Alpha7nAChR modulates STAT3 activation to control inflammation and improve survival in sepsis
Abstract
The alpha7 nicotinic acetylcholine receptor plays a critical role in the immune system controlling systemic inflammation in sepsis. The signaling pathway of this mechanism has remained elusive possibly due to the lack of specific agonists and the irreconcilable results using different cell lines. Here, we report that the anti‐inflammatory potential of the alpha7nAChR is mediated by unphosphorylated STAT3, and that STAT3 can prevent systemic inflammation and improve survival in sepsis. Alpha7nAChR activation or JAK2 inhibition prevents STAT3 tyrosine phosphorylation in activated macrophages. Inhibition of STAT3 tyrosine phosphorylation mimics the alpha7nAChR‐signaling to control NF‐kB, cytokine production in macrophages, and systemic inflammation in sepsis by inhibiting cytokine production in the spleen. Consistently, inhibition of STAT3 expression prevents the alpha7nAChR‐signaling, but inhibition of STAT3 tyrosine phosphorylation enhances the anti‐inflammatory potential of alpha7nAChR. STAT3 prevents the production of late mediators of sepsis, including HMGB1 extracellular secretion from macrophages and rescues mice from polymicrobial sepsis. These results reveal the clinical implications and pharmacological advantages of unphosphorylated STAT3 in infectious diseases. Studies funded by USAMRMC#05308004, AHA06352230N, NIH‐GM084125.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Apr 01, 2010
- Source ID
- 10.1096/fasebj.24.1_supplement.752.2
Entities
People
- Bolin Cai
- Edwin Deitch
- Esmerij Vander Zanden
- Geber Pena
- Jun Liu
- Luis Ulloa
- Woulter Dejonge
Organizations
- Academic Medical Center
- American Heart Association
- National Institutes of Health
- United States Army Medical Research and Development Command
- University of Medicine and Dentistry of New Jersey