Crosstalk Between CD11b and Piezo1 Mediates Macrophage Responses to Mechanical Cues

Macrophages are versatile cells of the innate immune system that perform diverse functions by responding to dynamic changes in their microenvironment. While the effects of soluble cues, including cytokines and chemokines, have been widely studied, the effects of physical cues, including mechanical stimuli, in regulating macrophage form and function are less well understood. In this study, we examined the effects of static and cyclic uniaxial stretch on macrophage inflammatory and healing activation. We found that cyclic stretch altered macrophage morphology and responses to IFNγ/LPS and IL4/IL13. Interestingly, we found that both static and cyclic stretch suppressed IFNγ/LPS induced inflammation. In contrast, IL4/IL13 mediated healing responses were suppressed with cyclic but enhanced with static stretch conditions. Mechanistically, both static and cyclic stretch increased expression of the integrin CD11b (αM integrin), decreased expression of the mechanosensitive ion channel Piezo1, and knock down of either CD11b or Piezo1 through siRNA abrogated stretch-mediated changes in inflammatory responses. Moreover, we found that knock down of CD11b enhanced the expression of Piezo1, and conversely knock down of Piezo1 enhanced CD11b expression, suggesting the potential for crosstalk between integrins and ion channels. Finally, stretch-mediated differences in macrophage activation were also dependent on actin, since pharmacological inhibition of actin polymerization abrogated the changes in activation with stretch. Together, this study demonstrates that the physical environment synergizes with biochemical cues to regulate macrophage morphology and function, and suggests a role for CD11b and Piezo1 crosstalk in mechanotransduction in macrophages.

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The Form and Function of PIEZO2

Annual Review of Biochemistry ◽

10.1146/annurev-biochem-081720-023244 ◽

2021 ◽

Vol 90 (1) ◽

pp. 507-534

Author(s):

Marcin Szczot ◽

Alec R. Nickolls ◽

Ruby M. Lam ◽

Alexander T. Chesler

Keyword(s):

Shear Stress ◽

Ion Channels ◽

Molecular Level ◽

Sensory Biology ◽

Mechanical Stimuli ◽

Functional Roles ◽

Form And Function ◽

The Past ◽

And Function ◽

Sense Of Touch

Mechanosensation is the ability to detect dynamic mechanical stimuli (e.g., pressure, stretch, and shear stress) and is essential for a wide variety of processes, including our sense of touch on the skin. How touch is detected and transduced at the molecular level has proved to be one of the great mysteries of sensory biology. A major breakthrough occurred in 2010 with the discovery of a family of mechanically gated ion channels that were coined PIEZOs. The last 10 years of investigation have provided a wealth of information about the functional roles and mechanisms of these molecules. Here we focus on PIEZO2, one of the two PIEZO proteins found in humans and other mammals. We review how work at the molecular, cellular, and systems levels over the past decade has transformed our understanding of touch and led to unexpected insights into other types of mechanosensation beyond the skin.

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The Role of Microglia in Brain Aging: A Focus on Sex Differences

Oxford Research Encyclopedia of Neuroscience ◽

10.1093/acrefore/9780190264086.013.309 ◽

2020 ◽

Author(s):

Jeffrey S. Darling ◽

Kevin Sanchez ◽

Andrew D. Gaudet ◽

Laura K. Fonken

Keyword(s):

Sex Differences ◽

Inflammatory Responses ◽

Brain Aging ◽

Disease Risk ◽

Brain Structures ◽

Functional Changes ◽

Form And Function ◽

Cytokines And Chemokines ◽

Age Related ◽

Increased Risk

Microglia, the primary innate immune cells of the brain, are critical for brain maintenance, inflammatory responses, and development in both sexes across the lifespan. Indeed, changes in microglia form and function with age have physiological and behavioral implications. Microglia in the aged brain undergo functional changes that enhance responses to diverse environmental insults. The heightened sensitivity of aged microglia amplifies proinflammatory responses, including increased production of proinflammatory cytokines and chemokines, elevated danger signals, and deficits in debris clearance. Elevated microglia activity and neuroinflammation culminate in neuropathology, including increased risk for neurodegenerative diseases and cognitive decline. Importantly, there are sex differences in several age-related neuroinflammatory pathologies. Microglia coordinate sex-dependent development within distinct brain structures and behaviors and are, in turn, sensitive to sex-specific hormones. This implies that microglia may confer differential disease risk by undergoing sex-specific changes with age. Understanding how aging and sex influence microglial function may lead to targeted therapies for age- and sex-associated diseases and disorders.

