ORIGINAL RESEARCH article
Front. Immunol.
Sec. Cytokines and Soluble Mediators in Immunity
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1610033
This article is part of the Research TopicBiomarker-Driven Strategies for Personalized Management of Systemic Inflammatory Response SyndromeView all 10 articles
Disrupted macrophage autophagy as a driver of cell death and LPS-induced lethal shock in systemic inflammation
Provisionally accepted- 1CNRS UMR 7355, Orleans, France
- 2Memorial Sloan Kettering Cancer Center, New York, New York, United States
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ABSTRACT Systemic Inflammatory Response Syndrome (SIRS) can be primed by infectious or noninfectious 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 24 h) 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.
Keywords: SIRS, Autophagy, macrophage, Iron, ROS, Cell Death
Received: 11 Apr 2025; Accepted: 29 Sep 2025.
Copyright: © 2025 Chekroune, Carignon, Taleb, Rose, Mercier and Mura. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Catherine Mura, catherine.mura@cnrs-orleans.fr
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