Lagrange Brice, Benaoudia Sacha, Wallet Pierre, Magnotti Flora, Provost Angelina, Michal Fanny, Martin Amandine, Di Lorenzo Flaviana, Py Bénédicte F, Molinaro Antonio, Henry Thomas
CIRI, Centre International de Recherche en Infectiologie, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, École Normale Supérieure de Lyon, Univ Lyon, F-69007, Lyon, France.
Department of Chemical Sciences, University of Napoli Federico II, Complesso Universitario Monte Santangelo, Via Cintia 4, I-80126, Napoli, Italy.
Nat Commun. 2018 Jan 16;9(1):242. doi: 10.1038/s41467-017-02682-y.
Caspase-4/5 in humans and caspase-11 in mice bind hexa-acylated lipid A, the lipid moeity of lipopolysaccharide (LPS), to induce the activation of non-canonical inflammasome. Pathogens such as Francisella novicida express an under-acylated lipid A and escape caspase-11 recognition in mice. Here, we show that caspase-4 drives inflammasome responses to F. novicida infection in human macrophages. Caspase-4 triggers F. novicida-mediated, gasdermin D-dependent pyroptosis and activates the NLRP3 inflammasome. Inflammasome activation could be recapitulated by transfection of under-acylated LPS from different bacterial species or synthetic tetra-acylated lipid A into cytosol of human macrophage. Our results indicate functional differences between human caspase-4 and murine caspase-11. We further establish that human Guanylate-binding proteins promote inflammasome responses to under-acylated LPS. Altogether, our data demonstrate a broader reactivity of caspase-4 to under-acylated LPS than caspase-11, which may have important clinical implications for management of sepsis.
人类的半胱天冬酶-4/5和小鼠的半胱天冬酶-11结合六酰化脂多糖（LPS）的脂质部分脂酰A，以诱导非经典炎性小体的激活。诸如新凶手弗朗西斯菌等病原体表达欠酰化的脂酰A，并在小鼠中逃避半胱天冬酶-11的识别。在此，我们表明半胱天冬酶-4驱动人类巨噬细胞对新凶手弗朗西斯菌感染的炎性小体反应。半胱天冬酶-4触发新凶手弗朗西斯菌介导的、gasdermin D依赖性细胞焦亡，并激活NLRP3炎性小体。通过将来自不同细菌物种的欠酰化LPS或合成四酰化脂酰A转染到人巨噬细胞的细胞质中，可以重现炎性小体的激活。我们的结果表明人类半胱天冬酶-4和小鼠半胱天冬酶-11之间存在功能差异。我们进一步证实人类鸟苷酸结合蛋白促进炎性小体对欠酰化LPS的反应。总之，我们的数据表明半胱天冬酶-4对欠酰化LPS的反应性比半胱天冬酶-11更广泛，这可能对脓毒症的治疗具有重要的临床意义。
