Mechanosensitive Piezo1 protein as a novel regulator in macrophages and macrophage-mediated inflammatory diseases

Abstract

Macrophages are the most important innate immune cells in humans. They are almost ubiquitous in peripheral tissues with a large variety of different mechanical milieus. Therefore, it is not inconceivable that mechanical stimuli have effects on macrophages. Emerging as key molecular detectors of mechanical stress, the function of Piezo channels in macrophages is becoming attractive. In this review, we addressed the architecture, activation mechanisms, biological functions, and pharmacological regulation of the Piezo1 channel and review the research advancements in functions of Piezo1 channels in macrophages and macrophage-mediated inflammatory diseases as well as the potential mechanisms involved.

Keywords: Piezo1 channel; inflammatory diseases; macrophages; mechanical forces; mechanotransduction.

Figure 1

The mechanogating mechanisms by the extracellular force and the 38-TM structure of the mouse Piezo1 channel. (A) The mechanogating mechanisms of Piezo1 by the extracellular force. (B) Each blade-like propeller is evenly distributed around the central pore and contains unique 38 transmembrane α-helices, as divided into the following structures: N-terminal blade, C-terminal pore region, the long intracellular beam, and anchor domain. The final two α-helices (37 and 38) at the C-terminal, termed as the inner helix and outer helix, respectively, form a central ion pore region of Piezo1 with the C-terminal intracellular domain. The loci of L1342 and L1345 in the long beam structure act as the fulcrum to form an intramolecular lever–like transmission device, thus effectively transmitting and amplifying the subtle mechanical stress or small molecular compounds sensed by transmembrane helical units to the central pore.

Figure 2

The role of Piezo1 in macrophage-mediated inflammatory diseases. Piezo1 regulates the inflammatory responses, such as Alzheimer’s disease, pulmonary inflammation, atherosclerosis, and osteoarthritis. iMGLs, human-induced pluripotent stem cell–derived microglia-like cells; ARDS, acute respiratory distress syndrome; ox-LDL, oxidized low-density lipoprotein; ECs, endothelial cells.