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Published on: May 2, 2018
Apoptotic cells protect mice against lipopolysaccharide-induced shock
Yi Ren1, Yi Xie, Guoping Jiang
1Department of Surgery, University of Hong Kong, Hong Kong, China. ren@dls.rutgers.edu
Abstract:
LPS is a main causative agent of septic shock. There is a lack of effective therapies. In vitro studies have shown that uptake of apoptotic cells actively inhibits the secretion by activated macrophages (Mphi) of proinflammatory mediators such as TNF-alpha and that such uptake increases the antiinflammatory and immunosuppressive cytokine TGF-beta. We therefore investigated the protective effect of apoptotic cells against LPS-induced endotoxic shock in mice. The current report is the first study to demonstrate that administration of apoptotic cells can protect mice from LPS-induced death, even when apoptotic cells were administered 24 h after LPS challenge. The beneficial effects of administration of apoptotic cells included 1) reduced circulating proinflammatory cytokines, 2) suppression of polymorphonuclear neutrophil infiltration in target organs, and 3) decreased serum LPS levels. LPS can quickly bind to apoptotic cells and these LPS-coated apoptotic cells can be recognized and cleared by Mphi in a CD14/thrombospondin/vitronectin receptor-dependent manner, accompanied with suppression of TNF-alpha and enhancement of IL-10 expression by LPS-activated Mphi. Apoptotic cells may therefore have therapeutic potential for the treatment of septic shock.
Insights
Administration of apoptotic cells protects mice from lethal endotoxic shock by reducing inflammatory cytokines and neutrophil infiltration. This novel therapy shows promise for treating sepsis, even when administered 24 hours after LPS challenge.
Area of Science:
- Immunology
- Cell Biology
- Pathology
Background:
- Lipopolysaccharide (LPS) is a primary cause of septic shock, a life-threatening condition with limited effective treatments.
- In vitro studies indicate that macrophages (Mphi) engulfing apoptotic cells reduce pro-inflammatory mediator secretion (e.g., TNF-alpha) and increase anti-inflammatory cytokine production (e.g., TGF-beta).
Purpose of the Study:
- To investigate the therapeutic potential of administering apoptotic cells in an LPS-induced endotoxic shock mouse model.
- To determine if apoptotic cell administration can protect against LPS-induced mortality and ameliorate key pathological features of septic shock.
Main Methods:
- Mice were challenged with LPS to induce endotoxic shock.
- Apoptotic cells were administered at various time points, including 24 hours post-LPS challenge.
- Key indicators of septic shock, including circulating cytokines, neutrophil infiltration, and serum LPS levels, were assessed.
Main Results:
- Administration of apoptotic cells significantly protected mice from LPS-induced death, even when given 24 hours after LPS exposure.
- Treatment with apoptotic cells led to reduced levels of circulating pro-inflammatory cytokines and suppressed polymorphonuclear neutrophil infiltration in target organs.
- Apoptotic cells effectively bound LPS, facilitating their clearance by macrophages in a CD14/thrombospondin/vitronectin receptor-dependent manner, which suppressed TNF-alpha and enhanced IL-10 expression.
Conclusions:
- Apoptotic cells demonstrate significant protective effects against LPS-induced endotoxic shock in mice.
- The mechanism involves enhanced clearance of LPS-bound apoptotic cells by macrophages, leading to a shift in cytokine profiles towards an anti-inflammatory state.
- Apoptotic cell therapy represents a promising novel therapeutic strategy for managing septic shock.
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