression of miR-155 facilitates the overexpression of ILC2s, triggering many type 2 cytokines and a series of allergic phenotypes. The same conclusion came from Wan's study of AR mouse models, where miR-155 not only promoted Th2 differentiation but also increased the number of ILC2s [53]. With the mouse model of asthma, however, Martin concluded that miR-155 could protect ILC2 from apoptosis in a way that boosted the type 2 immune response, given the small effect of miR-155 on ILC2 cell proliferation as well as cytokines [54]. Indeed, they have mutual recognition of miR-155 as required for ILC2s to respond to IL-33 amplification [55]. The proliferation in the absence of miR-155 can be complex for those ILC2s, albeit through intrinsic mechanisms that need further investigation. Nevertheless, one thing is sure, miR-155 is instrumental in the proliferation, activation, and functional stability of ILC2s.

## **2.2 MiR-146**

The anti-inflammatory properties of MiR-146a can be seen in human bronchial epithelial cells during rhinovirus infection and allergic inflammation and in the airways of mice [56]. Targeting miR-146 may be a novel strategy for the treatment of allergic asthma. In mouse models of asthma, treatment of IL-33-activated ILC2s with miR-146a decreased the ability of ILC2s to secrete cytokines, whereas no effects were observed in IL-25-activated ILC2s. Meanwhile, the ability of ILC2 to secrete IL-13 and IL-5 was increased after miR-146a inhibitor treatment, and the results after miR-146 administration showed no significant change in IL-33 and IL-25 expression levels in mice [57, 58]. Thus, miR-146a may reduce the airway inflammatory response in asthma by blocking the IL-33 pathway, by inhibiting IRAK1 and TRAF6, downstream molecules of ST2 signal pathway, to negatively regulate IL-33/ST2-activated ILC2 to inhibit asthma [59]. But a pathway other than IL-25 cannot be excluded. Consequently, we conclude that miR-146a could be one of the most effective therapeutic options for the anti-inflammatory treatment of asthma.
