TLR4 and Sepsis: Upon secretion, extracellular SAA uses TLR4 (21) and RAGE (22) to induce hemichannels (e.g., connexin 43 and pannexin 1) (23, 24) and secretory phospholipase A2 (e.g., sPLA2-IIE/V) (25), thereby triggering HMGB1 release and serving as a mediator of lethal sepsis (26).