Mechanical Stiffness Controls Dendritic Cell Metabolism and Function

Chakraborty, Mainak; Chu, Kevin Y.; Shrestha, Annie; Revelo, Xavier S.; Zhang, Xiangyue; Gold, Matthew; Khan, Saad; Lee, Megan; Huang, Camille; Akbari, Masoud; Barrow, Fanta; Chan, Yi Tao; Lei, Helena; Kotoulas, Nicholas Konstantine; Jovel, Juan; Pastrello, Chiara; Kotlyar, Max; Goh, Cynthia; Michelakis, Evangelos D.; Clemente-Casares, Xavier; Ohashi, Pamela S.; Engleman, Edgar G.; Winer, Shawn; Jurišica, Igor; Tsai, Sue; Winer, Daniel A.

doi:10.1016/j.celrep.2020.108609

Cited by 141 publications

(136 citation statements)

References 77 publications

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“…In addition, we uncovered the first detailed molecular mechanism through which keratinocytes integrate chemical and mechanical inputs from the environment to regulate IL-6 production. These findings emphasize biophysical cues, particularly matrix stiffness, as a central regulator of cell signaling in keratinocytes, consistent with previous observations in other cell types (43)(44)(45), and highlight the role of the stiffnessmediated mechanotransduction pathway in enhancing proinflammatory cytokine production in response to external stimuli, such as DNCB (Figure 4G).…”

Section: Discussionsupporting

confidence: 91%

Matrix Stiffening Enhances DNCB-Induced IL-6 Secretion in Keratinocytes Through Activation of ERK and PI3K/Akt Pathway

Chung

Shin

et al. 2021

Front. Immunol.

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Matrix stiffness, a critical physical property of the cellular environment, is implicated in epidermal homeostasis. In particular, matrix stiffening during the pathological progression of skin diseases appears to contribute to cellular responses of keratinocytes. However, it has not yet elucidated the molecular mechanism underlying matrix-stiffness-mediated signaling in coordination with chemical stimuli during inflammation and its effect on proinflammatory cytokine production. In this study, we demonstrated that keratinocytes adapt to matrix stiffening by increasing cell–matrix adhesion via actin cytoskeleton remodeling. Specifically, mechanosensing and signal transduction are coupled with chemical stimuli to regulate cytokine production, and interleukin-6 (IL-6) production is elevated in keratinocytes on stiffer substrates in response to 2,4-dinitrochlorobenzene. We demonstrated that β1 integrin and focal adhesion kinase (FAK) expression were enhanced with increasing stiffness and activation of ERK and the PI3K/Akt pathway was involved in stiffening-mediated IL-6 production. Collectively, our results reveal the critical role of matrix stiffening in modulating the proinflammatory response of keratinocytes, with important clinical implications for skin diseases accompanied by pathological matrix stiffening.

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Section: Discussionsupporting

confidence: 91%

Matrix Stiffening Enhances DNCB-Induced IL-6 Secretion in Keratinocytes Through Activation of ERK and PI3K/Akt Pathway

Chung

Shin

et al. 2021

Front. Immunol.

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“…These examples emphasize the need for caution when extrapolating data from one model to the next. Aging immunology studies should also better integrate emerging insights from geroscience, especially from inflammaging research, which has recently described pivotal roles for mitochondrial dysfunction, proteostasis, nutrient sensing and physical changes in the tissue microenvironment in modulating immune pathways [197][198][199][200] .…”

Section: Discussionmentioning

confidence: 99%

SARS-CoV-2, COVID-19 and the aging immune system

et al. 2021

Self Cite

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The coronavirus disease 2019 (COVID-19) pandemic is a global health threat with particular risk for severe disease and death in older adults and in adults with age-related metabolic and cardiovascular disease. Recent advances in the science of aging have highlighted how aging pathways control not only lifespan but also healthspan -the healthy years of life. Here, we discuss the aging immune system and its ability to respond to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We specifically focus on the intersect of severe COVID-19 and immunosenescence to highlight pathways that may be determinant for the risk of complications and death following infection with SARS-CoV-2. New or adapted therapeutics that target agingassociated pathways may be important tools to reduce the burden of death and long-term disability caused by this pandemic. Proposed interventions aimed at immunosenescence could enhance immune function not only in older adults but in susceptible younger individuals as well, ultimately improving complications of severe COVID-19 for all ages.

