TLR4 and HMGB1: partners in crime?

Chen et al. confirmed the role of Toll-like receptor 4 (TLR4) in ischemic kidney injury using mice harboring spontaneous disabling mutations of the receptor and generated chimeras between TLR4-/- and TLR4+/+ mice. The major findings demonstrate the necessity of TLR4 in leukocytes, as well as in epithelial and endothelial cells, for the full-blown ischemic response and strongly suggest that the release of high-mobility group box 1 protein (HMGB1) from injured epithelia and/or endothelia activates leukocytes to generate proinflammatory cytokines, further exacerbating the injury to ischemic kidneys. These important findings provide an excellent platform for discussing the complexity of danger/alarm signaling in the kidney.