DNA methyltransferase 1 deficiency improves macrophage motility and wound healing by ameliorating cholesterol accumulation

Zhao, Chuanrong; Yang, Qianru; Tang, Runze; Li, Wang; Wang, Jin; Yang, Fangfang; Zhao, Jianan; Zhu, Juanjuan; Pang, Wei; Li, Ning; Zhang, Xu; Tian, Xiao Yu; Yao, Weijuan; Zhou, Jing

doi:10.1038/s41536-023-00306-2

Cited by 9 publications

(4 citation statements)

References 71 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The diffusion constant for TAM diffusion roughly matches the time scale of motility of mouse nacrophages in transwell migration (68) and TAXIScan (69) assays which produce a range of speeds from roughly 0.55 − 1.0 𝜇/𝑚𝑖𝑛 (68). Table 1: All parameters are held fixed through all simulations except for the two rates which are estimated through the training process: the exhaustion rates of activated CD8+ T cells by both melanoma cells (𝑏 𝐶 ) and TAMs (𝑏 𝑀 ).…”

Section: Activatedmentioning

confidence: 52%

Spatial organization and stochastic fluctuations of immune cells impact clinical responsiveness to immune checkpoint inhibitors in patients with melanoma

Giuliani,

Stewart,

et al. 2023

Preprint

View full text Add to dashboard Cite

High-dimensional, spatial single-cell technologies such as CyTOF imaging mass cytometry (IMC) provide detailed information regarding locations of a large variety of cancer and immune cells in microscopic scales in tumor microarray (TMA) slides obtained from patients prior to immune checkpoint inhibitor (ICI) therapy. An important question is how the initial spatial organization of these cells in the tumor microenvironment (TME) change with time, regulate tumor growth and eventually outcomes as patients undergo ICI therapy. Utilizing IMC data of melanomas of patients who later underwent ICI therapy, we develop a spatially resolved interacting cell systems model that is calibrated against patient response data to address the above question. We find that the tumor fate in these patients is determined by the spatial organization of activated CD8+ T cells, macrophages, and melanoma cells and the interplay between these cells that regulate exhaustion of CD8+ T cells. We find that fencing of tumor cell boundaries by exhausted CD8+T cells is dynamically generated from the initial conditions that can play a pro-tumor role. Furthermore, we find that specific spatial features such as co-clustering of activated CD8+ T cells and macrophages in the pre-treatment samples determine the fate of the tumor progression, despite stochastic fluctuations and changes over the treatment course. Our framework enables determination of mechanisms of interplay between a key subset of tumor and immune cells in the TME that regulate clinical response to ICIs.SignificanceRecent advances in single cell technologies allows for spatial imaging a wide variety of cancer and immune cells in tissue samples obtained from solid tumors. This detailed snapshot data of microscale organization of tumor and immune cells could provide valuable insights into underlying biology and clinical responsiveness to cancer immunotherapy. By combining published data from imaging mass-cytometry and patient response against ICI drugs with data analysis rooted in statistical physics and statistical inference theory, we developed and studied the dynamics of mechanistic spatially resolved models: we show that tumor growth during ICI treatment is regulated by non-intuitive interplay between CD8+ T cells and tumor associated macrophages, formation of a pro-tumor fencing of exhausted CD8+ T cells around melanoma cells, specific features of spatial organization of these cells prior to treatment, and stochastic fluctuations in the dynamics. The mechanisms unveiled in our studies are general and can pertain to the response of other solid tumors to ICI therapy.

show abstract

Section: Activatedmentioning

confidence: 52%

Spatial organization and stochastic fluctuations of immune cells impact clinical responsiveness to immune checkpoint inhibitors in patients with melanoma

Giuliani,

Stewart,

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…Previously reported that enhanced LPS‐induced inflammation was via stiffness‐dependent stimulation and LPS could stimulate changes in cellular mechanical properties in terms of elasticity and viscoelasticity. 27 , 28 It has been shown that LPS could directly induce cell swelling response in a TLR4‐dependent manner. 29 Of note, TRPV4 regulates LPS‐stimulated macrophage phagocytosis in a matrix stiffness‐dependent manner.…”