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“…Physical cues and external stimuli in the microenvironment drive a cell’s physiological function and lead to numerous downstream signaling effects. Piezo1 has been identified as a critical sensor of mechanical stress in numerous myeloid and lymphoid cells, indicating its role in the immune system by linking mechanical forces with immune regulation [ 135 , 136 , 137 , 138 ]. In one study, Piezo1 was determined as the primary sensor of physical forces in myeloid cells, as Piezo1-deficient leukocytes were unable to transduce mechanical signals [ 135 ].…”

Section: Piezo1 In Immune Cellsmentioning

confidence: 99%

“…However, the authors also reported exacerbated autoinflammation in a model of pulmonary fibrosis through the activation of Piezo1 [ 139 ]. Finally, Piezo1 has been shown to play an important role in dendritic cell (DC) activation and function when exposed to mechanical stress [ 138 ]. In this study, Yoda1 strongly upregulated the production of pro-inflammatory cytokines IL-6 and TNF- α [ 138 ].…”

Section: Piezo1 In Immune Cellsmentioning

confidence: 99%

“…Finally, Piezo1 has been shown to play an important role in dendritic cell (DC) activation and function when exposed to mechanical stress [ 138 ]. In this study, Yoda1 strongly upregulated the production of pro-inflammatory cytokines IL-6 and TNF- α [ 138 ]. The authors also found that Piezo1-deficient DCs mildly suppressed the DC-mediated anti-tumor response in a syngeneic ovalbumin (OVA) mouse model [ 138 ].…”

Section: Piezo1 In Immune Cellsmentioning

confidence: 99%

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Channeling the Force: Piezo1 Mechanotransduction in Cancer Metastasis

Dombroski

Hope

Sarna

et al. 2021

Cells

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Cancer metastasis is one of the leading causes of death worldwide, motivating research into identifying new methods of preventing cancer metastasis. Recently there has been increasing interest in understanding how cancer cells transduce mechanical forces into biochemical signals, as metastasis is a process that consists of a wide range of physical forces. For instance, the circulatory system through which disseminating cancer cells must transit is an environment characterized by variable fluid shear stress due to blood flow. Cancer cells and other cells can transduce physical stimuli into biochemical responses using the mechanosensitive ion channel Piezo1, which is activated by membrane deformations that occur when cells are exposed to physical forces. When active, Piezo1 opens, allowing for calcium flux into the cell. Calcium, as a ubiquitous second-messenger cation, is associated with many signaling pathways involved in cancer metastasis, such as angiogenesis, cell migration, intravasation, and proliferation. In this review, we discuss the roles of Piezo1 in each stage of cancer metastasis in addition to its roles in immune cell activation and cancer cell death.

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Mechanical Stiffness Controls Dendritic Cell Metabolism and Function

Abstract: Highlights d Environmental stiffness promotes DC inflammatory function d Tension primes DC metabolism, even without pattern recognition receptor input d TAZ bridges mechanosensory signals to DC metabolism and function d Tension directs phenotypes of human monocyte-derived DCs

Cited by 141 publications

References 77 publications

Matrix Stiffening Enhances DNCB-Induced IL-6 Secretion in Keratinocytes Through Activation of ERK and PI3K/Akt Pathway

Matrix Stiffening Enhances DNCB-Induced IL-6 Secretion in Keratinocytes Through Activation of ERK and PI3K/Akt Pathway

SARS-CoV-2, COVID-19 and the aging immune system

Channeling the Force: Piezo1 Mechanotransduction in Cancer Metastasis

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