Nutrition & Food Science
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Item ROLE OF TRPV4 MECHANOSENSING REGULATING MACROPHAGE FUNCTIONS IN INFLAMMATORY DISEASES(2024) Dutta, Bidisha; Rahaman, Shaik O; Nutrition; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Macrophages are the most versatile cells of the hematopoietic system with roles in homeostasis, host-tissue development, innate immune response and tissue repair. Although the inflammatory activation and maintenance signals are tightly regulated, an imbalance in them results in unchecked inflammation resulting in cellular and tissue damage. Macrophages can affect most if not all phases of inflammation owing to their ability to adopt distinct functional states, secrete cytokines and phagocytose pathogens and debris. Recent evidence suggests that beyond biochemical cues, mechanical forces, like changing matrix stiffness in the tissue microenvironment, can shape immune cell functions involved in inflammation. These cells convert mechanical stimuli to biochemical signals in a process called mechanotransduction, regulating a multitude of cellular functions. However, knowledge about the molecular mediators of mechanotransduction and their functions in macrophage phenotypic and functional change is largely missing, highlighting the need for studying mechanosensory molecules such as ion channels. The present study focuses on the role of a specific mechanosensitive ion channel, Transient Receptor Potential Vanilloid 4 (TRPV4), in the regulation of macrophage mediated inflammatory responses. Given its emerging role in inflammatory diseases like fibrosis, arthritis, foreign body response (FBR), TRPV4’s contribution to macrophage behavior in inflammation is of growing interest. Employing cellular imaging and molecular biology techniques such as Ca2+ influx assays, immunohistochemistry, immunoblotting, and single nuclei RNA sequencing we delineate mechanisms by which biomechanical stimuli-mediated activation of TRPV4 affects macrophage function. We elucidate TRPV4’s role in macrophage mechanotransduction, providing a mechanistic understanding of inflammatory disease pathophysiology which could lead to the development of potential therapeutics for disease intervention.Item TRPV4, A CALCIUM-PERMEABLE CHANNEL, PLAYS A ROLE IN MATRIX STIFFNESS INDUCED MACROPHAGE POLARIZATION(2020) Dutta, Bidisha; Rahaman, Shaik Ohidar; Nutrition; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Phenotypic polarization of macrophages is deemed essential in innate immunity and various pathophysiological processes, but little is known about how mechanical forces like matrix stiffness regulate the polarization and the associated signaling mechanisms. Here we report that calcium ion channel Transient Receptor Potential Vanilloid 4 (TRPV4), a mechanosensitive receptor/channel, mediates the substrate stiffness-induced macrophage polarization. Using atomic force microscopy, we show that fibrosis-induced tissue stiffness is dependent on TRPV4. M1 macrophages were found to be the predominant macrophage subtype in stiffer tissues and loss of TRPV4 significantly decreased the level of M1 macrophages. These findings were further validated by our in vitro assays indicating that increase in substrate stiffness leads to an increased secretion of M1 proinflammatory mediators, which is further enhanced by the addition of soluble factors. Taken together, these findings provide new insights about the role of TRPV4 in matrix stiffness-induced macrophage polarization that can be explored in tissue engineering and in the development of targeted therapeutics.