School of Biological Sciences, University of Ulsan, Ulsan 44610, Korea.
National Creative Research Laboratory for Ca(2+) signaling Network, Chonbuk National University Medical School, Jeonju 54907, Korea; Dalian University Medical College, Dalian 116622, China.
Cell Rep. 2020 Jan 28;30(4):1063-1076.e5. doi: 10.1016/j.celrep.2019.12.090.
The resolution phase of acute inflammation is essential for tissue homeostasis, yet the underlying mechanisms remain unclear. We demonstrate that resolution of inflammation involves interactions between CD38 and tristetraprolin (TTP). During the onset of acute inflammation, CD38 levels are increased, leading to the production of Ca-signaling messengers, nicotinic acid adenine dinucleotide phosphate (NAADP), ADP ribose (ADPR), and cyclic ADPR (cADPR) from NAD(P). To initiate the onset of resolution, TTP expression is increased by the second messengers, NAADP and cADPR, which downregulate CD38 expression. The activation of TTP by Sirt1-dependent deacetylation, in response to increased NAD levels, suppresses the acute inflammatory response and decreases Rheb expression, inhibits mTORC1, and induces autophagolysosomes for bacterial clearance. TTP may represent a mechanistic target of anti-inflammatory agents, such as carbon monoxide. TTP mediates crosstalk between acute inflammation and autophagic clearance of bacteria from damaged tissue in the resolution of inflammation during sepsis.
急性炎症的消退阶段对于组织稳态至关重要，但其中的潜在机制仍不清楚。我们证明，炎症的消退涉及 CD38 和三磷酸鸟苷酶（TTP）之间的相互作用。在急性炎症的起始阶段，CD38 水平增加，导致 NAD(P) 产生钙信号信使，如烟酰胺腺嘌呤二核苷酸磷酸（NAADP）、二磷酸腺苷核糖（ADPR）和环二磷酸腺苷（cADPR）。为了启动消退的开始，第二信使 NAADP 和 cADPR 增加 TTP 的表达，从而下调 CD38 的表达。在 NAD 水平升高的情况下，Sirt1 依赖性去乙酰化激活 TTP，抑制急性炎症反应并降低 Rheb 表达，抑制 mTORC1，并诱导自噬溶酶体清除细菌。TTP 可能是抗炎药物的作用机制靶点，如一氧化碳。TTP 介导了急性炎症和细菌自噬清除受损组织之间的串扰，从而在脓毒症期间的炎症消退中发挥作用。
