Abstract
The cecal ligation and perforation (CLP) model is the gold standard for the polymicrobial sepsis. In the CLP mice, the myeloid cells play an important role in septic shock. The phenotypes and the activation state of the macrophage and neutrophil correlate with their metabolism. In the present study, we generated the specific myeloid deletion of PDK1 and mTOR mice, which was the important regulator of metabolic signaling. We found that the deletion of PDK1 in the myeloid cells could aggravate the early septic shock in the CLP mice, as well as the deletion of mTORC1 and mTORC2. Moreover, PDK1 deletion attenuated the inflammation induced by LPS in the late stage on CLP mice, which was exacerbated in mTORC1 and mTORC2 knockout mice. Both PDK1 and mTORC1/2 could not only regulate the cellular metabolism but also play important roles on the myeloid cells in the secondary stimulation of sepsis. The present study will provide a theoretical prospect for the therapy of the septic shock in different stages.
Highlights
The cecal ligation and perforation (CLP) model is considered a gold standard of the experimental sepsis [1], which can imitate the clinical sepsis more accurately than the injection of endotoxin or purified bacteria
The early sepsis in CLP has been confirmed with the transient systemic bacteremia and elevated cytokine levels in about the first five days, and the late stage has been confirmed with the enhanced peritoneal bacterial overgrowth and reduced circulating proinflammatory cytokines in the five days [2]
Phosphoinositide-dependent kinase-1 (PDK1)/mammalian target of rapamycin (mTOR) signaling has been confirmed to regulate the metabolism of tumor [17, 18], T cell [19, 20], B cell [21], and NK cells [22] but has rarely been associated with the myeloid cell metabolism especially in CLP-induced sepsis
Summary
The cecal ligation and perforation (CLP) model is considered a gold standard of the experimental sepsis [1], which can imitate the clinical sepsis more accurately than the injection of endotoxin or purified bacteria. Sepsis is initiated by a systemic hyperinflammatory reaction that is named the early stage. The inflammation shifts within a few days to a protracted anti-inflammatory and immunosuppressive state, named the late stage. The patients with the impaired immunity are more susceptible to secondary infections. The early sepsis in CLP has been confirmed with the transient systemic bacteremia and elevated cytokine levels in about the first five days, and the late stage has been confirmed with the enhanced peritoneal bacterial overgrowth and reduced circulating proinflammatory cytokines in the five days [2]. There are different immune responses between the early and late stages of sepsis. Different regulatory factors may play important roles in the two stages
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