Syracuse

Human caspase-4 detects tetra-acylated LPS and cytosolic Francisella and functions differently from murine caspase-11

Archive ouverte

Lagrange, Brice | Benaoudia, Sacha | Wallet, Pierre | Magnotti, Flora | Provost, Angelina | Michal, Fanny | Martin, Amandine | Di Lorenzo, Flaviana | Py, Bénédicte F. | Molinaro, Antonio | Henry, Thomas

Edité par CCSD ; Nature Publishing Group -

International audience. 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.

• Description
• Sujet/Public
• Outil
• Outil d'anticipation
• Mémoire et thèse
• Gestion