Erlotinib protests against LPS-induced parthanatos through inhibiting macrophage surface TLR4 expression
Qiong Xue1, Xiaolei Liu2, Cuiping Chen2
1The Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
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.
Insights
Sepsis involves macrophage cell death via parthanatos, triggered by lipopolysaccharide (LPS) through Toll-like receptor 4 (TLR4) and reactive oxygen species (ROS). This pathway, involving PARP-1 activation, is a key finding in endotoxemia research.
Area of Science:
- Immunology
- Cell Biology
- Pathology
Background:
- Sepsis is a critical systemic inflammatory response to infection.
- Macrophages are key immune cells in sepsis, producing inflammatory mediators and reactive species.
- Cell death pathways like necroptosis and pyroptosis are studied, but parthanatos in sepsis macrophages is less understood.
Purpose of the Study:
- To investigate the role of parthanatos in macrophages during sepsis.
- To elucidate the molecular mechanisms linking Toll-like receptor 4 (TLR4) to cell death in endotoxemia.
- To explore the involvement of Poly (ADP-ribose) polymerase 1 (PARP-1) in LPS-induced macrophage death.
Main Methods:
- Macrophages were treated with lipopolysaccharide (LPS) to induce endotoxemia.
- Observed PARP-1 activation, poly (ADP-ribose) (PAR) formation, and apoptosis-inducing factor (AIF) translocation.
- Utilized inhibitors erlotinib and 3-AB to assess the role of parthanatos.
- Measured cell surface TLR4 expression and reactive oxygen species (ROS) production.
Main Results:
- LPS treatment induced PARP-1 activation, PAR formation, and AIF translocation in macrophages, indicative of parthanatos.
- Erlotinib and 3-AB significantly inhibited these parthanatos markers.
- LPS increased cell surface TLR4 expression, which was linked to ROS production and subsequent parthanatos.
- TLR4 activation by LPS regulates PARP-1 activation in macrophages.
Conclusions:
- Parthanatos is a significant cell death pathway in macrophages during endotoxemia.
- TLR4 signaling, ROS production, and PARP-1 activation are crucial components of LPS-induced parthanatos.
- This study reveals a novel mechanism of TLR4-mediated macrophage death in sepsis.
