Cyclic GMP-AMP promotes the acute phase response and protects against Escherichia coli infection in mice.

Abstract

The acute phase response, as a component of the innate immune system, is part of the first line of defense against invading pathogens. The Stimulator of Interferon Genes (STING) pathway initiates innate immune responses upon recognition of exogenous bacterial and viral DNA. However, whether STING signaling pathway plays any roles in regulating acute phase response during bacterial infection remains unknown. In this study, we used STING-deficient (Tmem173gt) and wildtype mice to investigate acute phase responses to bacterial infection (Escherichia coli, E. coli) and test the effect of exogenous cyclic GMP-AMP (cGAMP, a STING agonist) treatment. Bacterial infection of STING-deficient mice resulted in an increase in mortality and bacterial dissemination. Also, inflammation-induced acute phase response was drastically reduced in STING-deficient mice, showing significant reduction in expression of cytokine TNF-α and acute phase proteins. In contrast, exogenous cGAMP treatment enhanced inflammation-induced acute phase response by increasing the expression of TNF-α and acute phase proteins. Also, cGAMP accelerated bacterial clearance and improved survival rate of wildtype mice, but not STING-deficient mice. Interestingly, cGAMP treatment mitigated bacterial infection induced liver injury in both wildtype and STING-deficient mice. Further in vitro evidence showed that cGAMP treatment retarded TNF-α-mediated hepatocyte apoptosis, potentially accelerating autophagy. Taken together, our results indicated that cGAMP/STING signaling pathway is critical for organism to initiate blood-borne innate immune-responses to defend bacterial infection, and cGAMP is envisaged as a drug candidate for further clinical trial.

• Authors: Yongsheng Yu, Huan Guo, Wenli Jiang, Chenxi Zhang, Chunlei Xing, Dagui Chen, Can Xu, Li Su
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 188 Pg. 114541 (06 2021) ISSN: 1873-2968 [Electronic] England
• PMID: 33812857 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier Inc. All rights reserved.

Chemical References

• Membrane Proteins
• Sting1 protein, mouse
• Cyclic AMP
• Cyclic GMP

Topics

• Acute-Phase Reaction (genetics, metabolism, prevention & control)
• Animals
• Cyclic AMP (administration & dosage)
• Cyclic GMP (administration & dosage)
• Escherichia coli
• Escherichia coli Infections (genetics, metabolism, prevention & control)
• Hepatocytes (metabolism, microbiology)
• Male
• Membrane Proteins (agonists, deficiency, genetics)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Transgenic