RORγ regulates the NLRP3 inflammasome

Area of Science:

• Immunology
• Molecular Biology
• Pharmacology

Background:

• RAR-related orphan receptor γ (RORγ) is crucial for T helper 17 (T_h17) cell development.
• The NLRP3 inflammasome processes IL-1β and drives inflammatory diseases.
• RORγ's role in innate immunity and NLRP3 inflammasome regulation is not fully understood.

Purpose of the Study:

• To investigate the role of RORγ in NLRP3 inflammasome activation.
• To evaluate RORγ inverse agonists as potential therapeutics for NLRP3-associated inflammatory diseases.

Main Methods:

• Utilized RORγ-null mice and bone marrow-derived macrophages (BMDMs).
• Assessed IL-1β secretion and gene expression (Nlrp3, Il1b) via quantitative PCR.
• Examined RORγ binding to Nlrp3 and Il1b promoters using chromatin immunoprecipitation.
• Tested RORγ inverse agonists in LPS/ATP-stimulated BMDMs and mouse models of sepsis and fulminant hepatitis.

Main Results:

• RORγ-null BMDMs showed reduced IL-1β secretion and Nlrp3/Il1b expression.
• RORγ directly binds to ROR response elements in Nlrp3 and Il1b gene promoters.
• RORγ inverse agonists suppressed IL-1β secretion and gene expression in BMDMs.
• RORγ inverse agonists reduced mortality in LPS-induced sepsis and fulminant hepatitis mouse models.

Conclusions:

• RORγ plays a significant role in regulating NLRP3 inflammasome activity and innate immune responses.
• Targeting RORγ with inverse agonists represents a promising therapeutic strategy for NLRP3-associated inflammatory conditions.