Matrix rigidity plays a crucial role in regulating macrophage activation, particularly in the transition towards the M2 phenotype. However, the interplay between mechanical and biochemical signals in this process remains underexplored. In this study, we demonstrate that increased matrix rigidity enhances nuclear deformation and chromatin accessibility, thereby cooperating with biochemical cues to facilitate M2 macrophage activation.

Our findings reveal that macrophages cultured on stiffer substrates exhibit pronounced nuclear deformation, which correlates with increased chromatin accessibility and transcriptional activation of M2-associated genes. We further identified key epigenetic modifications, including histone acetylation, as mediators of this response. These insights were validated through a combination of in vitro experiments and transcriptomic analyses.

These results highlight the significance of matrix stiffness in shaping macrophage function and provide novel insights into the mechanobiology of immune responses. Understanding these interactions could lead to innovative therapeutic strategies for modulating macrophage behavior in tissue repair and disease contexts.

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