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Sci Adv. 2019 May 22;5(5):eaav5562. doi: 10.1126/sciadv.aav5562. eCollection 2019 May.

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

Chen R1,2, Zeng L3, Zhu S1,4, Liu J1, Zeh HJ5, Kroemer G6,7,8,9,10,11,12, Wang H13, Billiar TR14, Jiang J3, Tang D1,5, Kang R5.

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The Third Affiliated Hospital, Protein Modification and Degradation Laboratory, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong 510510, China.
Department of Infectious Diseases and State Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
State Key Laboratory of Trauma, Burns and Combined Injury, Research Institute of Surgery, Research Institute for Traffic Medicine of People's Liberation Army, Daping Hospital, Third Military Medical University, Chongqing 400042, China.
Department of Pediatrics, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
Department of Surgery, UT Southwestern Medical Center, Dallas, TX 75390, USA.
Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France.
Equipe 11 labellisée Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, 75006 Paris, France.
Institut National de la Santé et de la Recherche Médicale, U1138, Paris, France.
Université Pierre et Marie Curie, 75006 Paris, France.
Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, 94800 Villejuif, France.
Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, 75015 Paris, France.
Department of Women's and Children's Health, Karolinska University Hospital, 17176 Stockholm, Sweden.
Laboratory of Emergency Medicine, North Shore University Hospital and The Feinstein Institute for Medical Research, Manhasset, NY 11030, USA.
Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA.


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.

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