-
Categories
-
Pharmaceutical Intermediates
-
Active Pharmaceutical Ingredients
-
Food Additives
- Industrial Coatings
- Agrochemicals
- Dyes and Pigments
- Surfactant
- Flavors and Fragrances
- Chemical Reagents
- Catalyst and Auxiliary
- Natural Products
- Inorganic Chemistry
-
Organic Chemistry
-
Biochemical Engineering
- Analytical Chemistry
- Cosmetic Ingredient
-
Pharmaceutical Intermediates
Promotion
ECHEMI Mall
Wholesale
Weekly Price
Exhibition
News
-
Trade Service
Article | What do we think of when we mention GABA (γ-aminobutyric acid) in November? GABA is a major inhibitory neurotransmitter that regulates communication between neurons
.
Outside the brain, GABA, a neurotransmitter, has also been detected in the intestines, spleen, liver, and pancreas [1,2]
.
But whether GABA will play a "cross-border" role in the immune system is still unknown
.
On November 3, 2021, the Sidonia Fagarasan research group of the Yokohama Institute of Physics and Chemistry issued a paper entitled B cell-derived GABA elicits IL-10+ macrophages to limit anti-tumour immunity, and found that GABA derived from B cells induces macrophages to limit anti-tumour immunity.
Tumor immune response provides new insights into the immune regulation function of small molecular metabolites in the immune system except cytokines and membrane proteins
.
Small-molecule water-soluble metabolites are not only important intermediates in the process of intracellular biochemical reactions, but also "signal molecules" released into the extracellular environment, thereby affecting neighboring cells [3-5]
.
Lymphocytes are regulated by a variety of receptors and soluble small molecular metabolites, but there are still many small molecular metabolites whose functions have not been clearly understood
.
Therefore, the authors hope to identify the water-soluble metabolites that play a key regulatory role, which may act as environmental clues to mediate the interaction between immune cells
.
In order to find out the small water-soluble substances involved in the immune system, the authors analyzed the water-soluble metabolites in the steady-state and activated lymphocytes
.
There are about 200 kinds of metabolites between these two types of lymphocytes
.
The main differences in metabolic characteristics involved are the differences in the pathways of alanine, aspartic acid, and glutamate.
In addition, the metabolism of purine and pyrimidine and the tricarboxylic acid ring are also closely related to immune activation
.
Among these metabolites, GABA, a factor that was previously widely believed to play a role in the nervous system, aroused the authors' interest
.
No previous studies have shown that B cells can produce GABA, so the role of GABA in the immune system is also unclear
.
First, the authors confirmed that the B cells in the immune system are indeed the source of GABA production, and through the analysis of the key enzymes in GABA synthesis, they found that the expression level of GAD67 (Glutamate decarboxylase 67) instead of GAD65 in mouse and human B cells will increase
.
This result shows that the metabolism of glutamate in both mice and humans can indeed characterize the changes in B cell lineage
.
So how does GABA produced in B cells play a role in the immune system? To this end, the authors used the MC38 colon cancer model, in which B cells have been shown to inhibit anti-tumor T cell responses through antigen non-specific mechanisms [6]
.
The authors found that tumor growth in mouse strains lacking B cells was better controlled than wild-type tumors
.
In addition, compared with mice receiving placebo, implantation of slow-release GABA particles resulted in a significant increase in tumor growth in mice with B cell depletion
.
By adding the GABA receptor agonist tetrandrine toxin, the authors found that it would limit tumor growth and increase the cytotoxic activity of tumor-infiltrating CD8+ T cells
.
Therefore, the authors found that reducing GABA or affecting the GABA receptor signaling pathway can enhance cytotoxic T cell response and anti-tumor immunity, and the secretion of GABA makes the host immune to tumor growth
.
So what is the cellular biological mechanism of GABA affecting the immune system? Previous studies have shown that tumor-associated macrophages (Tumour-associated macrophages, TAMs) can suppress anti-tumor immune responses
.
The authors found that GABA affects the physiological processes of macrophages and promotes a polarized response to an anti-inflammatory phenotype
.
Furthermore, the authors want to know how GABA regulates macrophages
.
Studies have shown that TAMs originate from monocytes.
Therefore, the authors speculate that GABA regulates macrophages by affecting the differentiation of monocytes into macrophages
.
In order to test this hypothesis, the authors added GABA to the culture medium and found that it increased the number of cells and increased cell survival, and also promoted the expression of the anti-inflammatory macrophage characteristic factor FRβ (Folate receptor β)
.
Gene transcript analysis also proved that genes related to cell cycle and folate metabolism were significantly up-regulated
.
Therefore, the authors confirmed that GABA promotes the differentiation, expansion and survival of macrophages with anti-inflammatory properties
.
Furthermore, in order to confirm the role of GABA in B cells, the authors constructed a mouse strain that specifically knocked out GAD67 in B cells, and found that conditional inactivation of GAD67 would lead to a significant decrease in GABA content in B cells, and found that B GABA produced by cells can significantly limit the anti-tumor T cell response
.
