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Written by | A fish
in the nineteenth century, physiologist Claude Bernard wrote that "only the stability of the internal environment can have free and independent existence", and later, the characteristics of living systems that can maintain their own stability in response to various changes in the external environment were named "internal homeostasis"
.
For multicellular organisms, energy management (metabolism) and protection from foreign invasion (immune function) are fundamental survival needs, which may have evolved through a common homeostatic mechanism, and also represent a trade-off between two opposing forces: the need to store energy and the immune defense
that consumes energy.
It has long been discovered that infectious diseases are associated with transient hyperglycemia, and many years before aspirin's anti-inflammatory effects were discovered, it was found to improve insulin sensitivity, and more and more studies have gradually begun to focus on the link between
metabolic status and immune response.
Recently, Giuseppe Matarese and others from Frederick II University of Naples, Italy, published an opinion article entitled Regulatory T cells as metabolic sensors in Immunity, summarizing FoxP3 + CD4+CD25+ regulatory T cells as metabolic sensors have unique biological characteristics, which can be used as metabolic centers to receive local or systemic metabolic signals, adjust their own intracellular metabolic state and anti-inflammatory function according to the needs of the body, and regulate the body's immune tolerance, which also makes the strategy of restoring homeostasis by targeting regulatory T cells may become a potential target for the
。
The simplified model of the immune metabolism regulatory circuit includes a sensor, a controller, and an effector, the sensor is responsible for detecting the metabolic state, and the controller is responsible for judging the difference between this state and the normal state, thereby affecting the effector, and the effector directly regulates the immune state
.
CD4+ T cells have been identified as controllers of pro-inflammatory responses as early as the seventies, and it is only in recent decades that CD4+CD25+FoxP3+ regulatory T (Treg) cells with immunosuppressive functions have been discovered.
Treg cells rely on a different intracellular metabolic state to promote proliferation and functionIn
order to perform defense functions during infection, immune cells need to use anabolic energy to synthesize new cellular components, promote cell division, or obtain specialized functions
.
Induction of intracellular mTOR is a common feature
of macrophage, dendritic cell, and lymphocyte activation.
CD4+CD25-FoxP3-regular T cells (Tconv) are resting and need to complete mTOR-driven metabolic remodeling through T cell receptor (TCR) activation, enhancing glycolysis, glutamine breakdown, and mitochondrial respiration to meet increased
energy requirements 。 The metabolic state of human natural Treg cells is significantly different, manifested by strong mTOR pathway and glycolytic activation, higher intracellular ATP levels and proliferative potential
.
Treg cell function has been shown to depend on cholesterol and lipid metabolism, and in human natural Treg cells, upregulation of key inhibitory molecules, such as CTLA-4 and ICOS, relies on efficient fatty acid synthesis activity, in addition, oxidative metabolism also plays a key role
in natural and induced Treg cell function.
Many studies have shown that Treg cell function is controlled by anti-growth intracellular signals, such as AMPK, which can sense energy deficit and antagonize mTOR
.
Sustained AMPK activation is associated with low expression of the glucose transporter GLUT1 and participation in fatty acid oxidation to maintain survival and inhibitory function
of human and mouse Treg cells.
Another key activator of cell proliferation and aerobic glycolysis, weakening of the serine-threonine kinase AKT phosphatidylinositol-3-OH kinase (PI3K) pathway is also important
to promote and maintain the stability of human and mouse Treg cells.
Treg cell proliferation may depend on anabolic growth and activation of mTOR and glycolysis, similar to Tconv cells, but unlike Tconv cells, the high anabolic state of Treg cells makes them have the following characteristics: (1) their steady-state amplification may be strictly dependent on physiological fluctuations in nutrient accessibility; (2) Its immunosuppressive function may be related to intracellular low trophic status signals, such as AKT-PI3K-mTOR weakening, and AMPK, FoxO, autophagy and lipid metabolism activation
.
Treg cells respond to intracellular metabolic signals Treg cells have a unique sensitivity
to systemic metabolic signals
, and the physiology and behavior of most living organisms are intrinsically regulated by biorhythms, such as the diet-hunger cycle, which influences many factors and fluctuations in signaling pathways
。 There are many molecules in peripheral blood that stimulate anabolic increase, such as insulin, insulin-like growth factors, leptin, etc.
, and there are also many molecules that induce catabolism, such as glucocorticoids, ghrelin, sirtuins, etc
.
The body's energy state is perceived not only by the hypothalamus, but also by immune cells
.
Tconv cells respond to insulin by promoting proliferation and the production of cytokines, while high insulin levels inhibit the immunosuppressive function
of Treg cells.
