MD-2 is required for disulfide HMGB1-dependent TLR4 signaling(The Journal of Experimental Medicine 2015)

報告日期: 2015/03/17
報告時間: 15:10/16:00
報告學生: Nurhafiza Binti Zainal
講評老師: 張志鵬
附件下載: 下載[1453-1425856676-1.pdf] 

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

Huan Yang et al. (2015) J. Exp. Med. 212: 5-14

Speaker: Nurhafiza Zainal                                     Time: 15:10~16:00, March 17, 2015

Commentator: Dr. Chang Chih-Peng                                 Venue: Room 602

Abstract

Microbial-derived pro-inflammatory agents termed pathogen-associated molecular patterns (PAMPs) are some of the most potent triggers of inflammation. However, sterile stimuli including stress, ischemia, mechanical trauma and environmental cues such as ultra-violet radiation may also activate inflammation1. These damage-related stimuli are collectively known as damage-associated molecular patterns (DAMPs). Though both of PAMP- and DAMP-mediated inflammatory responses are important for host defense, prolonged release of DAMPs could contribute to sepsis and other inflammatory diseases2. HMGB1 is actively secreted from immune cells or passively released from damaged tissues. HMGB1 signals through a family of receptors including RAGE and TLR4, thus functioning as a DAMP that activates wide range of cytokines and chemokines3. In this study, the authors showed that the extracellular TLR4 adaptor, myeloid differentiation factor 2 (MD-2), binds specifically to disulfide isoform of HMGB1 with exclusion of other isoforms. Experiments using MD-2 knockout mice and MD-2 silencing macrophages demonstrated a requirement of MD-2 for HMGB1-dependent TLR4 signaling. They also identified a tetramer (FSSE, designated P5779) as a specific MD-2 antagonist that inhibits MD-2-HMGB1 interaction and TLR4 signaling. Nevertheless, P5779 does not interfere lipopolysaccharide-induced cytokine/chemokine production, thereby preserving PAMP-mediated MD-2-TLR4 responses. Moreover, P5779 is capable of protecting mice against hepatic ischemia/reperfusion injury, chemical toxicity and sepsis. These findings prove the possibilities to develop strategies that selectively reduce DAMP-mediated inflammatory responses while sustaining PAMP-mediated signaling.

References:

  1. Rock, K. L. et al. (2010) The sterile inflammatory response. Annu. Rev. Immunol. 28: 321-342.
  2. Valdes-Ferrer, S. I. et al. (2013) High-mobility group box 1 mediates persistent splenocyte priming in sepsis survivors: evidence from a murine model. Shock 40: 492-495.
  3. Yang, H. et al. (2013) The many faces of HMGB1: molecular structure-functional activity in inflammation, apoptosis and chemotaxis. J. Leukoc. Biol. 93: 865-873.