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.

journal_name

Sci Adv

journal_title

Science advances

authors

Chen R,Zeng L,Zhu S,Liu J,Zeh HJ,Kroemer G,Wang H,Billiar TR,Jiang J,Tang D,Kang R

doi

10.1126/sciadv.aav5562

subject

Has Abstract

pub_date

2019-05-22 00:00:00

pages

eaav5562

issue

5

issn

2375-2548

pii

aav5562

journal_volume

5

pub_type

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