Leptin can also promote Tconv cell metabolic activation and pro-inflammatory function, but inhibit Treg cell function and survival
.
Ghrelin can inhibit Tconv cell proliferation and cytokine production, but can induce Treg cells and promote their anti-inflammatory activity
.
Glucocorticoids can inhibit Tconv cell function, but promote Treg cell survival, maturation, and differentiation
.
In addition, Sirtuin3 can also promote Treg cell function
.
The ability of Treg cells to sense energy can be used clinically, for example, a hypoglycemic drug, metformin, which can reduce leptin levels and Tconv cell responses, increase Treg cells, and improve patients
with multiple sclerosis and metabolic symptoms.
Calorie restriction can also affect the inflammatory response
by regulating Treg cell proliferation.
Thus, circadian rhythms associated with the diet-hunger cycle can regulate Treg cell homeostasis, and at the extracellular level, indicators of low energy states, such as low insulin and leptin, high ghrelin, and glucocorticoids, may promote the anti-inflammatory activity of Treg cells, affecting the survival
of the body in an energy-deficient state.
In key metabolic tissues, Treg cells rapidly sense energyIn
addition to circulating in the blood, Treg cells can also settle in tissues to regulate metabolism, they can rapidly sense nutrient fluctuations, respond to metabolic changes and regulate immune responses
at the paracrine and endocrine levels.
There is a group of phenotypically and functionally distinct subsets of Treg cells in the small intestinal lamina propria, which are primarily induced by the tissue microenvironment
.
Glycolytic inhibition and oxidative phosphorylation allow it to survive in a low-glucose and high-lactic acid environment in the digestive tract, and intestinal resident Treg cells can also sense and be regulated by intestinal microorganisms, and the products of intestinal microbial fermentation, such as short-chain fatty acids, especially butyrate and propionate, promote the production and function
of Treg cells.
In addition, intestinally settled Treg cells can also rapidly sense locally produced hormones such as glucagon-like peptide (GLP-1), which can inhibit the proliferation of Tconv cells and maintain the number of
Treg cells.
After receiving metabolic signals, Treg cells can interact with other host cells to regulate glucose homeostasis and inflammatory
。
Adipose tissue (AT) also plays a key role in metabolic homeostasis regulation, where AT-resident Treg cells can efficiently ingest long-chain fatty acids and store lipids through lipid droplets
.
FoxP3 activity can maintain fatty acid oxidation, provide energy for intracellular metabolism, and protect Treg cells from long-chain fatty acid-induced cell death
.
In AT-resident Treg cells, PPAR-γ works with FoxP3 to control its unique transcription program and regulate the anti-inflammatory response
.
Functional Conclusion of Treg Cells in Different Metabolic Tissues
At an evolutionary level, the coordination of metabolic activity and immune function may be beneficial because activating the inflammatory response requires energy consumption, but may also be necessary for the survival of the body.
A systematic reallocation
of resources is therefore required.
This article describes three main characteristics of Treg cells that allow them to sense the intrinsic metabolic environment to control immune states: (1) high anabolic state; (2) abundant presence in key metabolic tissues; (3) Residence and recirculation
between lymphoid organs and non-lymphatic parts.
Treg cells may control different activities at different stages of the life cycle by utilizing different metabolic pathways such as glycolysis and lipid oxidation.
While mTOR-dependent glycolysis-lipid synthesis appears to be necessary for Treg cell development, proliferation, and migration, lipid oxidative metabolism is also necessary
for its immunosuppressive function.
In this paper, it is suggested that the behavior of such Treg cells in terms of intracellular metabolic needs (anabolism that promotes cell expansion, catabolism that promotes cell functional function) may appear to be divisive, but in fact fully reflects the body's immune resistance (active defense during infection, Treg cell proliferation) and disease tolerance Systematic strategies (to prevent inflammatory damage, Treg cell inhibition).
This paper also suggests that these different events are likely to cross and integrate in vivo, and may also affect more "active" (active release of inhibitory cytokines and killer molecules by Treg cells) or "inactive" (competition for co-stimulation of cytokines, inflammatory mediators, and Treg cells) immunosuppressive mechanisms in different homeostasis
。
In conclusion, this paper suggests that Treg cells are a core element in neuroendocrine and immune system interactions, precisely regulating energy balance and immune defense, so they may be potential therapeutic targets for autoimmune and metabolism-related diseases in the future
.
Original link: https://doi.
org/10.
1016/j.
immuni.
2022.
10.
