Year: 2015
Type: article
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.
DOI: 10.1084/jem.20141318
Authors: Huan Yang, Haichao Wang, Zhongliang Ju, Ahmed A. Ragab, Peter Lundbäck, Wei Long, Sergio I. Valdes-Ferrer, Mingzhu He, John P. Pribis, Jianhua Li, Ben Lu, Domokos Gero, Csaba Szabo, Daniel J. Antoine, Helena E. Harris, Doug T. Golenbock, Jianmin Meng, Jesse Roth, Sangeeta S. Chavan, Ulf Andersson, Timothy R. Billiar, Kevin J. Tracey, Yousef Al-Abed
Institutions: Feinstein Institute for Medical Research, North Shore University Hospital, Karolinska University Hospital, Karolinska Institutet, University of Pittsburgh, The University of Texas Medical Branch at Galveston, University of Liverpool, Medical Research Council, University of Massachusetts Chan Medical School
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
Awards: Mechanism of action and therapeutic potential of HMGB1 A box in sepsis, Centre for Drug Safety Science (CDSS), Phagocyte Receptors for Lipid A, G2934008973, Mechanisms of Novel Herbal Therapies for Sepsis., General Clinical Research Center, PKR mediated inflammasome activation and pyroptosis in sepsis, Regulation of cellular bioenergetics by hydrogen sulfide, HMG IN POST OPERATIVE AND TRAUMATIC STRESS, Molecular Biology of Hemorrhagic Shock
OpenAlex ID: W2132959555