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Disrupted macrophage autophagy as a driver of cell death and LPS-induced lethal shock in systemic inflammation.

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Název: Disrupted macrophage autophagy as a driver of cell death and LPS-induced lethal shock in systemic inflammation.
Autoři: Chekroune, Tarek, Carignon, Sandra, Taleb, Meriem, Savigny, Florence, Rose, Stéphanie, Maillet, Isabelle, Mura, Catherine
Zdroj: Frontiers in Immunology; 2025, p1-18, 18p
Témata: MACROPHAGES, AUTOPHAGY, CELL death, ENDOTOXINS, IRON metabolism, INFLAMMATION, TISSUE wounds, SYSTEMIC inflammatory response syndrome
Abstrakt: Systemic inflammatory response syndrome (SIRS) can be primed by infectious or non-infectious stimuli and may progress to life-threatening organ failure. An altered balance between pro- and anti-inflammatory response is commonly observed in SIRS, yet the core molecular events driving severe SIRS remain poorly defined. Moreover, the roles of macrophages and autophagy in SIRS have been pointed out. Here a high susceptibility to LPS-induced lethal shock in mice deficient in autophagy in myeloid cells (Atg5f/fLysM-cre+) following a single dose of 0.5 mg/kg (60% mortality vs. 0% in wild type after 24h) was observed. Using a very low dose of LPS (0.1 mg/kg), Atg5f/fLysM-cre+ mice showed rapid tissue injury, notably in the liver and spleen, accompanied by an altered macrophage phenotype. Macrophages in the spleen and the liver appeared swollen and showed a loss of cellular content, including iron. In contrast, hepatocytes in Atg5f/fLysM-cre+ mice accumulated more iron, which was associated with elevated reactive oxygen species levels compared to wild-type mice. Notably, the livers of LPS-treated Atg5f/fLysM-cre+ mice exhibited increased ferroptotic and apoptotic cell death and extensive pyroptosis in both the spleen and liver. Flow cytometric analysis, immunofluorescence, and RNA sequencing supported the marked pro-inflammatory phenotype of macrophages in LPS-treated Atg5f/fLysM-cre+ mice. In conclusion, during LPS-induced inflammation, autophagy deficiency in myeloid cells profoundly alters macrophage phenotype, disrupts iron trafficking, and promotes tissue injury through multiple forms of cell death. [ABSTRACT FROM AUTHOR]
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Databáze: Complementary Index
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Abstrakt:Systemic inflammatory response syndrome (SIRS) can be primed by infectious or non-infectious stimuli and may progress to life-threatening organ failure. An altered balance between pro- and anti-inflammatory response is commonly observed in SIRS, yet the core molecular events driving severe SIRS remain poorly defined. Moreover, the roles of macrophages and autophagy in SIRS have been pointed out. Here a high susceptibility to LPS-induced lethal shock in mice deficient in autophagy in myeloid cells (Atg5<sup>f/f</sup>LysM-cre<sup>+</sup>) following a single dose of 0.5 mg/kg (60% mortality vs. 0% in wild type after 24h) was observed. Using a very low dose of LPS (0.1 mg/kg), Atg5<sup>f/f</sup>LysM-cre<sup>+</sup> mice showed rapid tissue injury, notably in the liver and spleen, accompanied by an altered macrophage phenotype. Macrophages in the spleen and the liver appeared swollen and showed a loss of cellular content, including iron. In contrast, hepatocytes in Atg5<sup>f/f</sup>LysM-cre<sup>+</sup> mice accumulated more iron, which was associated with elevated reactive oxygen species levels compared to wild-type mice. Notably, the livers of LPS-treated Atg5<sup>f/f</sup>LysM-cre<sup>+</sup> mice exhibited increased ferroptotic and apoptotic cell death and extensive pyroptosis in both the spleen and liver. Flow cytometric analysis, immunofluorescence, and RNA sequencing supported the marked pro-inflammatory phenotype of macrophages in LPS-treated Atg5<sup>f/f</sup>LysM-cre<sup>+</sup> mice. In conclusion, during LPS-induced inflammation, autophagy deficiency in myeloid cells profoundly alters macrophage phenotype, disrupts iron trafficking, and promotes tissue injury through multiple forms of cell death. [ABSTRACT FROM AUTHOR]
ISSN:16643224
DOI:10.3389/fimmu.2025.1610033