Dynamics of Calcium Signal and Leukotriene C4Release in Mast Cells Network Induced by Mechanical Stimuli and Modulated by Interstitial Fluid Flow

Abstract

AbstractMast cells (MCs) play an important role in the immune system. Through connective tissues, mechanical stimuli activate intracellular calcium signaling pathways, induce a variety of mediators including leukotriene C4(LTC4) release, and affect MCs’ microenvironment. This paper focuses on MCs’ intracellular calcium dynamics and LTC4release responding to mechanical stimuli, explores signaling pathways in MCs and the effect of interstitial fluid flow on the transport of biological messengers and feedback in the MCs network. We use a mathematical model to show that (i) mechanical stimuli including shear stress induced by interstitial fluid flow can activate mechano-sensitive (MS) ion channels on MCs’ membrane and allow Ca2+entry, which increases intracellular Ca2+concentration and leads to LTC4release; (ii) LTC4in the extracellular space (ECS) acts on surface cysteinyl leukotriene receptors (LTC4R) on adjacent cells, leading to Ca2+influx through Ca2+release-activated Ca2+(CRAC) channels. An elevated intracellular Ca2+concentration further stimulates LTC4release and creates a positive feedback in the MCs network. The findings of this study may facilitate our understanding of the mechanotransduction process in MCs induced by mechanical stimuli, contribute to understanding of interstitial flow-related mechanobiology in MCs network, and provide a methodology for quantitatively analyzing physical treatment methods including acupuncture and massage in traditional Chinese medicine (TCM).