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Annexin A2 Modulates ROS and Impacts Inflammatory Response via IL-17 Signaling in Polymicrobial Sepsis Mice
Sisi He1,2, Xuefeng Li1,2, Rongpeng Li2
1State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, P. R. China.
Abstract:
Sepsis is a progressive disease manifesting excessive inflammatory responses, severe tissue injury, organ dysfunction, and, ultimately, mortality. Since currently, there are limited therapeutic options for this disease, further understanding the molecular pathogenesis of sepsis may help develop effective treatments. Here we identify a novel role for Annexin A2 (AnxA2), a multi-compartmental protein, in inhibiting pro-inflammatory response by regulating reactive oxygen species (ROS) and IL-17 signaling during sepsis. In cecal ligation and puncture (CLP) sepsis models, anxa2-/- mice manifested increased pro-inflammatory cytokines and neutrophil infiltration, but decreased bacterial clearance and animal survival. In addition, AnxA2 deficiency led to intensified ROS and IL-17A. Using site directed mutagenesis, we uncovered that cysteine 9 of AnxA2 was the most important aa (site) for regulation of ROS levels. Furthermore, ROS appears to be responsible for elevated IL-17A levels and subsequently exaggerated inflammatory response. Depletion of IL-17 via CRISPR/Cas9 KO strategy down-regulated inflammation and conferred protection against sepsis in anxa2-/- mice. Our findings reveal a previously undemonstrated function for AnxA2 in inflammatory response in polymicrobial sepsis models via an AnxA2-ROS-IL-17 axis, providing insight into the regulation of pathophysiology of sepsis.
Insights
Annexin A2 (AnxA2) inhibits sepsis inflammation by regulating reactive oxygen species (ROS) and IL-17 signaling. AnxA2 deficiency worsens sepsis outcomes, highlighting its protective role in this complex disease.
Area of Science:
- Immunology
- Molecular Biology
- Pathophysiology
Background:
- Sepsis is a life-threatening condition characterized by dysregulated inflammation and organ dysfunction.
- Limited therapeutic options necessitate a deeper understanding of sepsis molecular pathogenesis.
- Annexin A2 (AnxA2) is a multi-compartmental protein with an uncharacterized role in inflammatory diseases.
Purpose of the Study:
- To investigate the novel role of Annexin A2 (AnxA2) in regulating inflammatory responses during sepsis.
- To elucidate the molecular mechanisms by which AnxA2 influences sepsis pathophysiology, focusing on reactive oxygen species (ROS) and IL-17 signaling.
Main Methods:
- Utilized cecal ligation and puncture (CLP) sepsis models in wild-type and anxa2-/- mice.
- Employed site-directed mutagenesis to identify critical residues in AnxA2 for ROS regulation.
- Used CRISPR/Cas9 gene editing to deplete IL-17 in anxa2-/- mice to assess its role in sepsis.
Main Results:
- anxa2-/- mice exhibited exacerbated inflammation, increased neutrophil infiltration, and reduced survival compared to controls.
- AnxA2 deficiency was associated with elevated levels of reactive oxygen species (ROS) and IL-17A.
- Cysteine 9 of AnxA2 was identified as crucial for ROS level regulation.
- Depletion of IL-17A ameliorated inflammation and improved survival in anxa2-/- mice, indicating ROS-mediated IL-17A elevation drives sepsis pathology.
Conclusions:
- Annexin A2 (AnxA2) plays a critical inhibitory role in the inflammatory response during polymicrobial sepsis.
- The AnxA2-ROS-IL-17 signaling axis is a key regulator of sepsis pathophysiology.
- Targeting the AnxA2-ROS-IL-17 pathway may offer novel therapeutic strategies for sepsis treatment.
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