Year: 2022
Type: article
Abstract: Mutations and defects in nuclear lamins can cause major pathologies in affected tissues. Recent studies have also established potential links between lamins, inflammation, and inflammatory diseases but the underlying molecular mechanisms are unknown. We now report that pro-inflammatory activation of macrophages reduces levels of Lamin-A/C to augment pro-inflammatory gene expression and cytokine secretion. We show that activation of bone-marrow derived macrophages (BMDMs) degrades Lamin-A/C, as preceded by its phosphorylation, which is mediated by Caspase-6 and CDK1, respectively. Inhibiting Lamin-A/C phosphorylation and degradation severely inhibits pro-inflammatory gene expression and cytokine secretion. Using LPS-activated Lamin-A/C Knock Out BMDMs, we confirmed that the activation of the IFN-β-STAT pathway is amplified due to Lamin-A/C reduction, which ultimately augments the pro-inflammatory response. As Lamin-A/C is a previously unappreciated regulator of the pro-inflammatory macrophage response, our findings could provide novel opportunities to treat inflammatory diseases. In first proof-of-concept studies we show that macrophage pro-inflammation, as induced by Lipopolysaccharide or pathogenic E. coli, could be reduced by inhibiting Lamin-A/C phosphorylation and degradation. The inhibition of macrophage pro-inflammation could also be achieved by inhibiting members of the Lamin-A/C regulated IFN-β-STAT pathway, i.e., phospho-STAT1 and phospho-STAT3. This newly found mechanism to suppress the pro-inflammatory response of macrophages will provoke a re-thinking of how inflammation can be addressed therapeutically.
Source: iScience
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,000
Funders: Cornell University, University of Birmingham, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Eidgenössische Technische Hochschule Zürich, National Institutes of Health, National Heart, Lung, and Blood Institute, National Cancer Institute, National Institute of General Medical Sciences
Awards: G1438987936, Nuclear mechanobiology in confined migration, G2364984104, G2758371512, Targeting nuclear mechanical properties of monocytes for rapid diagnosis of inflammation and sepsis, Center on the Physics of Cancer Metabolism, Nuclear mechanics and mechanotransduction in muscular laminopathies, Mechanotransduction processes, from the cell periphery to the nucleus, in 2D versus 3D microenvironments
OpenAlex ID: W4308469417