| First Author | Chen R | Year | 2019 |
| Journal | Sci Adv | Volume | 5 |
| Issue | 5 | Pages | eaav5562 |
| PubMed ID | 31131320 | Mgi Jnum | J:388679 |
| Mgi Id | MGI:6455646 | Doi | 10.1126/sciadv.aav5562 |
| Citation | Chen R, et al. (2019) cAMP metabolism controls caspase-11 inflammasome activation and pyroptosis in sepsis. Sci Adv 5(5):eaav5562 |
| abstractText | 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-1beta, 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. |
