cox inhibitor DAMPs are endogenous danger signals that can
DAMPs are endogenous danger signals that can initiate and perpetuate a noninfectious cox inhibitor during cell death . HMGB1 is a well-studied nuclear DAMP in various types of regulated necrosis and has been implicated in the pathogenesis of infection and sterile inflammation. Our current data indicate that HMGB1 is a danger signal to drive inflammatory cytokine release in response to various ferroptosis activators. The release of HMGB1 can occur in an active manner, as a consequence of specific signaling events during cell death . We found that an ATG5-and ATG7-dependent autophagy pathway is required for HMGB1 release in ferroptosis, which is consistent with previous findings that autophagy is essential for HMGB1 release in targeted toxin-induced cell death . Importantly, we further demonstrated that autophagy-mediated HDAC inhibition can promote HMGB1 acetylation to induce HMGB1 release in ferroptosis. Consequently, an HDAC inhibitor has the ability to induce ferroptosis and HMGB1 release in an autophagy-dependent manner. Of note, our previous studies have shown that HMGB1 is location-dependent in promoting autophagy [26,27], suggesting that feedback mechanisms between HMGB1 and autophagy can occur to fine-tune ferroptosis activity.
AGER, also called RAGE, is a multiligand receptor that is able to bind several different ligands, including HMGB1 in the innate immune system. The activation of the HMGB1-AGER pathway is implicated in the onset and sustainment of the inflammatory response in sepsis, pancreatitis, diabetes, and various ischemia-reperfusion tissue injuries . Our current study demonstrated that AGER is required for HMGB1-mediated TNF release in macrophages in response to ferroptotic cells, suggesting that blocking the HMGB1-AGER pathway may limit ferroptosis-mediated inflammation.
Conflicts of interest
Acknowledgments We thank Dave Primm (Department of Surgery, University of Texas Southwestern Medical Center) for his critical reading of the manuscript. This work was supported by the Natural Science Foundation of Guangdong Province (2016A030308011), the National Natural Science Foundation of China (31671435, 81830048, and 81772508), the Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme (2017), the American Cancer Society (Research Scholar Grant RSG-16-014-01-CDD), and Lin He's Academician Workstation of New Medicine and Clinical Translation (2017).
Introduction Death is a common fate of all life, from organisms to cells. The understanding that cell death can be regulated by molecular mechanisms and can yield physiological benefits and pathological consequences for multicellular organisms emerged early in the 1960s, with the concept of ‘programmed cell death’ , , . It is now established that such programmed cell death is essential for normal development and homeostasis and, when dysregulated, contributes to a variety of pathological conditions. Regulated cell death is defined as a death process that relies on dedicated molecular machinery, and that thus can be modulated (delayed or accelerated) by specific pharmacological and genetic interventions. Programmed cell death refers to physiological instances of regulated cell death that occur in the context of development and tissue homeostasis, in the absence of any exogenous perturbations. Programmed cell death is therefore a subset of regulated cell death. Regulated cell death is used to describe cell death that originates from perturbations of the intracellular or extracellular microenvironment, executed by molecular mechanisms when other adaptive responses are incapable of restoring cellular homeostasis . Regulated cell death is thus mechanistically distinct from classic necrosis, or unregulated cell death caused by overwhelming stresses, such as dramatic heat shock, use of detergents, pore forming reagents, or highly reactive alkylating agents.