cAMP metabolism controls caspase-11 inflammasome activation and pyroptosis in sepsis
cAMP metabolism controls caspase-11 inflammasome activation and pyroptosis in sepsis
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DOI：
10.1126/sciadv.aav5562
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发表时间：
2019-05-01
期刊：
影响因子：
13.6
通讯作者：
Kang, Rui
中科院分区：
文献类型：
--
作者：
Chen, Ruochan;Zeng, Ling;Kang, Rui
胞质脂多糖（LPS）激活caspase-11依赖性非经典炎性小体的能力受到复杂控制，以避免过度的炎症反应。然而，很少有人知道的各种代谢途径在控制caspase-11激活的调节作用。在这里，我们证明，L-肾上腺素可以作用于受体ADRA 2B抑制激活的caspase-11炎症体的胞质LPS或大肠杆菌感染的巨噬细胞。L-肾上腺素通过ADCY 4酶诱导的cAMP产生促进蛋白激酶A（PKA）活化，然后阻断半胱天冬酶-11介导的白细胞介素-1 β蛋白水解成熟、gasdermin D（GSDMD）裂解和随后的DAMP释放。PDE 8A介导的cAMP水解的抑制限制了巨噬细胞中的半胱天冬酶-11炎性体活化和焦亡。因此，ADRA 2B-ADCY 4-PDE 8A-PKA轴的药理学调节、半胱天冬酶-11（Casp 11（-/-））的敲除或Gsdmd失活（Gsdmd（I105 N/I105 N））类似地保护poly（I：C）致敏小鼠免受LPS诱导的致死性。我们的研究结果提供了以前未确定的cAMP免疫调节机制的见解，并代表了免疫代谢构成脓毒症潜在治疗靶点的概念证明。
The ability of cytosolic lipopolysaccharide (LPS) to activate caspase-11-dependent nonclassical inflammasome is intricately controlled to avoid excessive inflammatory responses. However, very little is known about the regulatory role of various metabolic pathways in the control of caspase-11 activation. Here, we demonstrate that L-adrenaline can act on receptor ADRA2B to inhibit the activation of the caspase-11 inflammasome by cytosolic LPS or Escherichia coli infection in macrophages. L-adrenaline-induced cAMP production via the enzyme ADCY4 promotes protein kinase A (PKA) activation, which then blocks the caspase-11-mediated proteolytic maturation of interleukin-1 beta, gasdermin D (GSDMD) cleavage, and consequent DAMP release. Inhibition of PDE8A-mediated cAMP hydrolysis limits caspase-11 inflammasome activation and pyroptosis in macrophages. Consequently, pharmacological modulation of the ADRA2B-ADCY4-PDE8A-PKA axis, knockout of caspase-11 (Casp11(-/-)), or Gsdmd inactivation (Gsdmd(I105N/I105N)) similarly protects against LPS-induced lethality in poly(I:C)-primed mice. Our results provide previously unidentified mechanistic insight into immune regulation by cAMP and represent a proof of concept that immunometabolism constitutes a potential therapeutic target in sepsis.