The study shows that the natural peptide LL‑37 can help steroids work better in lung cells that are stressed by viral‑like double‑stranded RNA. In lab dishes and a mouse asthma model, LL‑37 teamed up with the viral mimic to boost anti‑inflammatory signals and block pathways that make steroids less effective. While promising, the work is still early and only in cells and mice, so it isn’t a ready‑to‑use protocol for people yet.

Glucocorticoids play a key role in treatment of inflammatory lung diseases including both airway and parenchymal lung diseases. RNA viral infections are major causes of chronic lung disease exacerbations and can determine glucocorticoid resistance. The antibacterial peptide LL-37, the only member of human cathelicidin family, also functions as antiviral-activity enhancer. However, whether it can alleviate the glucocorticoid resistance caused by RNA viruses remains unclear. Here, we used type I (BEAS-2B) and type II (A549) lung epithelial cells to assess the effect of LL-37 on dsRNA-induced glucocorticoid resistance. We verified that LL-37 and polyinosinic-polycytidylic acid (poly I:C, a mimic of viral dsRNA) interact and enter both cell lines. Co-treatment with LL-37 and poly I:C increased glucocorticoid-induced expression of promyelocytic leukemia zinc finger (PLZF), an anti-inflammatory protein, compared to poly I:C alone. Pre-treatment with LL-37 also restored transactivation of the glucocorticoid response element (GRE). Moreover, LL-37 rescued poly I:C-induced glucocorticoid resistance by increasing phosphorylation and nuclear translocation of glucocorticoid receptor. Importantly, LL-37 downregulated poly I:C-induced Erk and Akt signaling pathways in lung epithelial cells. Finally, we verified our data in vivo, showing that mCRAMP, the mouse LL-37 ortholog, can alleviate poly I:C-induced glucocorticoid insensitivity in a murine asthma model. In summary, this study showed that LL-37 restored glucocorticoid sensitivity impaired by dsRNA possibly by inhibiting Akt pathway, in addition to Erk1/2 pathway. These findings suggest LL-37 as a therapeutic agent for treatment of viral infections in inflammatory pulmonary diseases.