In general, the work found that GABA, which is a metabolite and neurotransmitter, is synthesized and secreted by activated B cells, and acts as a clue to the interaction between cells to affect the immune system's response
.
This work shows that the small molecular metabolites produced by the B cell lineage have an inflammatory regulation effect, and may become a drug target for immune response regulation in the future
.
Original link: https://doi.
org/10.
1038/s41586-021-04082-1 Platemaker: 11 References 1 Tsuji, M.
& Nakajima, T.
Studies on the formation of gamma-aminobutyric acid from putrescine in rat organs and purification of its synthetic enzyme from rat intestine.
Journal of biochemistry 83, 1407-1412, doi:10.
1093/oxfordjournals.
jbchem.
a132050 (1978).
2 Garry, DJ, Sorenson, RL & Coulter, HD Ultrastructural localization of gamma amino butyric acid immunoreactivity in B cells of the rat pancreas.
Diabetologia 30, 115-119, doi:10.
1007/bf00274582 (1987).
3 Loftus, RM & Finlay, DK Immunometabolism: Cellular Metabolism Turns Immune Regulator.
The Journal of biological chemistry 291, 1-10, doi:10.
1074/jbc.
R115.
693903 (2016).
4 Geltink, RIK, Kyle, RL & Pearce, EL Unraveling the Complex Interplay Between T Cell Metabolism and Function.
Annual review of immunology 36, 461-488, doi:10.
1146/annurev-immunol-042617-053019 (2018).
5 Makowski, L.
, Chaib, M.
& Rathmell, JC Immunometabolism: From basic mechanisms to translation.
Immunological reviews 295 , 5-14, doi:10.
1111/imr.
12858 (2020).
6 Zhang, Y.
, Morgan, R.
, Podack, ER & Rosenblatt, J.
B cell regulation of anti-tumor immune response.
Immunologic research 57, 115 -124, doi:10.
1007/s12026-013-8472-1 (2013).
Reprinting instructions [Original Articles] BioArt original articles, personal reposting and sharing are welcome, reprinting is prohibited without permission, the copyright of all published works is owned by BioArt haveImmunologic research 57, 115-124, doi:10.
1007/s12026-013-8472-1 (2013).
Reprinting instructions [Original Articles] BioArt original articles, personal forwarding and sharing are welcome, reprinting without permission is prohibited, all published works The copyright is owned by BioArtImmunologic research 57, 115-124, doi:10.
1007/s12026-013-8472-1 (2013).
Reprinting instructions [Original Articles] BioArt original articles, personal forwarding and sharing are welcome, reprinting without permission is prohibited, all published works The copyright is owned by BioArt
.
BioArt reserves all statutory rights and offenders must be investigated
.
.
Outside the brain, GABA, a neurotransmitter, has also been detected in the intestines, spleen, liver, and pancreas [1,2]
.
But whether GABA will play a "cross-border" role in the immune system is still unknown
.
On November 3, 2021, the Sidonia Fagarasan research group of the Yokohama Institute of Physics and Chemistry issued a paper entitled B cell-derived GABA elicits IL-10+ macrophages to limit anti-tumour immunity, and found that GABA derived from B cells induces macrophages to limit anti-tumour immunity.
Tumor immune response provides new insights into the immune regulation function of small molecular metabolites in the immune system except cytokines and membrane proteins
.
Small-molecule water-soluble metabolites are not only important intermediates in the process of intracellular biochemical reactions, but also "signal molecules" released into the extracellular environment, thereby affecting neighboring cells [3-5]
.
Lymphocytes are regulated by a variety of receptors and soluble small molecular metabolites, but there are still many small molecular metabolites whose functions have not been clearly understood
.
Therefore, the authors hope to identify the water-soluble metabolites that play a key regulatory role, which may act as environmental clues to mediate the interaction between immune cells
.
In order to find out the small water-soluble substances involved in the immune system, the authors analyzed the water-soluble metabolites in the steady-state and activated lymphocytes
.
There are about 200 kinds of metabolites between these two types of lymphocytes
.
The main differences in metabolic characteristics involved are the differences in the pathways of alanine, aspartic acid, and glutamate.
In addition, the metabolism of purine and pyrimidine and the tricarboxylic acid ring are also closely related to immune activation
.
Among these metabolites, GABA, a factor that was previously widely believed to play a role in the nervous system, aroused the authors' interest
.
No previous studies have shown that B cells can produce GABA, so the role of GABA in the immune system is also unclear
.
First, the authors confirmed that the B cells in the immune system are indeed the source of GABA production, and through the analysis of the key enzymes in GABA synthesis, they found that the expression level of GAD67 (Glutamate decarboxylase 67) instead of GAD65 in mouse and human B cells will increase
.
