Essential role of high-mobility group box proteins in nucleic acid-mediated innate immune responses

Central to protective and pathological immunity is the activation of innate immune responses upon recognition of nucleic acids by transmembrane Toll-like receptors (TLRs) and cytosolic receptors. In mammals, the transmembrane pattern recognition receptors TLR3, TLR7 and TLR9 recognize double-stranded RNA, single-stranded RNA and hypomethylated DNA, respectively, while the retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs), RIG-I and MDA5 are known to be cytosolic RNA-sensing receptors. In addition, cytosolic DNA-sensing receptors that include DAI, RIG-I/MDA5 and AIM2 also trigger innate immune responses. High-mobility group box (HMGB)1, 2 and 3 proteins, which also bind immunogenic nucleic acids, are generally involved in the nucleic acid receptor-mediated activation of innate immune responses. There is a hierarchy in the nucleic acid-mediated activation of immune responses, wherein the selective activation of the nucleic acid-sensing receptors is contingent on the more promiscuous sensing of nucleic acids by HMGBs. The aim of this review is to summarize this novel feature of HMGB proteins, as essential frontline instigators of nucleic acid-mediated activation of innate immune responses. In addition, we will discuss the therapeutic implications of these findings.