| First Author | Sha JF | Year | 2023 |
| Journal | Free Radic Biol Med | Volume | 200 |
| Pages | 102-116 | PubMed ID | 36907255 |
| Mgi Jnum | J:335035 | Mgi Id | MGI:7448132 |
| Doi | 10.1016/j.freeradbiomed.2023.03.007 | Citation | Sha JF, et al. (2023) TLR2-hif1alpha-mediated glycolysis contributes to pyroptosis and oxidative stress in allergic airway inflammation. Free Radic Biol Med 200:102-116 |
| abstractText | As a pattern recognition receptor which activates innate immune system, toll-like receptor 2 (TLR2) has been reportedly mediates allergic airway inflammation (AAI), yet the underlying mechanism remains elusive. Here, in a murine AAI model, TLR2(-/-) mice showed decreased airway inflammation, pyroptosis and oxidative stress. RNA-sequencing revealed that allergen-induced hif1 signaling pathway and glycolysis were significantly downregulated when TLR2 was deficient, which were confirmed by lung protein immunoblots. Glycolysis inhibitor 2-Deoxy-d-glucose (2-DG) inhibited allergen-induced airway inflammation, pyroptosis, oxidative stress and glycolysis in wild type (WT) mice, while hif1alpha stabilizer ethyl 3,4-dihydroxybenzoate (EDHB) restored theses allergen-induced changes in TLR2(-/-) mice, indicating TLR2-hif1alpha-mediated glycolysis contributes to pyroptosis and oxidative stress in AAI. Moreover, upon allergen challenge, lung macrophages were highly activated in WT mice but were less activated in TLR2(-/-) mice, 2-DG replicated while EDHB reversed such effect of TLR2 deficiency on lung macrophages. Likewise, both in vivo and ex vivo WT alveolar macrophages (AMs) exhibited higher TLR2/hif1alpha expression, glycolysis and polarization activation in response to ovalbumin (OVA), which were all inhibited in TLR2(-/-) AMs, suggesting AMs activation and metabolic switch are dependent on TLR2. Finally, depletion of resident AMs in TLR2(-/-) mice abolished while transfer of TLR2(-/-) resident AMs to WT mice replicated the protective effect of TLR2 deficiency on AAI when administered before allergen challenge. Collectively, we suggested that loss of TLR2-hif1alpha-mediated glycolysis in resident AMs ameliorates allergic airway inflammation that inhibits pyroptosis and oxidative stress, therefore the TLR2-hif1alpha-glycolysis axis in resident AMs may be a novel therapeutic target for AAI. |