This result shows that the metabolism of glutamate in both mice and humans can indeed characterize the changes in B cell lineage
.
So how does GABA produced in B cells play a role in the immune system? To this end, the authors used the MC38 colon cancer model, in which B cells have been shown to inhibit anti-tumor T cell responses through antigen non-specific mechanisms [6]
.
The authors found that tumor growth in mouse strains lacking B cells was better controlled than wild-type tumors
.
In addition, compared with mice receiving placebo, implantation of slow-release GABA particles resulted in a significant increase in tumor growth in mice with B cell depletion
.
By adding the GABA receptor agonist tetrandrine toxin, the authors found that it would limit tumor growth and increase the cytotoxic activity of tumor-infiltrating CD8+ T cells
.
Therefore, the authors found that reducing GABA or affecting the GABA receptor signaling pathway can enhance cytotoxic T cell response and anti-tumor immunity, and the secretion of GABA makes the host immune to tumor growth
.
So what is the cellular biological mechanism of GABA affecting the immune system? Previous studies have shown that tumor-associated macrophages (Tumour-associated macrophages, TAMs) can suppress anti-tumor immune responses
.
The authors found that GABA affects the physiological processes of macrophages and promotes a polarized response to an anti-inflammatory phenotype
.
Furthermore, the authors want to know how GABA regulates macrophages
.
Studies have shown that TAMs originate from monocytes.
Therefore, the authors speculate that GABA regulates macrophages by affecting the differentiation of monocytes into macrophages
.
In order to test this hypothesis, the authors added GABA to the culture medium and found that it increased the number of cells and increased cell survival, and also promoted the expression of the anti-inflammatory macrophage characteristic factor FRβ (Folate receptor β)
.
Gene transcript analysis also proved that genes related to cell cycle and folate metabolism were significantly up-regulated
.
Therefore, the authors confirmed that GABA promotes the differentiation, expansion and survival of macrophages with anti-inflammatory properties
.
Furthermore, in order to confirm the role of GABA in B cells, the authors constructed a mouse strain that specifically knocked out GAD67 in B cells, and found that conditional inactivation of GAD67 would lead to a significant decrease in GABA content in B cells, and found that B GABA produced by cells can significantly limit the anti-tumor T cell response
.
In general, the work found that GABA, which is a metabolite and neurotransmitter, is synthesized and secreted by activated B cells, and acts as a clue to the interaction between cells to affect the immune system's response
.
This work shows that the small molecular metabolites produced by the B cell lineage have an inflammatory regulation effect, and may become a drug target for immune response regulation in the future
.
Original link: https://doi.
org/10.
1038/s41586-021-04082-1 Platemaker: 11 References 1 Tsuji, M.
& Nakajima, T.
Studies on the formation of gamma-aminobutyric acid from putrescine in rat organs and purification of its synthetic enzyme from rat intestine.
Journal of biochemistry 83, 1407-1412, doi:10.
1093/oxfordjournals.
jbchem.
a132050 (1978).
2 Garry, DJ, Sorenson, RL & Coulter, HD Ultrastructural localization of gamma amino butyric acid immunoreactivity in B cells of the rat pancreas.
Diabetologia 30, 115-119, doi:10.
1007/bf00274582 (1987).
3 Loftus, RM & Finlay, DK Immunometabolism: Cellular Metabolism Turns Immune Regulator.
The Journal of biological chemistry 291, 1-10, doi:10.
1074/jbc.
R115.
693903 (2016).
4 Geltink, RIK, Kyle, RL & Pearce, EL Unraveling the Complex Interplay Between T Cell Metabolism and Function.
Annual review of immunology 36, 461-488, doi:10.
1146/annurev-immunol-042617-053019 (2018).
5 Makowski, L.
, Chaib, M.
& Rathmell, JC Immunometabolism: From basic mechanisms to translation.
Immunological reviews 295 , 5-14, doi:10.
1111/imr.
12858 (2020).
6 Zhang, Y.
, Morgan, R.
, Podack, ER & Rosenblatt, J.
B cell regulation of anti-tumor immune response.
Immunologic research 57, 115 -124, doi:10.
1007/s12026-013-8472-1 (2013).
Reprinting instructions [Original Articles] BioArt original articles, personal reposting and sharing are welcome, reprinting is prohibited without permission, the copyright of all published works is owned by BioArt haveImmunologic research 57, 115-124, doi:10.
1007/s12026-013-8472-1 (2013).
Reprinting instructions [Original Articles] BioArt original articles, personal forwarding and sharing are welcome, reprinting without permission is prohibited, all published works The copyright is owned by BioArtImmunologic research 57, 115-124, doi:10.
1007/s12026-013-8472-1 (2013).
Reprinting instructions [Original Articles] BioArt original articles, personal forwarding and sharing are welcome, reprinting without permission is prohibited, all published works The copyright is owned by BioArt
.
BioArt reserves all statutory rights and offenders must be investigated
.