006
Platemaker: Eleven
in the nineteenth century, physiologist Claude Bernard wrote that "only the stability of the internal environment can have free and independent existence", and later, the characteristics of living systems that can maintain their own stability in response to various changes in the external environment were named "internal homeostasis"
.
For multicellular organisms, energy management (metabolism) and protection from foreign invasion (immune function) are fundamental survival needs, which may have evolved through a common homeostatic mechanism, and also represent a trade-off between two opposing forces: the need to store energy and the immune defense
that consumes energy.
It has long been discovered that infectious diseases are associated with transient hyperglycemia, and many years before aspirin's anti-inflammatory effects were discovered, it was found to improve insulin sensitivity, and more and more studies have gradually begun to focus on the link between
metabolic status and immune response.
Recently, Giuseppe Matarese and others from Frederick II University of Naples, Italy, published an opinion article entitled Regulatory T cells as metabolic sensors in Immunity, summarizing FoxP3 + CD4+CD25+ regulatory T cells as metabolic sensors have unique biological characteristics, which can be used as metabolic centers to receive local or systemic metabolic signals, adjust their own intracellular metabolic state and anti-inflammatory function according to the needs of the body, and regulate the body's immune tolerance, which also makes the strategy of restoring homeostasis by targeting regulatory T cells may become a potential target for the
。
The simplified model of the immune metabolism regulatory circuit includes a sensor, a controller, and an effector, the sensor is responsible for detecting the metabolic state, and the controller is responsible for judging the difference between this state and the normal state, thereby affecting the effector, and the effector directly regulates the immune state
.
CD4+ T cells have been identified as controllers of pro-inflammatory responses as early as the seventies, and it is only in recent decades that CD4+CD25+FoxP3+ regulatory T (Treg) cells with immunosuppressive functions have been discovered.
Treg cells rely on a different intracellular metabolic state to promote proliferation and functionIn
order to perform defense functions during infection, immune cells need to use anabolic energy to synthesize new cellular components, promote cell division, or obtain specialized functions
.
Induction of intracellular mTOR is a common feature
of macrophage, dendritic cell, and lymphocyte activation.
CD4+CD25-FoxP3-regular T cells (Tconv) are resting and need to complete mTOR-driven metabolic remodeling through T cell receptor (TCR) activation, enhancing glycolysis, glutamine breakdown, and mitochondrial respiration to meet increased
energy requirements 。 The metabolic state of human natural Treg cells is significantly different, manifested by strong mTOR pathway and glycolytic activation, higher intracellular ATP levels and proliferative potential
.
Treg cell function has been shown to depend on cholesterol and lipid metabolism, and in human natural Treg cells, upregulation of key inhibitory molecules, such as CTLA-4 and ICOS, relies on efficient fatty acid synthesis activity, in addition, oxidative metabolism also plays a key role
in natural and induced Treg cell function.
Many studies have shown that Treg cell function is controlled by anti-growth intracellular signals, such as AMPK, which can sense energy deficit and antagonize mTOR
.
Sustained AMPK activation is associated with low expression of the glucose transporter GLUT1 and participation in fatty acid oxidation to maintain survival and inhibitory function
of human and mouse Treg cells.
Another key activator of cell proliferation and aerobic glycolysis, weakening of the serine-threonine kinase AKT phosphatidylinositol-3-OH kinase (PI3K) pathway is also important
to promote and maintain the stability of human and mouse Treg cells.
Treg cell proliferation may depend on anabolic growth and activation of mTOR and glycolysis, similar to Tconv cells, but unlike Tconv cells, the high anabolic state of Treg cells makes them have the following characteristics: (1) their steady-state amplification may be strictly dependent on physiological fluctuations in nutrient accessibility; (2) Its immunosuppressive function may be related to intracellular low trophic status signals, such as AKT-PI3K-mTOR weakening, and AMPK, FoxO, autophagy and lipid metabolism activation
.
Treg cells respond to intracellular metabolic signals Treg cells have a unique sensitivity
to systemic metabolic signals
, and the physiology and behavior of most living organisms are intrinsically regulated by biorhythms, such as the diet-hunger cycle, which influences many factors and fluctuations in signaling pathways
。 There are many molecules in peripheral blood that stimulate anabolic increase, such as insulin, insulin-like growth factors, leptin, etc.
, and there are also many molecules that induce catabolism, such as glucocorticoids, ghrelin, sirtuins, etc
.
The body's energy state is perceived not only by the hypothalamus, but also by immune cells
.
Tconv cells respond to insulin by promoting proliferation and the production of cytokines, while high insulin levels inhibit the immunosuppressive function
of Treg cells.
