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Updated: Jun 6, 2026
Metabolic Characterization of Polarized M1 and M2 Bone Marrow-derived Macrophages Using Real-time Extracellular Flux Analysis
Published on: November 28, 2015
Polarization increases nuclear stiffness in macrophages despite reduction in lamin A/C levels
Margaret A Elpers1,2, Jacob Odell2,3, Sarah J Henretta1,2
1Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY USA.
Abstract:
Macrophages are innate immune cells contributing to tissue homeostasis and various pathologies. Signals from their environment can lead macrophages to adapt distinct functional phenotypes, a process called polarization. Because macrophages have been previously shown to degrade the nuclear envelope proteins lamin A/C upon pro-inflammatory polarization, and lamins are considered key determinants of nuclear deformability, we aimed to address the effect of pro-inflammatory stimulation on nuclear mechanics. We present the surprising finding that polarized bone marrow-derived macrophages have less deformable nuclei than unpolarized macrophages, despite their reduced lamin A/C levels. Furthermore, pro-inflammatory macrophages exhibited altered chromatin dynamics relative to unpolarized macrophages, including redistribution of trimethylated histone H3K9 (H3K9me3) from the nuclear periphery to the interior and increased chromatin compaction. Our findings suggest a model in which pro-inflammatory stimulation of macrophages induces chromatin changes that drive nuclear stiffening, and that in these cells, chromatin, rather than the nuclear lamina, is the major driver for resisting nuclear deformation. These findings may have functional relevance for the physiological function of polarized macrophages, as the mechanical properties of the nucleus can influence how these cells adapt and respond to their environments in the context of cell migration or inflammatory disease pathologies.
Insights
Pro-inflammatory stimulation stiffens macrophage nuclei, contrary to expectations. This nuclear stiffening is driven by changes in chromatin, not the nuclear lamina, impacting cell function.
Area of Science:
- Cell biology
- Immunology
- Biophysics
Background:
- Macrophages are innate immune cells crucial for tissue homeostasis and disease.
- Macrophage polarization alters their function in response to environmental cues.
- Nuclear envelope proteins like lamin A/C influence nuclear mechanics and were previously thought to be key targets in polarization.
Purpose of the Study:
- To investigate the impact of pro-inflammatory stimulation on the nuclear mechanics of macrophages.
- To determine whether changes in nuclear envelope proteins or chromatin dynamics are responsible for altered nuclear mechanics.
Main Methods:
- Bone marrow-derived macrophages were subjected to pro-inflammatory stimulation.
- Nuclear deformability was measured using atomic force microscopy.
- Chromatin organization and histone modifications (H3K9me3) were analyzed using microscopy and biochemical techniques.
Main Results:
- Polarized macrophages exhibited significantly less deformable nuclei compared to unpolarized macrophages.
- Despite reduced lamin A/C levels in polarized cells, nuclear stiffness increased.
- Pro-inflammatory macrophages showed altered chromatin dynamics, including peripheral H3K9me3 redistribution and increased compaction.
Conclusions:
- Pro-inflammatory stimulation stiffens macrophage nuclei primarily through chromatin rearrangements, not changes in the nuclear lamina.
- Chromatin, rather than the nuclear lamina, is the main determinant of nuclear resistance to deformation in polarized macrophages.
- These findings suggest a novel mechanism by which nuclear mechanics influence macrophage function in inflammation and migration.
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