An endogenous caspase-11 ligand elicits interleukin-1 release from living dendritic cells

Ivan Zanoni, Yunhao Tan, Marco Di Gioia, Achille Broggi, Jianbin Ruan, Jianjin Shi, Carlos A. Donado, Feng Shao, Hao Wu, James R. Springstead, Jonathan C. Kagan

2016 Science 352 (6290), 1232-1236

Speaker: Ka Fu Lei (李嘉芙)                                                       Time: 14:00~15:00, Apr. 26, 2017

Commentator: Chih-Peng Chang  , Ph.D (張志鵬 老師)            Place: Room 601

Abstract:

        Cytosolic caspase-11 is an intracellular sensor of lipopolysaccharides (LPS) during the infection of intracellular Gram-negative bacteria like Salmonella. More importantly, mouse work showed that upon LPS stimulation, caspase-11 instead of TLR4 plays a crucial role in activating non-canonical inflammasome and pyroptosis, leading to sepsis and septic shock. In addition to LPS, host danger molecules, like oxidized phospholipids derived from PAPC (oxPAPC), are shown to promote or inhibit TLR4-dependent inflammation. Given these facts, the author tests the idea whether oxPAPC can activate caspase-11-mediated non-canonical inflammasome. They first found that, unlike LPS, oxPAPC did not activate the TLR4 pathway and also failed to induce cytokine production, including IL-6, TNF-α, and IFN-β, from dendritic cells (DCs). Notably, oxPAPC, like ATP, was shown to induce IL-1β maturation and release from LPS-primed DCs. Further, their results showed that both NLRP3 inflammasome and caspase-11-mediated noncanonical inflammasome were critical for oxPAPC-induced IL-1β release. In vivo study results showed that LPS plus oxPAPCtreatment enhanced DC-mediated priming T cells and adaptive immune responses in wild type mice but failed to do so in caspase-11 or caspase-1/-11 dKO mice. Biochemical results that oxPAPC and LPS interacted with caspase-11 via its different domains and induce different inflammasome-dependent activities. OxPAPC induced IL-1β release only, but LPS induced both IL-1β release and pyroptosis. Together, the Authors suggest that while DCs encounters with oxPAPC, T cell activation will be promoted. Further, if the encounter happen after priming with DAMPs, an ‘hyperactive’ state of DCs induced by caspase-11 will be induce, which trigger strong adaptive immune responses and IL-1β release. Author suggested that hyperactive DCs are excellent inducers of T cell-mediated immunity and may benefit vaccine development.

References:

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