Abstract
Sepsis is a life-threatening cascading systemic inflammatory response syndrome on account of serve infection. In inflamed tissues, activated macrophages generate large amounts of inflammatory cytokines reactive species, and are exposed to the damaging effects of reactive species. However, comparing with necroptosis and pyroptosis, so far, there are few studies focusing on the overproduction-related cell death, such as parthanatos in macrophage during sepsis. In LPS-treated macrophage, we observed PARP-1 activation, PAR formation and AIF translocation. All these phenomena could be inhibited by both erlotinib and 3-AB, indicating the presence of parthanatos in endotoxemia. We further found that LPS induced the increase of cell surface TLR4 expression responsible for the production of ROS and subsequent parthanatos in endotoxemia. All these results shed a new light on how TLR4 regulating the activation of PARP-1 by LPS in macrophage.
Highlights
In the circumstance of DNA damage, nuclear enzyme, poly (ADPribose) (PAR) polymerase-1 (PARP-1), activates and facilitates DNA repair [1]
Erlotinib and 3-AB increase survival of mice or reduce cell death rate treated with LPS some studies have demonstrated that the main ways of cell death induced by LPS are necrosis and pyroptosis
3-AB pretreatment significantly improved Erlotinib attenuates LPS-induced parthanatos in vivo and survival in LPS-treated mice with indicating that PARP-1 might in vitro play a critical role in endotoxemia. To further confirm these To further the character of epidermal growth factor receptor (EGFR) on parthanatos, wild-type (WT) results in vivo, peritoneal lavage fluid macrophages were C57BL/6 mice were treated with LPS with or without erlotinib or collected from normal and endotoxemic mice with or without 3-AB pretreatment
Summary
In the circumstance of DNA damage, nuclear enzyme, poly (ADPribose) (PAR) polymerase-1 (PARP-1), activates and facilitates DNA repair [1]. Excessive activation of PARP-1 depletes cellular NAD+ and slows down ATP formation, resulting in the formation of PAR polymers. Apoptosis-inducing factor (AIF) translocates from mitochondria into cytoplasm, launching a caspaseindependent cell death program, called parthanatos (PARP-1dependent cell death) [2,3,4]. Some studies demonstrated that reactive oxygen species (ROS) is critical to the process of parthanatos after genotoxic agents and treatment [5,6,7]. Oxidative stress/ROS overproduction is an important initiator. Parthanatos has been reported to participate in many diseases, such as ischemia-reperfusion injury, neurobiological disorders, and inflammatory injury [8,9,10,11]
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