HMGB1: RECEPTORS AND BIOLOGICAL ACTIVITIES
Several potential receptors for HMGB1 have been described. Among them, the receptor for Advanced Glycation End-products (RAGE) is certainly one of the most relevant. RAGE is a trans-membrane protein that belongs to the immunoglobulin superfamily.
RAGE acts as a receptor for multiple ligands including HMGB1, the amyloid peptide, some members of S100∕calgranulin peptides and above all advanced glycation end products (AGEs). AGEs are a group of heterogeneous complex molecules produced by the non-enzymatic glycation between aldoses and free amino groups on proteins [21], DNA [22] or lipids [23]. RAGE is expressed at high level in lung type-1 pneumocytes, but its expression is found at low levels in almost all cell types. Increased levels of RAGE expression has been observed in patients suffering from diabetes, Alzheimer’s disease and atherosclerosis [24]. Engagement of RAGE by its ligands results in the activation of several intracellular signaling pathways, including the mitogen activated protein (MAP) kinases ERK and p38 [25], that eventually lead to NF-kB activation [26]. Although it is not clear whether different ligands promote different cell responses, these pathways have been frequently associated with the production of pro- inflammatory cytokines, cell migration, survival and proliferation.Accumulating evidences lead to the notion that HMGB1 could also be recognized by at least two Toll-Like receptors (TLRs). Park et al. first demonstrated that TLR-2 and TLR-4 could be engaged by HMGB1 [27], an event that would be especially important for leucocytes activation. Importantly, interaction of HMGB1 with TLR-2 and TLR-4 also mediates NF-kB activation (even through different pathways), which promotes inflammatory responses similar to those triggered by bacterial components (Fig. 3).
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Figure 3. HMGB1 signal transduction pathways. HMGB1 binds to the receptor for advanced glycation end products (RAGE) and two members of the toll like receptors (TLRs). These interactions induce the NFkB nuclear translocation via the ras/MAP kinase or the MyD88/IRAK/MAP kinase pathways, respectively.