Luteolin attenuates type 2 inflammation in asthmatic mice induced by OVA by regulating IL-33/ST2- GSK3β-M2 macrophage polarization

Allergic asthma is a prevalent non-infectious inflammatory disease characterized by type 2 inflammation. Although multiple treatment options are available, their efficacy is often limited due to the heterogeneous nature of asthma. Luteolin (LUT), a naturally occurring flavonoid, has demonstrated therapeutic potential in various inflammatory conditions. The aim of this research is to investigate the underlying pathogenesis mechanisms of allergic asthma and to evaluate the therapeutic effects of LUT on allergic asthma via IL-33/ST2 signaling pathway. We established a murine model of allergic asthma by sensitizing and challenging BALB/c mice with ovalbumin (OVA), followed by treatment with LUT. The effects of LUT in allergic asthma mice were evaluated via the following techniques: pathological staining, Immunohistochemical staining (IHC), enzyme-linked immunosorbent assay (ELISA), real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot (WB). Additionally, we also used IL-33 to stimulate RAW264.7 cells. Assays in vitro including cell counting Kit-8 (CCK-8), RT-qPCR and WB were performed to investigate potential mechanisms of LUT on IL-33/ST2 pathway activation and M2 macrophages polarization. LUT was verified to have crucial effects on ameliorating asthmatic mice lung function as evidenced by down-regulated airway resistance by 23 % and 48 % (p < 0.05 vs. OVA/saline group); regulating airway type 2 inflammation via decrease the content of type 2 inflammatory cytokines (IL-4, IL-5, and IL-13) by 17 %-78 % (**p < 0.01; ^***p < 0.001 vs. OVA/saline group); decreasing airway inflammatory cells infiltration by 54 % and 65 % (^***p < 0.001 vs. OVA/saline group); inhibiting mucus secretion by 75 % and 89 % (^***p < 0.001 vs. OVA/saline group). Mechanistic research revealed that LUT can treat asthma via IL-33/ST2-GSK3β-M2 macrophages polarization pathway, thereby regulating airway inflammation, remodeling, and immune responses in allergic asthma. Collectively, these findings support LUT as a promising therapeutic agent for allergic asthma through targeted modulation of the IL-33/ST2-GSK3β-M2 macrophage polarization axis.

Allergic asthma; IL-33/ST pathway; Luteolin; M2 macrophage; Type 2 inflammation.