Abstract
Cells in the human body experience and integrate a wide variety of environmental cues. A growing interest in tissue mechanics in the past four decades has shown that the mechanical properties of tissue drive key biological processes and facilitate disease development. However, tissue stiffness is not only a potent behavioral cue, but also a product of cellular signaling activity. This review explores both roles of tissue stiffness in the context of inflammation and fibrosis, and the important molecular players driving such processes. During inflammation, proinflammatory cytokines upregulate tissue stiffness by increasing hydrostatic pressure, ECM deposition, and ECM remodeling. As the ECM stiffens, cells involved in the immune response employ intricate molecular sensors to probe and alter their mechanical environment, thereby facilitating immune cell recruitment and potentiating the fibrotic phenotype. This powerful feedforward loop raises numerous possibilities for drug development and warrants further investigation into the mechanisms specific to different fibrotic diseases.
Highlights
From the ancient times of Aristotle to the modern day, man’s understanding of mechanics has evolved greatly beyond basic physical laws deduced from the study of a lever [1]
The myriadaof proteins assembles into several layers the extracellular matrix (ECM), a membrane-proximal integrin signaling layer, a force transduction layer, and the focal adhesion, including a layer of transmembrane integrins that directly bind to the an actin regulatory layer that is bound to filamentous actin [62]
This force transmitted through the focal adhesion kinase/phospho-paxillin/vinculin axis is critical for the cell to tug at a wide range of substrate rigidities and acquire information from their microenvironment, which in turn affects contractility and allows cells to migrate towards stiffer substrates [72]
Summary
From the ancient times of Aristotle to the modern day, man’s understanding of mechanics has evolved greatly beyond basic physical laws deduced from the study of a lever [1]. Contrary to our relatively recent discovery of mechanics, cells in the human body have long been utilizing the same physical principles to navigate complex microenvironments and operate microscopic machinery. This is not a one-way street—mechanical stimuli from their surroundings affect cells, prompting them to push and pull, break down and build, and transport and retain, reshaping the very environment they reside in. We discuss key molecular mechanisms that cells employ to sense and respond to their mechanical microenvironment and how such mechanisms are intertwined with inflammatory pathways mediated by canonical soluble factors.
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