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MD-2 is required for disulfide HMGB1-dependent TLR4 signaling
Huan Yang1, Haichao Wang2, Zhongliang Ju3
1Department of Biomedical Science and Department of Medicinal Chemistry, The Feinstein Institute for Medical Research, Manhasset, NY 11030 kjtracey@nshs.edu hyang@nshs.edu.
The Journal of Experimental Medicine
|January 7, 2015
Summary
Researchers discovered how the immune system distinguishes between different forms of HMGB1, a molecule involved in inflammation. A specific peptide, P5779, blocks harmful HMGB1 signaling while preserving responses to pathogens.
Area of Science:
- Immunology
- Molecular Biology
- Biochemistry
Background:
- Innate immune receptors recognize pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) to manage inflammation.
- High-mobility group box 1 (HMGB1) is a DAMP released by damaged cells, with its function influenced by redox modifications.
- The mechanism by which Toll-like receptor 4 (TLR4) distinguishes between HMGB1 isoforms was previously unclear.
Purpose of the Study:
- To elucidate the molecular mechanism of HMGB1 isoform recognition by the TLR4 signalosome.
- To identify specific antagonists of HMGB1-mediated TLR4 signaling.
- To evaluate the therapeutic potential of such antagonists in inflammatory conditions.
Main Methods:
- Biochemical assays to determine the interaction between myeloid differentiation factor 2 (MD-2) and HMGB1 isoforms.
- Studies using MD-2-deficient mice and silenced macrophages to assess the role of MD-2 in HMGB1-TLR4 signaling.
- Peptide library screening to identify HMGB1-MD-2 interaction inhibitors.
- In vivo experiments to evaluate the protective effects of the identified antagonist in models of tissue injury and sepsis.
Main Results:
- Myeloid differentiation factor 2 (MD-2) specifically binds to the cytokine-inducing disulfide isoform of HMGB1.
- HMGB1-dependent TLR4 signaling requires MD-2.
- A novel HMGB1-derived peptide, P5779, acts as a specific antagonist of MD-2, inhibiting HMGB1-TLR4 interactions.
- P5779 selectively blocks DAMP-induced inflammation without affecting PAMP-induced TLR4 responses.
- P5779 demonstrated protective effects in mouse models of hepatic ischemia/reperfusion injury, chemical toxicity, and sepsis.
Conclusions:
- Innate immune systems selectively recognize specific HMGB1 isoforms through MD-2.
- The identified peptide P5779 represents a potential therapeutic strategy for attenuating DAMP-mediated inflammation.
- This approach allows for the preservation of essential antimicrobial immune responses while mitigating detrimental inflammation.
