Rhinovirus (RV)
infections are associated with
asthma exacerbations. MicroRNA-146a and microRNA-146b (miR-146a/b) are anti-inflammatory
miRNAs that suppress signaling through the
nuclear factor kappa B (NF-κB) pathway and inhibit pro-inflammatory
chemokine production in primary human bronchial epithelial cells (HBECs). In the current study, we aimed to explore whether miR-146a/b could regulate cellular responses to RVs in HBECs and airways during RV-induced
asthma exacerbation. We demonstrated that expression of miR-146a/b and pro-inflammatory
chemokines was increased in HBECs and mouse airways during RV
infection. However, transfection with
cell-penetrating peptide (CPP)-miR-146a nanocomplexes before
infection with RV significantly reduced the expression of the pro-inflammatory
chemokines CCL5,
IL-8 and CXCL1, increased
interferon-λ production, and attenuated
infection with the
green fluorescent protein (GFP)-expressing RV-A16 in HBECs. Concordantly, compared to wild-type (wt) mice, Mir146a/b-/- mice exhibited more severe airway neutrophilia and increased T helper (Th)1 and Th17 cell infiltration in response to RV-A1b
infection and a stronger Th17 response with a less prominent Th2 response in house dust mite extract (HDM)-induced allergic airway
inflammation and RV-induced exacerbation models. Interestingly,
intranasal administration of CPP-miR-146a nanocomplexes reduced HDM-induced allergic airway
inflammation without a significant effect on the Th2/Th1/Th17 balance in wild-type mice. In conclusion, the overexpression of miR-146a has a strong anti-inflammatory effect on RV
infection in HBECs and a mouse model of allergic airway
inflammation, while a lack of miR-146a/b leads to attenuated type 2 cell responses in mouse models of allergic airway
inflammation and RV-induced exacerbation of allergic airway
inflammation. Furthermore, our data indicate that the application of CPP-miR-146a nanocomplexes has therapeutic potential for targeting airway
inflammation.