Phospho-Tyr705 of STAT3 is a therapeutic target for sepsis through regulating inflammation and coagulation.

Abstract

BACKGROUND:

Sepsis is an infection-induced aggressive and life-threatening organ dysfunction with high morbidity and mortality worldwide. Infection-associated inflammation and coagulation promote the progression of adverse outcomes in sepsis. Here, we report that phospho-Tyr705 of STAT3 (pY-STAT3), not total STAT3, contributes to systemic inflammation and coagulopathy in sepsis.

METHODS:

Cecal ligation and puncture (CLP)-induced septic mice were treated with BP-1-102, Napabucasin, or vehicle control respectively and then assessed for systemic inflammation, coagulation response, lung function and survival. Human pulmonary microvascular endothelial cells (HPMECs) and Raw264.7 cells were exposed to lipopolysaccharide (LPS) with pharmacological or genetic inhibition of pY-STAT3. Cells were assessed for inflammatory and coagulant factor expression, cell function and signaling.

RESULTS:

Pharmacological inhibition of pY-STAT3 expression by BP-1-102 reduced the proinflammatory factors, suppressed coagulation activation, attenuated lung injury, alleviated vascular leakage and improved the survival rate in septic mice. Pharmacological or genetic inhibition of pY-STAT3 diminished LPS-induced cytokine production in macrophages and protected pulmonary endothelial cells via the IL-6/JAK2/STAT3, NF-κB and MAPK signaling pathways. Moreover, the increase in procoagulant indicators induced by sepsis such as tissue factor (TF), the thrombin-antithrombin complex (TAT) and D-Dimer were down-regulated by pY-STAT3 inhibition.

CONCLUSIONS:

Our results revealed a therapeutic role of pY-STAT3 in modulating the inflammatory response and defective coagulation during sepsis. Video Abstract.

• Authors: Shunyao Xu, Xiaojun Pan, Lingjie Mao, Hao Pan, Wenwei Xu, Yufeng Hu, Xueshu Yu, Zhiqiang Chen, Songzan Qian, Yincai Ye, Yueyue Huang, Jingye Pan
• Journal: Cell communication and signaling : CCS (Cell Commun Signal) Vol. 18 Issue 1 Pg. 104 (07 08 2020) ISSN: 1478-811X [Electronic] England
• PMID: 32641132 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Aminosalicylic Acids
• BP-1-102
• Benzofurans
• Inflammation Mediators
• Lipopolysaccharides
• Naphthoquinones
• STAT3 Transcription Factor
• Sulfonamides
• Toll-Like Receptor 4
• napabucasin
• Phosphotyrosine
• Thromboplastin

Topics

• Aminosalicylic Acids
• Animals
• Benzofurans (pharmacology)
• Blood Coagulation (drug effects)
• Cecum (pathology)
• Cell Membrane Permeability (drug effects)
• Endothelial Cells (drug effects, metabolism)
• Humans
• Inflammation (blood, complications)
• Inflammation Mediators (metabolism)
• Ligation
• Lipopolysaccharides
• Macrophages (drug effects, metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Models, Biological
• Molecular Targeted Therapy
• Naphthoquinones (pharmacology)
• Phosphotyrosine (metabolism)
• Punctures
• RAW 264.7 Cells
• STAT3 Transcription Factor (metabolism)
• Sepsis (blood, complications)
• Sulfonamides
• Suppression, Genetic (drug effects)
• Survival Analysis
• Thromboplastin (metabolism)
• Toll-Like Receptor 4 (metabolism)