![]() ![]() These mechanosensors transduce cues leading to Ca 2+ fluxes, cytoskeletal reorganization and transcriptional regulation. Major mechanosensors include adhesion molecules (such as integrins), ion channels (including transient receptor potential vanilloid type 4 (TRPV4) and the PIEZO family of mechanically activated cation ion channels) and cytoskeletal components 21, 22, 23. Immune cells share with other cells conserved pathways by which they can sense and respond to these mechanical cues (Fig. It is important to note that immune cells do not just passively experience these exogenous cues but can also contribute to them, generating either reciprocal or additive forces upon the matrix and upon neighbouring cells. As we detail in the sections below, evolutionarily conserved pathways sense changes in these physical aspects of the ECM and can trigger mechanosensors in immune cells. In addition, the physical properties of the tissue surrounding the cells, including matrix rigidity, topography or architecture, also provide isometric mechanical cues that impact cellular function (Box 1 and reviewed elsewhere 18, 19, 20). Cells within tissues experience multiple types of mechanical force, including tension, compression, shear stress, interstitial flow and hydrostatic pressure (Box 1 and reviewed in refs. ![]() We begin by examining how immune cells sense exogenous forces. We detail how such signals tune immune cell responses and provide an integrated picture of immunity through the lens of mechanobiology to better highlight the emerging field of mechanoimmunology. In this Review, we discuss the tissue-level mechanical cues and forces that intersect with immune cell activation and effector functions, including danger sensing and cytokine production. Previous reviews have focused on the role of mechanical forces in immune cell trafficking 12 and molecular-level forces in triggering immune cell receptor activation 13, 14. These tissue-level forces tune subsequent immune responses. Cells that become resident in tissues experience stretching and shearing forces over time, as they are mechanically influenced by the extracellular matrix (ECM), interstitial fluids and neighbouring cells. Understanding how these tissue-scale biophysical cues impact immune cell activation, metabolic reprogramming and downstream effector functions may provide new insights to treat these disorders.Įven under homeostatic conditions, immune cells face numerous forces as they circulate the body and encounter various tissue types. By contrast, other diseased tissues, such as abscesses and the necrotic core of tumours 10, 11, are associated with mechanically softer tissue than in the healthy state. In atherosclerosis, lung fibrosis and the peri-tumoural environment 6, 7, 8, 9 there is enhanced tissue rigidity. Dysregulated tissue mechanics are seen in many diseases. In pathophysiological environments where tissue mechanics are altered, profound changes in mechanotransduction components occur at the cellular level, such as in adhesion molecules, ion channels and cytoskeletal proteins, and in their associated signalling pathways. Although fundamental roles for mechanical stimuli have long been recognized in developmental biology and in organ systems that receive significant mechanical stress, such as the cardiovascular and skeletal systems, these stimuli are now emerging as important orchestrators of inflammation and immune responses 1, 2, 3, 4, 5. Mechanotransduction is the process by which cells convert mechanical cues to biochemical signals, activating cellular pathways and influencing their function. Here, we review the emerging field of mechanoimmunology, focusing on how mechanical cues at the scale of the tissue environment regulate immune cell behaviours to initiate, propagate and resolve the immune response. Tissue mechanics can change temporally during an infection or inflammatory response, offering a novel layer of dynamic immune regulation. Changes in tissue mechanics may also represent a new form of ‘danger signal’ that alerts the innate and adaptive immune systems to the possibility of injury or infection. Such pathways impact important cellular functions including cell activation, cytokine production, metabolism, proliferation and trafficking. ![]() These mechanical cues are converted into biochemical signals through the process of mechanotransduction, and multiple pathways of mechanotransduction have been identified in immune cells. Indeed, changes in biophysical properties of tissue alter the mechanical signals experienced by cells in many disease conditions, in inflammatory states and in the context of ageing. Immune responses are governed by signals from the tissue microenvironment, and in addition to biochemical signals, mechanical cues and forces arising from the tissue, its extracellular matrix and its constituent cells shape immune cell function. ![]()
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