Section: Discussionmentioning

confidence: 99%

LPS exacerbates TRPV4‐mediated itch through the intracellular TLR4‐PI3K signalling

Hao,

Wu,

Wang

et al. 2024

J Cellular Molecular Medi

View full text Add to dashboard Cite

Pruritus is often accompanied with bacterial infections, but the underlying mechanism is not fully understood. Although previous studies revealed that lipopolysaccharides (LPS) could directly activate TRPV4 channel and TRPV4 is involved in the generation of both acute itch and chronic itch, whether and how LPS affects TRPV4‐mediated itch sensation remains unclear. Here, we showed that LPS‐mediated TRPV4 sensitization exacerbated GSK101‐induced scratching behaviour in mice. Moreover, this effect was compromised in TLR4‐knockout mice, suggesting LPS acted through a TLR4‐dependent mechanism. Mechanistically, LPS enhanced GSK101‐evoked calcium influx in mouse ear skin cells and HEK293T cells transfected with TRPV4. Further, LPS sensitized TRPV4 channel through the intracellular TLR4‐PI3K‐AKT signalling. In summary, our study found a modulatory role of LPS in TRPV4 function and highlighted the TLR4‐TRPV4 interaction in itch signal amplification.

show abstract

“…Moreover, IBD-associated mucosal inflammation is associated with aberrant DNA methylation whereas SCFAs exhibit anti-inflammatory effects in IBD via IECs-induced changes in the transcription of inflammatory markers ( 216 – 218 ). On the other hand, gut dysbiosis, the presence of bacterial pathogens or LPS affect epigenetic mechanisms connected to inflammation and metabolism by acting on host DNMTs or by producing the enzyme itself ( 219 – 222 ).…”

Section: Scfa-epigenetic Regulationmentioning

confidence: 99%

The potential of short-chain fatty acid epigenetic regulation in chronic low-grade inflammation and obesity

Kopczyńska,

Kowalczyk

2024

Front. Immunol.

View full text Add to dashboard Cite

Obesity and chronic low-grade inflammation, often occurring together, significantly contribute to severe metabolic and inflammatory conditions like type 2 diabetes (T2D), cardiovascular disease (CVD), and cancer. A key player is elevated levels of gut dysbiosis-associated lipopolysaccharide (LPS), which disrupts metabolic and immune signaling leading to metabolic endotoxemia, while short-chain fatty acids (SCFAs) beneficially regulate these processes during homeostasis. SCFAs not only safeguard the gut barrier but also exert metabolic and immunomodulatory effects via G protein-coupled receptor binding and epigenetic regulation. SCFAs are emerging as potential agents to counteract dysbiosis-induced epigenetic changes, specifically targeting metabolic and inflammatory genes through DNA methylation, histone acetylation, microRNAs (miRNAs), and long non-coding RNAs (lncRNAs). To assess whether SCFAs can effectively interrupt the detrimental cascade of obesity and inflammation, this review aims to provide a comprehensive overview of the current evidence for their clinical application. The review emphasizes factors influencing SCFA production, the intricate connections between metabolism, the immune system, and the gut microbiome, and the epigenetic mechanisms regulated by SCFAs that impact metabolism and the immune system.

show abstract

DNA methyltransferase 1 deficiency improves macrophage motility and wound healing by ameliorating cholesterol accumulation

Cited by 9 publications

References 71 publications

Spatial organization and stochastic fluctuations of immune cells impact clinical responsiveness to immune checkpoint inhibitors in patients with melanoma

Spatial organization and stochastic fluctuations of immune cells impact clinical responsiveness to immune checkpoint inhibitors in patients with melanoma

LPS exacerbates TRPV4‐mediated itch through the intracellular TLR4‐PI3K signalling

The potential of short-chain fatty acid epigenetic regulation in chronic low-grade inflammation and obesity

Contact Info

Product

Resources

About