Role of scavenger receptors as damage-associated molecular pattern receptors in Toll-like receptor activation

Area of Science:

• Immunology
• Cell Biology

Background:

• Damage-associated molecular patterns (DAMPs) like High-mobility group box 1 (HMGB1) are key in sterile inflammation.
• HMGB1 signals via RAGEs and TLRs, but its low affinity for TLRs leaves activation mechanisms unclear.

Purpose of the Study:

• To elucidate the mechanism of HMGB1-mediated Toll-like receptor (TLR) activation.
• To investigate the role of scavenger receptors in HMGB1 internalization and signaling.

Main Methods:

• Utilized fluorescently labeled HMGB1 to track internalization into macrophages.
• Employed maleylated bovine serum albumin (M-BSA) as a class A scavenger receptor inhibitor.
• Examined HMGB1 and TLR4 co-localization and cytokine production in M1 and M2 macrophages.
• Assessed M-BSA efficacy in LPS-induced sepsis and DSS-induced colitis models.

Main Results:

• HMGB1 was efficiently internalized into macrophages via class A scavenger receptors.
• Only M1-type macrophages secreted cytokines in response to HMGB1.
• M-BSA inhibited HMGB1 internalization and subsequent cytokine production, but not LPS-induced responses.
• The C-terminal acidic domain of HMGB1 mediates scavenger receptor uptake and cytokine release.
• M-BSA disrupted HMGB1 and TLR4 co-localization, indicating scavenger receptors act as co-receptors for TLR activation.
• M-BSA demonstrated therapeutic effects in sepsis and colitis models.

Conclusions:

• Class A scavenger receptors function as co-receptors with TLRs for HMGB1 signaling in M1-type inflammatory macrophages.
• Targeting scavenger receptor-mediated HMGB1 uptake offers a potential therapeutic strategy for sterile inflammatory diseases.