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Blockage of lamin-A/C loss diminishes the pro-inflammatory macrophage response
Johanna L Mehl1, Ashley Earle2,3, Jan Lammerding2
1Laboratory of Applied Mechanobiology, Institute of Translational Medicine, Department of Health Sciences and Technology, ETH Zurich, Vladimir-Prelog-Weg 1-5/10, HCI E357.1, Zurich 8093, Switzerland.
Abstract:
Mutations and defects in nuclear lamins can cause major pathologies, including inflammation and inflammatory diseases. Yet, the underlying molecular mechanisms are not known. We now report that the pro-inflammatory activation of macrophages, as induced by LPS or pathogenic E. coli, reduces Lamin-A/C levels thereby augmenting pro-inflammatory gene expression and cytokine secretion. We show that the activation of bone-marrow-derived macrophages (BMDMs) causes the phosphorylation and degradation of Lamin-A/C, as mediated by CDK1 and Caspase-6, respectively, necessary for upregulating IFN-β expression. Enhanced IFN-β expression subsequently increases pro-inflammatory gene expression via the IFN-β-STAT axis. Pro-inflammatory gene expression was also amplified in the complete absence of Lamin-A/C. Alternatively, pharmacological inhibition of either Lamin-A/C phosphorylation or degradation significantly downregulated pro-inflammatory gene expression, as did the targeting of IFN-β-STAT pathway members, i.e. phospho-STAT1 and phospho-STAT3. As Lamin-A/C is a previously unappreciated regulator of the pro-inflammatory macrophage response, our findings suggest novel opportunities to treat inflammatory diseases.
Insights
Nuclear lamins regulate macrophage inflammation. Macrophage activation degrades Lamin-A/C, increasing inflammatory gene expression via IFN-β. Targeting this pathway offers new treatments for inflammatory diseases.
Area of Science:
- Cell Biology
- Immunology
- Molecular Biology
Background:
- Nuclear lamins are crucial structural proteins within the cell nucleus.
- Defects in nuclear lamins are linked to various pathologies, including inflammatory diseases.
- The precise molecular mechanisms by which lamins influence inflammation remain largely unknown.
Purpose of the Study:
- To investigate the role of Lamin-A/C in macrophage pro-inflammatory activation.
- To elucidate the molecular pathways linking Lamin-A/C levels to inflammatory gene expression.
- To explore potential therapeutic targets for inflammatory diseases based on Lamin-A/C regulation.
Main Methods:
- Utilized lipopolysaccharide (LPS) and pathogenic *E. coli* to induce pro-inflammatory activation in bone-marrow-derived macrophages (BMDMs).
- Assessed changes in Lamin-A/C levels, phosphorylation, and degradation.
- Investigated the roles of CDK1 and Caspase-6 in Lamin-A/C regulation.
- Analyzed the impact of Lamin-A/C modulation on Interferon-beta (IFN-β) and downstream inflammatory gene expression via the IFN-β-STAT axis.
- Employed pharmacological inhibitors targeting Lamin-A/C phosphorylation/degradation and IFN-β-STAT pathway components.
Main Results:
- Pro-inflammatory macrophage activation led to reduced Lamin-A/C levels.
- CDK1-mediated phosphorylation and Caspase-6-mediated degradation of Lamin-A/C were identified as key events.
- Lamin-A/C degradation was necessary for upregulating IFN-β expression.
- Enhanced IFN-β expression subsequently amplified pro-inflammatory gene expression through the IFN-β-STAT pathway.
- Pharmacological inhibition of Lamin-A/C degradation or IFN-β-STAT signaling significantly reduced inflammatory responses.
Conclusions:
- Lamin-A/C acts as a novel regulator of the pro-inflammatory macrophage response.
- The phosphorylation and degradation of Lamin-A/C are critical steps in initiating macrophage-driven inflammation.
- Targeting Lamin-A/C stability or the IFN-β-STAT pathway presents promising therapeutic strategies for inflammatory diseases.
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