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

Ruochan Chen, Ling Zeng, Shan Zhu, Jiao Liu, Herbert J. Zeh, Guido Kroemer, Haichao Wang, Timothy R. Billiar, Jianxin Jiang, Daolin Tang, Rui Kang
2019 Science Advances  
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.
more » ... ine–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.
doi:10.1126/sciadv.aav5562 pmid:31131320 pmcid:PMC6531004 fatcat:wtmk6hfbmjd47ljc6boc52w2aa