Redox-sensitive high mobility group box 1 (HMGB1) is a multifunctional regulator of cellular senescence, inflammation, and immunosuppression: Impact on the aging process

Aging is a multifaceted process involving cellular senescence and a significant remodeling of the immune network driven by the senescence-associated secretory phenotype (SASP). This progressive process needs adaptable drivers to push it forward. The redox-sensitive high mobility group box 1 (HMGB1) protein is a perfect example of this kind of oxidative stress- and aging-related multifunctional protein. The HMGB1 protein is an important non-histone DNA chaperone which maintains chromatin integrity and contributes to gene expression and DNA repair. Diverse intrinsic and exogenous insults induce the translocation of the nuclear HMGB1 protein into cytoplasm and subsequently into the extracellular space. Interestingly, cellular senescence is associated with a robust release of HMGB1 from chromatin and subsequently it is secreted with other SASP factors. The extracellular HMGB1 is a pleiotropic immune regulator since it can organize both proinflammatory and immunosuppressive responses in a context-dependent manner. For instance, HMGB1 stimulates proinflammatory responses via TLR and RAGE signaling as well as by activating NLRP3 inflammasomes and cooperating with the complement system. HMGB1 can also delay the resolution of acute inflammation and thus elicit chronic inflammation. An increase in chemotaxis of myeloid cells by HMGB1 stimulates the recruitment of immunosuppressive cells, such as MDSCs and Tregs. HMGB1 also promotes the polarization of M1 macrophages toward the immunosuppressive M2 phenotype and enhances the function of inhibitory immune checkpoints. Given that the redox-sensitive HMGB1 protein is a driver of cellular senescence and a multifunctional regulator of the immune network, it seems that HMGB1 has a crucial role in the inflammaging process.