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Macrophage-Targeted Magnesium Ion-Nourisher for NLRP3 Inflammasome Inhibition to Enhance Liver Inflammatory Disease
Li Wang1, Zhuo Yan2, Sindhu Yalavarthi1
1Department of Nanoscience, Joint School of Nanoscience and Nanoengineering, University of North Carolina at Greensboro, Greensboro, NC, 27401, USA.
Abstract:
Magnesium (Mg) exerts important functions in immune regulation. Fluctuations of Mg levels significantly impact immune cell behavior, such as differentiation and inflammatory phenotypes of macrophages. However, exploiting Mg as an immunomodulatory intervention is challenging due to its unclear mechanism and broad impact across diverse cells. To overcome this, a nanosized Mg ion-nourisher is engineered, termed MgC@PS, that enables efficient macrophage-targeted intracellular Mg2⁺ (iMg2+) delivery by exploiting macrophages' efferocytosis in response to phosphatidylserine. It is found that targeted enrichment of magnesium ions (Mg2⁺) into macrophages effectively inhibits NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome activation-induced pyroptosis, and alleviates hyperactive inflammatory responses. Single-cell RNA sequencing reveals fortified resilience of Kupffer cells from pyroptosis and upregulation of antioxidant gene expression after MgC@PS treatment. Moreover, by incorporating stem cell components into the MgC@PS, the integrity of the intestinal barrier, addressing the barrier leakage commonly observed in the gut-liver axis. These findings demonstrate the pivotal role of iMg2⁺ in mitigating macrophage-mediated liver-gut inflammation. Targeted delivery of Mg to macrophages emerges as a promising strategy to inhibit excessive inflammation and promote tissue recovery.
Insights
Targeted delivery of magnesium ions (Mg2+) using MgC@PS nanoparticles effectively reduces macrophage-driven inflammation and pyroptosis. This approach enhances Kupffer cell resilience and intestinal barrier integrity, promoting tissue recovery.
Area of Science:
- Immunology
- Nanomedicine
- Cell Biology
Background:
- Magnesium (Mg) plays a crucial role in immune regulation, influencing macrophage behavior and inflammatory responses.
- Current strategies for Mg-based immunomodulation are limited by unclear mechanisms and broad cellular effects.
- Targeted delivery of Mg is needed to precisely control its immunomodulatory functions.
Purpose of the Study:
- To engineer a nanoparticle system for targeted intracellular delivery of Mg2+ to macrophages.
- To investigate the effects of targeted Mg2+ delivery on NLRP3 inflammasome activation, pyroptosis, and inflammation.
- To assess the impact of this strategy on Kupffer cell resilience and the gut-liver axis.
Main Methods:
- Development of a nanosized Mg ion-nourisher (MgC@PS) utilizing phosphatidylserine-mediated efferocytosis for macrophage targeting.
- In vitro and in vivo assessment of MgC@PS effects on macrophage inflammatory phenotypes and pyroptosis.
- Single-cell RNA sequencing to analyze gene expression changes in Kupffer cells.
- Evaluation of intestinal barrier integrity following MgC@PS treatment.
Main Results:
- MgC@PS efficiently delivered Mg2+ into macrophages, inhibiting NLRP3 inflammasome activation and pyroptosis.
- Targeted Mg2+ enrichment alleviated hyperactive inflammatory responses and enhanced Kupffer cell resilience.
- MgC@PS treatment upregulated antioxidant gene expression in Kupffer cells.
- Incorporation of stem cell components into MgC@PS improved intestinal barrier integrity, counteracting gut-liver axis leakage.
Conclusions:
- Intracellular Mg2+ is pivotal in mitigating macrophage-mediated liver-gut inflammation.
- Targeted delivery of Mg to macrophages via MgC@PS is a promising strategy for inhibiting excessive inflammation.
- This approach promotes tissue recovery and offers a novel therapeutic avenue for inflammatory diseases.
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