UC Irvine

Macrophages are mechanosensitive cells of the innate immune system that play a critical role in maintaining tissue homeostasis, pathogen defense, and response to injury. This diversity in macrophage function stems from their ability to respond to biochemical or mechanical cues within their microenvironment. The role of biochemical stimuli in influencing macrophage function have been well studied. However, despite their abundance in mechanically active tissues or the presence of altered tissue mechanics in various pathological conditions, such as in response to implanted materials or atherosclerosis, the role of mechanical stimuli and the associated molecular mechanisms responsible for changes in macrophage function are poorly understood. In this study, we found that the mechanosensitive and Ca2+ permeable ion channel Piezo1 plays a critical role in regulating macrophage response to inflammatory or healing agonists as well as oxidized lipoproteins. In addition, we also determined a role for the Piezo1 channel in sensing and transducing environmental stiffness or mechanical stretch.

First, we determined a role for Piezo1 in regulating macrophage activation in response to inflammatory or healing biochemical stimuli, the impact of stiffness in influencing this process, and the role of this mechanically gated channel in regulating the host response to implanted materials of varying stiffness. Additionally, we investigated the effects of mechanical stretch in regulating macrophage activation, while also exploring the role of Piezo1 in modulating stretch-mediated changes in cell function. Finally, we evaluated the role of Piezo1 and mechanics in regulating macrophage uptake of oxidized low-density lipoproteins, a key process involved in atherosclerotic plaque formation. These findings further elucidate the importance of mechanical stimuli in regulating macrophage function and identifies the Piezo1 ion channel as a critical molecule responsible for macrophage mechanosensation of stiffness and stretch. Together, this work provides novel insight into immune cell mechanobiology, while also improving our current knowledge of disease and potentially uncovering molecular targets to regulate macrophage function.