Zanoni Ivan, Tan Yunhao, Di Gioia Marco, Springstead James R, Kagan Jonathan C
Harvard Medical School and Division of Gastroenterology, Boston Children's Hospital, Boston, MA, USA; Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy.
Harvard Medical School and Division of Gastroenterology, Boston Children's Hospital, Boston, MA, USA.
Immunity. 2017 Oct 17;47(4):697-709.e3. doi: 10.1016/j.immuni.2017.09.010.
A heterogeneous mixture of lipids called oxPAPC, derived from dying cells, can hyperactivate dendritic cells (DCs) but not macrophages. Hyperactive DCs are defined by their ability to release interleukin-1 (IL-1) while maintaining cell viability, endowing these cells with potent aptitude to stimulate adaptive immunity. Herein, we found that the bacterial lipopolysaccharide receptor CD14 captured extracellular oxPAPC and delivered these lipids into the cell to promote inflammasome-dependent DC hyperactivation. Notably, we identified two specific components within the oxPAPC mixture that hyperactivated macrophages, allowing these cells to release IL-1 for several days, by a CD14-dependent process. In murine models of sepsis, conditions that promoted cell hyperactivation resulted in inflammation but not lethality. Thus, multiple phagocytes are capable of hyperactivation in response to oxPAPC, with CD14 acting as the earliest regulator in this process, serving to capture and transport these lipids to promote inflammatory cell fate decisions.
一种名为氧化磷脂酰乙醇胺（oxPAPC）的脂质异质混合物源自濒死细胞，它能使树突状细胞（DC）过度活化，但不会使巨噬细胞过度活化。过度活化的DC的定义是，它们在维持细胞活力的同时能够释放白细胞介素-1（IL-1），使这些细胞具有强大的刺激适应性免疫的能力。在此，我们发现细菌脂多糖受体CD14捕获细胞外的oxPAPC，并将这些脂质转运到细胞内，以促进炎性小体依赖性DC过度活化。值得注意的是，我们在oxPAPC混合物中鉴定出两种特定成分，它们能使巨噬细胞过度活化，通过依赖CD14的过程使这些细胞持续数天释放IL-1。在脓毒症小鼠模型中，促进细胞过度活化的条件会引发炎症，但不会导致死亡。因此，多种吞噬细胞能够对oxPAPC产生过度活化反应，CD14在此过程中作为最早的调节因子，负责捕获和转运这些脂质，以促进炎症细胞命运的决定。
