The HMGB1-MD-2 axis as a novel therapeutic target in inflammatory diseases (CCR5P.210)

Abstract

Abstract Innate immune cells express receptors for pathogen-associated molecular patterns (PAMP e.g. LPS) as well as damage-associated molecular patterns (DAMP e.g. HMGB1), and orchestrate inflammatory responses to both infection and sterile injury. Secreted by activated immune cells or passively released by damaged cells, HMGB1 is subjected to redox modulation that distinctly influences its extracellular functions. Previously, it was unknown how the TLR4 signalosome distinguishes between HMGB1 isoforms. Here we demonstrate that the TLR4 adaptor molecule, myeloid differentiation factor 2 (MD-2), binds specifically to the cytokine-inducing disulfide HMGB1 isoform, to the exclusion of other isoforms. Screening of HMGB1 peptide libraries identified a tetramer (FSSE, designated as P5779) as a specific MD-2-antagonist preventing MD-2/HMGB1 interaction and subsequent TLR4 signaling mediating cytokine and chemokine release. Moreover, P5779 does not interfere with LPS-induced cytokine production, thereby preserving PAMP-mediated TLR4-MD2 responses. P5779 conferred protection in animal models of hepatic ischemia/reperfusion injury, chemical toxicity and sepsis. Taken together, these findings reveal a novel mechanism by which innate systems selectively recognize specific HMGB1 isoforms and suggest strategies to attenuate DAMP-mediated inflammatory responses while preserving anti-microbial immune responsiveness.