Macrophages Mediate Mesoscale Brain Mechanical Homeostasis

Abstract Mechanical cues orchestrate cellular behavior in the brain, yet how they interface with immune regulation remains unresolved. Here, gigahertz‐frequency Brillouin microscopy with optical trap‐based active microrheology is integrated to map the mechanical impact of macrophage activity across timescales. It is revealed that microglia, brain's resident macrophages, actively sustain tissue viscoelasticity, rather than quiescently residing within the tissues under normal conditions. Moreover, macrophage colony‐stimulating factor 1 receptor (csf1r)‐driven stromal remodeling alters brain mechanical properties in vivo. These findings establish a direct link between immune activity, viscoelastic integrity, and structural plasticity of neural tissue. By bridging high‐frequency material responses with immune‐driven remodeling, the approach provides a framework for decoding how biophysical properties regulate slower‐timescale signaling and offers mechanistic insights for increasing the efficacy of csf1r‐targeted therapies in cancer and neurodegeneration.