Heparin, a mammalian polysaccharide, is a widely used anticoagulant medicine to treat thrombotic disorders. It is also known to improve outcomes in sepsis, a leading cause of mortality resulted from infection-induced immune dysfunction. Whereas it is relatively clear how heparin exerts its anticoagulant effect, the immunomodulatory mechanisms enabled by heparin remain enigmatic. Here, we show that heparin prevented caspase-11-dependent immune responses and lethality in sepsis independent of its anticoagulant properties. Heparin or a chemically modified form of heparin without anticoagulant function inhibited the alarmin HMGB1-lipopolysaccharide (LPS) interaction and prevented the macrophage glycocalyx degradation by heparanase. These events blocked the cytosolic delivery of LPS in macrophages and the activation of caspase-11, a cytosolic LPS receptor that mediates lethality in sepsis. Survival was higher in septic patients treated with heparin than those without heparin treatment. The identification of this previously unrecognized heparin function establishes a link between innate immune responses and coagulation.

肝素是一种哺乳动物多糖，是一种广泛用于治疗血栓性疾病的抗凝药物。它还可以改善败血症的结果，败血症是感染引起的免疫功能障碍导致死亡的主要原因。虽然肝素如何发挥其抗凝作用相对清楚，但肝素所启用的免疫调节机制仍然是个谜。在这里，我们表明肝素阻止了依赖于 caspase-11 的免疫反应和脓毒症的致死率，而与其抗凝特性无关。肝素或没有抗凝功能的化学修饰形式的肝素抑制了警报素 HMGB1-脂多糖 (LPS) 的相互作用，并阻止了乙酰肝素酶对巨噬细胞糖萼的降解。这些事件阻止了巨噬细胞中 LPS 的胞质传递和 caspase-11 的激活，一种胞质 LPS 受体，在败血症中介导致死率。使用肝素治疗的脓毒症患者的存活率高于未使用肝素治疗的患者。这种以前未被认识的肝素功能的鉴定建立了先天免疫反应和凝血之间的联系。