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RhoA/ROCK signaling is critical to FAK activation by cyclic stretch in cardiac myocytes

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00692.2004 ◽

2005 ◽

Vol 289 (4) ◽

pp. H1488-H1496 ◽

Cited By ~ 85

Author(s):

Adriana S. Torsoni ◽

Talita M. Marin ◽

Licio A. Velloso ◽

Kleber G. Franchini

Keyword(s):

Cardiac Myocytes ◽

Antisense Oligonucleotide ◽

Actin Polymerization ◽

Ventricular Myocytes ◽

Coiled Coil ◽

Cyclic Stretch ◽

Neonatal Rat ◽

Mechanical Stimuli ◽

Neonatal Rat Ventricular Myocytes ◽

In Cells

Focal adhesion kinase (FAK) has been shown to be activated in cardiac myocytes exposed to mechanical stress. However, details of how mechanical stimuli induce FAK activation are unknown. We investigated whether signaling events mediated by the RhoA/Rho-associated coiled coil-containing kinase (ROCK) pathway are involved in regulation of stretch-induced FAK phosphorylation at Tyr397 in neonatal rat ventricular myocytes (NRVMs). Immunostaining showed that RhoA localized to regions of myofilaments alternated with phalloidin (actin) staining. The results of coimmunoprecipitation assays indicated that FAK and RhoA are associated in nonstretched NRVMs, but cyclic stretch significantly reduced the amount of RhoA recovered from anti-FAK immunoprecipitates. Cyclic stretch induced rapid and sustained (up to 2 h) increases in phosphorylation of FAK at Tyr397 and ERK1/2 at Thr202/Tyr204. Blockade of RhoA/ROCK signaling by pharmacological inhibitors of RhoA ( Clostridium botulinum C3 exoenzyme) or ROCK (Y-27632, 10 μmol/l, 1 h) markedly attenuated stretch-induced FAK and ERK1/2 phosphorylation. Similar effects were observed in cells treated with the inhibitor of actin polymerization cytochalasin D. Transfection of NRVMs with RhoA antisense oligonucleotide attenuated stretch-induced FAK and ERK1/2 phosphorylation and expression of β-myosin heavy chain mRNA. Similar results were seen in cells transfected with FAK antisense oligonucleotide. These findings demonstrate that RhoA/ROCK signaling plays a crucial role in stretch-induced FAK phosphorylation, presumably by coordinating upstream events operationally linked to the actin cytoskeleton.

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Emerging Complexity in CD4+T Lineage Programming and Its Implications in Colorectal Cancer

Frontiers in Immunology ◽

10.3389/fimmu.2021.694833 ◽

2021 ◽

Vol 12 ◽

Author(s):

Daniel DiToro ◽

Rajatava Basu

Keyword(s):

Colorectal Cancer ◽

T Cells ◽

Intestinal Inflammation ◽

Inflammatory Responses ◽

Single Layer ◽

Form And Function ◽

Cell Responses ◽

Intestinal Immune System ◽

Broad Array ◽

And Function

The intestinal immune system has the difficult task of protecting a large environmentally exposed single layer of epithelium from pathogens without allowing inappropriate inflammatory responses. Unmitigated inflammation drives multiple pathologies, including the development of colorectal cancer. CD4+T cells mediate both the suppression and promotion of intestinal inflammation. They comprise an array of phenotypically and functionally distinct subsets tailored to a specific inflammatory context. This diversity of form and function is relevant to a broad array of pathologic and physiologic processes. The heterogeneity underlying both effector and regulatory T helper cell responses to colorectal cancer, and its impact on disease progression, is reviewed herein. Importantly, T cell responses are dynamic; they exhibit both quantitative and qualitative changes as the inflammatory context shifts. Recent evidence outlines the role of CD4+T cells in colorectal cancer responses and suggests possible mechanisms driving qualitative alterations in anti-cancer immune responses. The heterogeneity of T cells in colorectal cancer, as well as the manner and mechanism by which they change, offer an abundance of opportunities for more specific, and likely effective, interventional strategies.

