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J Exp Med. 2015 Jan 12;212(1):5-14. doi: 10.1084/jem.20141318. Epub 2015 Jan 5.

MD-2 is required for disulfide HMGB1-dependent TLR4 signaling.

Author information

1
Department of Biomedical Science and Department of Medicinal Chemistry, The Feinstein Institute for Medical Research, Manhasset, NY 11030 kjtracey@nshs.edu hyang@nshs.edu.
2
Department of Emergency Medicine, North Shore University Hospital, Manhasset, NY 11030.
3
Department of Biomedical Science and Department of Medicinal Chemistry, The Feinstein Institute for Medical Research, Manhasset, NY 11030.
4
Department of Medicine and Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital, SE-171 77 Stockholm, Sweden Department of Medicine and Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital, SE-171 77 Stockholm, Sweden.
5
Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213.
6
Department of Anesthesiology, The University of Texas Medical Branch, Galveston, TX 77555.
7
Medical Research Council Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool L69 3BX, England, UK.
8
Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01655.

Abstract

Innate immune receptors for pathogen- and damage-associated molecular patterns (PAMPs and DAMPs) orchestrate inflammatory responses to infection and injury. Secreted by activated immune cells or passively released by damaged cells, HMGB1 is subjected to redox modification that distinctly influences its extracellular functions. Previously, it was unknown how the TLR4 signalosome distinguished between HMGB1 isoforms. Here we demonstrate that the extracellular TLR4 adaptor, myeloid differentiation factor 2 (MD-2), binds specifically to the cytokine-inducing disulfide isoform of HMGB1, to the exclusion of other isoforms. Using MD-2-deficient mice, as well as MD-2 silencing in macrophages, we show a requirement for HMGB1-dependent TLR4 signaling. By screening HMGB1 peptide libraries, we identified a tetramer (FSSE, designated P5779) as a specific MD-2 antagonist preventing MD-2-HMGB1 interaction and TLR4 signaling. P5779 does not interfere with lipopolysaccharide-induced cytokine/chemokine production, thus preserving PAMP-mediated TLR4-MD-2 responses. Furthermore, P5779 can protect mice against hepatic ischemia/reperfusion injury, chemical toxicity, and sepsis. These findings reveal a novel mechanism by which innate systems selectively recognize specific HMGB1 isoforms. The results may direct toward strategies aimed at attenuating DAMP-mediated inflammation while preserving antimicrobial immune responsiveness.

PMID:
25559892
PMCID:
PMC4291531
DOI:
10.1084/jem.20141318
[Indexed for MEDLINE]
Free PMC Article

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