Therapeutic effects of myocardin-related transcription factor A (MRTF-A) knockout on experimental mice with nonalcoholic steatohepatitis induced by high-fat diet

Zhang, Lei; Li, Hualong; Zhang, Dingding; Cui, Xiao-Chun

doi:10.1177/09603271211002886

“…For instance, MRTF-A is upregulated in blood-circulating Mϕ associated with atherosclerotic lesions, thus a drug that supplants MRTF-A ( Velasquez et al, 2013 ; Yu-Wai-Man et al, 2017 ) may inadvertently accelerate atherosclerosis in space. Similar conclusions can be made with spaceflight diseases such as non-alcoholic fatty liver disease ( Beheshti et al, 2019 ), related to MRTF ( Zhang L. et al, 2021 ). Currently, no safe drugs have been proven for the treatment of space-induced cardiovascular disease, and evaluations of potential drugs is often contradictory ( Meerman et al, 2021 ).…”

Section: Conclusion and Recommendationssupporting

confidence: 70%

MRTF may be the missing link in a multiscale mechanobiology approach toward macrophage dysfunction in space

An

¹

2022

Front. Cell Dev. Biol.

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Macrophages exhibit impaired phagocytosis, adhesion, migration, and cytokine production in space, hindering their ability to elicit immune responses. Considering that the combined effect of spaceflight microgravity and radiation is multiscale and multifactorial in nature, it is expected that contradictory findings are common in the field. This theory paper reanalyzes research on the macrophage spaceflight response across multiple timescales from seconds to weeks, and spatial scales from the molecular, intracellular, extracellular, to the physiological. Key findings include time-dependence of both pro-inflammatory activation and integrin expression. Here, we introduce the time-dependent, intracellular localization of MRTF-A as a hypothetical confounder of macrophage activation. We discuss the mechanosensitive MRTF-A/SRF pathway dependence on the actin cytoskeleton/nucleoskeleton, microtubules, membrane mechanoreceptors, hypoxia, oxidative stress, and intracellular/extracellular crosstalk. By adopting a multiscale perspective, this paper provides the first mechanistic answer for a three-decade-old question regarding impaired cytokine secretion in microgravity—and strengthens the connection between the recent advances in mechanobiology, microgravity, and the spaceflight immune response. Finally, we hypothesize MRTF involvement and complications in treating spaceflight-induced cardiovascular, skeletal, and immune disease.

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“…For instance, MRTF-A is upregulated in blood-circulating Mφ associated with atherosclerotic lesions, thus treatment that supplants MRTF-A may inadvertently accelerate atherosclerosis in space. Similar conclusions can be made with spaceflight diseases such non-alcoholic fatty liver disease (Beheshti et al, 2019), related to MRTF (Zhang et al, 2021). Currently, no safe drugs have been proven for the treatment of space-induced cardiovascular disease, and evaluations of potential drugs is often contradictory (Meerman et al, 2021).…”

Section: Conclusion and Recommendationssupporting

confidence: 61%

MRTF May Be the Missing Link in a Multiscale Mechanobiology Approach toward Macrophage Dysfunction in Space

An¹

2022

Preprint

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Macrophages exhibit impaired phagocytosis, adhesion, migration, and cytokine production in space, hindering their ability to elicit immune responses. The combined effect of spaceflight microgravity and radiation on macrophage dysfunction is multiscale and multifactorial in nature. However, spaceflight and simulated microgravity experiments often take single-scale approaches. This hypothesis and theory paper reanalyzes research in the macrophage spaceflight response across multiple scales, from the molecular, intracellular, extracellular, to the physiological. Here, we introduce the time-dependent, mechanotransducive MRTF-A/SRF pathway, which depends on intracellular localization, to elucidate seemingly contradictory macrophage responses across time scales. We discuss the MRTF-A/SRF pathway dependence on the actin cytoskeleton/nucleoskeleton, microtubules, mechanosensitive membrane proteins, hypoxia, oxidative stress, and crosstalk with other pathways and cells. By adopting a multiscale perspective, this paper identifies potential mechanisms for adverse macrophage responses and strengthens the connection between microgravity, mechanobiology, and the spaceflight immune response. Finally, we hypothesize MRTF involvement and complications in treating spaceflight-induced cardiovascular, skeletal, and immune disease.

show abstract

“…For instance, MRTF-A is upregulated in blood-circulating Mφ associated with atherosclerotic lesions, thus a drug that supplants MRTF-A may inadvertently accelerate atherosclerosis in space. Similar conclusions can be made with spaceflight diseases such non-alcoholic fatty liver disease (Beheshti et al, 2019), related to MRTF (Zhang et al, 2021). Currently, no safe drugs have been proven for the treatment of spaceinduced cardiovascular disease, and evaluations of potential drugs is often contradictory (Meerman et al, 2021).…”

Section: Conclusion and Recommendationssupporting

confidence: 60%

MRTF May Be the Missing Link in a Multiscale Mechanobiology Approach toward Macrophage Dysfunction in Space

An

2022

Preprint

0

View full text Add to dashboard Cite

Macrophages exhibit impaired phagocytosis, adhesion, migration, and cytokine production in space, hindering their ability to elicit immune responses. Considering that the combined effect of spaceflight microgravity and radiation is multiscale and multifactorial in nature, it is expected that contradictory findings are common in the field. This theory paper reanalyzes research on the macrophage spaceflight response across multiple timescales from seconds to weeks, and spatial scales from the molecular, intracellular, extracellular, to the physiological. Key findings include time-dependence of both pro-inflammatory activation and integrin expression. Here, we introduce the time-dependent, intracellular localization of MRTF-A as a hypothetical confounder of macrophage activation. We discuss the mechanosensitive MRTF-A/SRF pathway dependence on the actin cytoskeleton/nucleoskeleton, microtubules, membrane mechanoreceptors, hypoxia, oxidative stress, and intracellular/extracellular crosstalk. By adopting a multiscale perspective, this paper provides the first mechanistic answer for a three-decade-old question regarding impaired cytokine secretion in microgravity—and strengthens the connection between the recent advances in mechanobiology, microgravity, and the spaceflight immune response. Finally, we hypothesize MRTF involvement and complications in treating spaceflight-induced cardiovascular, skeletal, and immune disease.

show abstract

Therapeutic effects of myocardin-related transcription factor A (MRTF-A) knockout on experimental mice with nonalcoholic steatohepatitis induced by high-fat diet

Cited by 7 publications

References 43 publications

MRTF may be the missing link in a multiscale mechanobiology approach toward macrophage dysfunction in space

MRTF may be the missing link in a multiscale mechanobiology approach toward macrophage dysfunction in space

MRTF May Be the Missing Link in a Multiscale Mechanobiology Approach toward Macrophage Dysfunction in Space

MRTF May Be the Missing Link in a Multiscale Mechanobiology Approach toward Macrophage Dysfunction in Space

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