Toll-like receptor 4-dependent pathways as sensors of endogenous “danger” signals. New evidences and potential therapeutic targets

Toll-like receptors (TLRs) are a family of proteins involved in the recognition of pathogen-associated molecular motifs that activate both innate and adaptive immune responses. TLR4 is the member of the family that binds to bacterially produced lipopolysaccharide (LPS). Although still on debate, increasing evidences show that TLRs are also able to recognize endogenous molecules. Two recent reports have highlighted the role of TLR4 signaling pathways as sensors of endogenous 'danger' signals and their association to pathogenesis. Vogl and colleagues describe a connection between TLR4 and septic shock through the calciumbinding S100 family of myeloid-related proteins (Mrp) 8 and 14, two proinflammatory molecules secreted by phagocytes upon activation. Apetoh and colleagues describe a new pathway whereby tumor cells dying after chemotherapy release the high-mobility group box 1 protein (HMGB1), which is recognized by TLR4 and induces an immune response that is required for the success of therapy. These interesting studies not only increase our understanding of the biology of TLR4, but also support the 'danger' model since both reports identify 'self' molecules, produced after tissue damage or chemotherapy-induced cell death, that act as 'alarm' signals activating the immune response through TLR4- dependent pathways. Moreover, these articles identify new targets for developing novel therapeutic treatments for septic shock and for the improvement of the efficacy of anticancer drugs.