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Updated: Apr 15, 2026
Screening Assays to Characterize Novel Endothelial Regulators Involved in the Inflammatory Response
Published on: September 15, 2017
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.
Abstract:
Sepsis, a hyperinflammatory response that can result in multiple organ dysfunctions, is a leading cause of mortality from infection. Here, we show that orphan nuclear receptor Nur77 (also known as TR3) can enhance resistance to lipopolysaccharide (LPS)-induced sepsis in mice by inhibiting NF-κB activity and suppressing aberrant cytokine production. Nur77 directly associates with p65 to block its binding to the κB element. However, this function of Nur77 is countered by the LPS-activated p38α phosphorylation of Nur77. Dampening the interaction between Nur77 and p38α would favor Nur77 suppression of the hyperinflammatory response. A compound, n-pentyl 2-[3,5-dihydroxy-2-(1-nonanoyl) phenyl]acetate, screened from a Nur77-biased library, blocked the Nur77-p38α interaction by targeting the ligand-binding domain of Nur77 and restored the suppression of the hyperinflammatory response through Nur77 inhibition of NF-κB. This study associates the nuclear receptor with immune homeostasis and implicates a new therapeutic strategy to treat hyperinflammatory responses by targeting a p38α substrate to modulate p38α-regulated functions.
Insights
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.
