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Impeding the interaction between Nur77 and p38 reduces LPS-induced inflammation
Li Li1, Yuan Liu1, Hang-zi Chen1
1State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, State-Province Joint Engineering Laboratory of Targeted Drugs from Natural Products, School of Life Sciences, Xiamen University, Xiamen, Fujian Province, China.
Nature Chemical Biology
|March 31, 2015
Summary
Orphan nuclear receptor Nur77 enhances sepsis resistance by inhibiting NF-κB and cytokine production. A novel compound targeting Nur77-p38α interaction offers a therapeutic strategy for hyperinflammatory responses.
Area of Science:
- Immunology
- Molecular Biology
- Pharmacology
Background:
- Sepsis is a life-threatening hyperinflammatory response to infection, leading to organ dysfunction and high mortality.
- Nuclear receptors play critical roles in regulating immune responses and maintaining homeostasis.
Purpose of the Study:
- To investigate the role of orphan nuclear receptor Nur77 in lipopolysaccharide (LPS)-induced sepsis.
- To identify therapeutic strategies targeting Nur77 for hyperinflammatory conditions.
Main Methods:
- Utilized a mouse model of LPS-induced sepsis.
- Investigated the interaction between Nur77 and NF-κB signaling pathway components.
- Screened a compound library to identify inhibitors of the Nur77-p38α interaction.
Main Results:
- Nur77 inhibits NF-κB activity and suppresses aberrant cytokine production, enhancing resistance to sepsis.
- LPS-induced p38α phosphorylation of Nur77 counteracts its anti-inflammatory function.
- A novel compound blocked Nur77-p38α interaction, restoring Nur77's ability to inhibit NF-κB and suppress hyperinflammation.
Conclusions:
- Nur77 is a key regulator of immune homeostasis and sepsis resistance.
- Targeting the Nur77-p38α interaction presents a promising therapeutic avenue for treating hyperinflammatory diseases.
