TLR4 and Sepsis: Tobacco smoke extract (TSE) can induce the release of EVs containing HMGB1 from macrophages, which can bind to receptors in a variety of pro-inflammatory pathways (such as receptor for advanced glycation end products, TLR2, TLR4), and then exert the HMGB1 pro-inflammatory effect, promoting the occurrence of sepsis (Tsung et al., 2014; Chen et al., 2016).