cAMP metabolism controls caspase-11 inflammasome activation and pyroptosis in sepsis.

Abstract

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-1β, 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 (GsdmdI105N/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.

• Authors: Ruochan Chen, Ling Zeng, Shan Zhu, Jiao Liu, Herbert J Zeh, Guido Kroemer, Haichao Wang, Timothy R Billiar, Jianxin Jiang, Daolin Tang, Rui Kang
• Journal: Science advances (Sci Adv) Vol. 5 Issue 5 Pg. eaav5562 (05 2019) ISSN: 2375-2548 [Electronic] United States
• PMID: 31131320 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• ADRA2B protein, human
• Adra2b protein, mouse
• Inflammasomes
• Lipopolysaccharides
• Receptors, Adrenergic, alpha-2
• Cyclic AMP
• Cyclic AMP-Dependent Protein Kinases
• Casp4 protein, mouse
• Caspases
• Caspases, Initiator
• caspase 11, human
• Adenylyl Cyclases
• adenylyl cyclase 4

Topics

• Adenylyl Cyclases (metabolism)
• Animals
• Caspases (metabolism)
• Caspases, Initiator (metabolism)
• Cell Survival
• Cyclic AMP (metabolism)
• Cyclic AMP-Dependent Protein Kinases (metabolism)
• Enzyme Activation
• Escherichia coli (metabolism)
• Female
• Humans
• Hydrolysis
• Inflammasomes
• Inflammation
• Lipopolysaccharides
• Macrophages (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Monocytes (metabolism)
• Phosphorylation
• Pyroptosis
• Receptors, Adrenergic, alpha-2 (metabolism)
• Sepsis (physiopathology)
• Shock, Septic
• THP-1 Cells