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Scanning tunneling microscopy (STM) of DNA and RNA

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100152148 ◽

1989 ◽

Vol 47 ◽

pp. 34-35

Author(s):

Patricia G. Arscott ◽

Gil Lee ◽

Victor A. Bloomfield ◽

D. Fennell Evans

Keyword(s):

Molecular Structures ◽

Inorganic Materials ◽

Resolving Power ◽

Scanning Tunneling ◽

Tunneling Microscopy ◽

Form And Function ◽

Dna And Rna ◽

Calf Thymus ◽

And Function ◽

The Relationship

STM is one of the most promising techniques available for visualizing the fine details of biomolecular structure. It has been used to map the surface topography of inorganic materials in atomic dimensions, and thus has the resolving power not only to determine the conformation of small molecules but to distinguish site-specific features within a molecule. That level of detail is of critical importance in understanding the relationship between form and function in biological systems. The size, shape, and accessibility of molecular structures can be determined much more accurately by STM than by electron microscopy since no staining, shadowing or labeling with heavy metals is required, and there is no exposure to damaging radiation by electrons. Crystallography and most other physical techniques do not give information about individual molecules.We have obtained striking images of DNA and RNA, using calf thymus DNA and two synthetic polynucleotides, poly(dG-me5dC)·poly(dG-me5dC) and poly(rA)·poly(rU).

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The molecular mechanism of mechanotransduction in vascular homeostasis and disease

Clinical Science ◽

10.1042/cs20190488 ◽

2020 ◽

Vol 134 (17) ◽

pp. 2399-2418

Author(s):

Yoshito Yamashiro ◽

Hiromi Yanagisawa

Keyword(s):

Shear Stress ◽

Blood Vessels ◽

Vessel Wall ◽

Vascular Diseases ◽

Cell Interactions ◽

Aortic Aneurysms ◽

Cyclic Stretch ◽

Mechanical Stimuli ◽

Vascular Homeostasis ◽

Matrix Cell

Abstract Blood vessels are constantly exposed to mechanical stimuli such as shear stress due to flow and pulsatile stretch. The extracellular matrix maintains the structural integrity of the vessel wall and coordinates with a dynamic mechanical environment to provide cues to initiate intracellular signaling pathway(s), thereby changing cellular behaviors and functions. However, the precise role of matrix–cell interactions involved in mechanotransduction during vascular homeostasis and disease development remains to be fully determined. In this review, we introduce hemodynamics forces in blood vessels and the initial sensors of mechanical stimuli, including cell–cell junctional molecules, G-protein-coupled receptors (GPCRs), multiple ion channels, and a variety of small GTPases. We then highlight the molecular mechanotransduction events in the vessel wall triggered by laminar shear stress (LSS) and disturbed shear stress (DSS) on vascular endothelial cells (ECs), and cyclic stretch in ECs and vascular smooth muscle cells (SMCs)—both of which activate several key transcription factors. Finally, we provide a recent overview of matrix–cell interactions and mechanotransduction centered on fibronectin in ECs and thrombospondin-1 in SMCs. The results of this review suggest that abnormal mechanical cues or altered responses to mechanical stimuli in EC and SMCs serve as the molecular basis of vascular diseases such as atherosclerosis, hypertension and aortic aneurysms. Collecting evidence and advancing knowledge on the mechanotransduction in the vessel wall can lead to a new direction of therapeutic interventions for vascular diseases.

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