From mechanosensing to immune regulation: mechanisms of acupuncture signal initiation and amplification mediated by macrophages.

The core mechanism of acupuncture therapy lies in converting local mechanical stimulation into systemic physiological regulatory effects. Building on this concept, this review highlights the central role of macrophages in this mechanotransduction event, mainly occurring in the acupoint(s). During acupuncture, the practitioner's manipulation techniques, such as lifting-thrusting and twisting, cause significant mechanical stress at an acupoint through the entanglement and traction of collagen fibers through the acupuncture needle. This physical signal is transmitted through the extracellular matrix (ECM) and delivered to the mechanosensitive cells, such as fibroblasts and macrophages. Concurrently, while fibroblasts receive the mechanical stimuli, they also release alarmin proteins, such as interleukin-33 (IL-33), to further regulate macrophages' activities. As a key mechanical sensing and effect unit, macrophages perceive mechanical signals through multiple pathways, including Piezo1, transient receptor potential vanilloid 4 (TRPV4) mechanically sensitive channels, the integrin family of mechanotransduction receptors, and podosomes on the cell body. These pathways promptly initiate intracellular Ca