Leptin can also promote Tconv cell metabolic activation and pro-inflammatory function, but inhibit Treg cell function and survival
.
Ghrelin can inhibit Tconv cell proliferation and cytokine production, but can induce Treg cells and promote their anti-inflammatory activity
.
Glucocorticoids can inhibit Tconv cell function, but promote Treg cell survival, maturation, and differentiation
.
In addition, Sirtuin3 can also promote Treg cell function
.
The ability of Treg cells to sense energy can be used clinically, for example, a hypoglycemic drug, metformin, which can reduce leptin levels and Tconv cell responses, increase Treg cells, and improve patients
with multiple sclerosis and metabolic symptoms.
Calorie restriction can also affect the inflammatory response
by regulating Treg cell proliferation.
Thus, circadian rhythms associated with the diet-hunger cycle can regulate Treg cell homeostasis, and at the extracellular level, indicators of low energy states, such as low insulin and leptin, high ghrelin, and glucocorticoids, may promote the anti-inflammatory activity of Treg cells, affecting the survival
of the body in an energy-deficient state.
In key metabolic tissues, Treg cells rapidly sense energyIn
addition to circulating in the blood, Treg cells can also settle in tissues to regulate metabolism, they can rapidly sense nutrient fluctuations, respond to metabolic changes and regulate immune responses
at the paracrine and endocrine levels.
There is a group of phenotypically and functionally distinct subsets of Treg cells in the small intestinal lamina propria, which are primarily induced by the tissue microenvironment
.
Glycolytic inhibition and oxidative phosphorylation allow it to survive in a low-glucose and high-lactic acid environment in the digestive tract, and intestinal resident Treg cells can also sense and be regulated by intestinal microorganisms, and the products of intestinal microbial fermentation, such as short-chain fatty acids, especially butyrate and propionate, promote the production and function
of Treg cells.
In addition, intestinally settled Treg cells can also rapidly sense locally produced hormones such as glucagon-like peptide (GLP-1), which can inhibit the proliferation of Tconv cells and maintain the number of
Treg cells.
After receiving metabolic signals, Treg cells can interact with other host cells to regulate glucose homeostasis and inflammatory
。
Adipose tissue (AT) also plays a key role in metabolic homeostasis regulation, where AT-resident Treg cells can efficiently ingest long-chain fatty acids and store lipids through lipid droplets
.
FoxP3 activity can maintain fatty acid oxidation, provide energy for intracellular metabolism, and protect Treg cells from long-chain fatty acid-induced cell death
.
In AT-resident Treg cells, PPAR-γ works with FoxP3 to control its unique transcription program and regulate the anti-inflammatory response
.
Functional Conclusion of Treg Cells in Different Metabolic Tissues
At an evolutionary level, the coordination of metabolic activity and immune function may be beneficial because activating the inflammatory response requires energy consumption, but may also be necessary for the survival of the body.
A systematic reallocation
of resources is therefore required.
This article describes three main characteristics of Treg cells that allow them to sense the intrinsic metabolic environment to control immune states: (1) high anabolic state; (2) abundant presence in key metabolic tissues; (3) Residence and recirculation
between lymphoid organs and non-lymphatic parts.
Treg cells may control different activities at different stages of the life cycle by utilizing different metabolic pathways such as glycolysis and lipid oxidation.
While mTOR-dependent glycolysis-lipid synthesis appears to be necessary for Treg cell development, proliferation, and migration, lipid oxidative metabolism is also necessary
for its immunosuppressive function.
In this paper, it is suggested that the behavior of such Treg cells in terms of intracellular metabolic needs (anabolism that promotes cell expansion, catabolism that promotes cell functional function) may appear to be divisive, but in fact fully reflects the body's immune resistance (active defense during infection, Treg cell proliferation) and disease tolerance Systematic strategies (to prevent inflammatory damage, Treg cell inhibition).
This paper also suggests that these different events are likely to cross and integrate in vivo, and may also affect more "active" (active release of inhibitory cytokines and killer molecules by Treg cells) or "inactive" (competition for co-stimulation of cytokines, inflammatory mediators, and Treg cells) immunosuppressive mechanisms in different homeostasis
。
In conclusion, this paper suggests that Treg cells are a core element in neuroendocrine and immune system interactions, precisely regulating energy balance and immune defense, so they may be potential therapeutic targets for autoimmune and metabolism-related diseases in the future
.
Original link: https://doi.
org/10.
1016/j.
immuni.
2022.
10.
006
Platemaker: Eleven
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