Editors' ChoiceInflammation

Blocking DAMPs but not PAMPs

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Sci. Signal.  20 Jan 2015:
Vol. 8, Issue 360, pp. ec13
DOI: 10.1126/scisignal.aaa6950

Innate immune cells, such as macrophages, secrete inflammatory cytokines in response to receptor stimulation by pathogen-associated molecular patterns (PAMPs), such as microbial lipopolysaccharide (LPS), a Toll-like receptor 4 (TLR4) ligand. Inflammation is also stimulated by damage-associated molecular patterns (DAMPs), such as the nuclear protein HMGB1, which is secreted by activated immune cells and passively released by damaged cells. LPS binds to a complex containing the adaptor protein MD-2 before it binds to TLR4. Extracellular HMGB1 also stimulates the TLR4 complex; however, HMGB1 exists in multiple redox states, and only the disulfide form of HMGB1 causes inflammation. Yang et al. found that only the disulfide form of HMGB1 bound to MD-2 with high affinity in vitro and stimulated mouse macrophages to secrete the inflammatory cytokine tumor necrosis factor (TNF). These effects were abolished by chemical modification of Cys106 of HMGB1. Knockdown of MD-2 in mouse or human innate immune cells inhibited the disulfide HMGB1–dependent production of TNF. Screening of an HMGB1-derived peptide library revealed a tetramer peptide (P5779) that inhibited the binding of HMGB1 to MD-2. P5779 inhibited the HMGB1-stimulated release of TNF from human macrophages in a dose-dependent manner, but it did not inhibit LPS-stimulated cytokine production. Administration of P5779 to mice subjected to drug-induced liver toxicity, ischemia and reperfusion injury, or sepsis resulted in reduced inflammatory cytokine production, decreased disease severity, and increased survival. Together, these results suggest that only the disulfide form of HMGB1 binds to MD-2 to stimulate inflammation and that targeting this interaction therapeutically might specifically block signaling by this DAMP while sparing PAMP signaling through TLR4.

H. Yang, H. Wang, Z. Ju, A. A. Ragab, P. Lundbäck, W. Long, S. I. Valdes-Ferrer, M. He, J. P. Pribis, J. Li, B. Lu, D. Gero, C. Szabo, D. J. Antoine, H. E. Harris, D. T. Golenbock, J. Meng, J. Roth, S. S. Chavan, U. Andersson, T. R. Billiar, K. J. Tracey, Y. Al-Abed, MD-2 is required for disulfide HMGB1–dependent TLR4 signaling. J. Exp. Med. 212, 5–14 (2015). [Abstract] [Full Text]