Background: Toll-like receptor 2 (TLR2) and galectin-3 (Gal-3) mediate the pathological process of asthma, but the underlying mechanism is not fully understood. We hypothesized that TLR2 pathway may regulate expression of Gal-3 in allergic airway inflammation. Methods: Wild-type (WT) and TLR2−/− mice were sensitized on day 0 and challenged with ovalbumin (OVA) on days 14–21 to establish a model of allergic airway inflammation, and were treated with U0126. Airway inflammation was analyzed by hematoxylin-eosin (HE) and Periodic Acid-Schiff (PAS) staining; cytokines and anti-OVA immunoglobulin E (IgE) were tested by ELISA; and related protein expression in lung tissues was measured by western blot. Results: We found that the expression levels of TLR2 and Gal-3 markedly increased concomitantly with airway inflammation after OVA induction, while TLR2 deficiency significantly alleviated airway inflammation and reduced Gal-3 expression. Moreover, the expression levels of phosphorylated mitogen-activated protein kinases (p-MAPKs) were significantly elevated in OVA-challenged WT mice, while TLR2 deficiency only significantly decreased phosphorylated extracellular signal-regulated kinase (p-ERK) levels. Although blockade of ERK by U0126 had no effect on OVA-induced TLR2 activation, TLR2 deficiency significantly reduced p-ERK expression, suggesting that TLR2 is an upstream signal molecule of ERK. Furthermore, U0126 treatment significantly alleviated allergic airway inflammation and decreased Gal-3 levels in OVA-challenged WT mice, but had no further effect in OVA-challenged TLR2−/− mice. We further demonstrated that TLR2 regulates Gal-3 expression through the ERK pathway in S. aureus-infected macrophages in vitro.Conclusions: Our findings showed that the TLR2-ERK signaling pathway regulates Gal-3 expression in a murine model of allergic airway inflammation.
Background: Existing investigations suggest that the blockade of phosphoinositide 3-kinase (PI3K) activity contributes to inflammatory solution in allergic asthma, but whether this inhibition directly attenuates neutrophilic airway inflammation in vivo is still unclear. We explored the pharmacological effects of LY294002, a specific inhibitor of PI3K on the progression of neutrophilic airway inflammation and investigated the underlying mechanism. Methods and Results: Female C57BL/6 mice were intranasally sensitized with ovalbumin (OVA) together with LPS on days 0 and 6, and challenged with OVA on days 14-17 to establish a neutrophilic airway disease model. In the challenge phase, a subset of mice was treated intratracheally with LY294002. We found that treatment of LY294002 attenuates clinic symptoms of inflammatory mice. Histological studies showed that LY294002 significantly inhibited inflammatory cell infiltration and mucus production. The treatment also significantly inhibited OVA-LPS induced increases in inflammatory cell counts, especially neutrophil counts, and IL-17 levels in bronchoalveolar lavage fluid (BALF). LY294002 treated mice exhibited significantly increased IL-10 levels in BALF compared to the untreated mice. In addition, LY294002 reduced the plasma concentrations of IL-6 and IL-17. The anti-inflammatory effects of LY29402 were correlated with the downregulation of NLRP3 inflammasome. Conclusions: Our findings suggested that LY294002 as a potential pharmacological target for neutrophilic airway inflammation.
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