BMAL2 promotes eCIRP-induced macrophage endotoxin tolerance

Area of Science:

• Immunology
• Circadian Biology
• Molecular Medicine

Background:

• Disruption of the circadian clock is linked to inflammatory and immunological disorders.
• Extracellular cold-inducible RNA-binding protein (eCIRP), released during sepsis, can induce macrophage endotoxin tolerance.
• BMAL2 is a key circadian protein involved in transcriptional activation.

Purpose of the Study:

• To investigate if eCIRP induces BMAL2 expression and promotes macrophage endotoxin tolerance through TREM-1.
• To explore the role of BMAL2 in regulating PD-L1 expression in macrophages.

Main Methods:

• Sepsis model in mice (CLP), ELISA for eCIRP, and macrophage treatment with recombinant eCIRP.
• qPCR to assess gene expression (PD-L1, IL-10, STAT3, BMAL2, CRY1, PER2) and TREM-1's role.
• Computational modeling and BIAcore assay to determine BMAL2-PD-L1 promoter interaction.

Main Results:

• Septic mice showed increased serum eCIRP; eCIRP pre-treatment induced macrophage endotoxin tolerance (reduced TNFα, IL-6).
• eCIRP upregulated PD-L1, IL-10, STAT3, and circadian genes (BMAL2, CRY1, PER2) via TREM-1.
• BMAL2 expression correlated with PD-L1; BMAL2 positively regulates PD-L1 in macrophages.

Conclusions:

• eCIRP upregulates BMAL2 expression through TREM-1, inducing macrophage endotoxin tolerance in sepsis.
• Targeting eCIRP to maintain circadian rhythm may correct endotoxin tolerance and enhance host resistance.
• BMAL2 plays a crucial role in eCIRP-mediated immune tolerance during sepsis.