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Cited by 263Adipokines, Inflammation, and Metabolic DiseasesPsoriasis: Treatment and PathogenesisT-cell and B-cell Immunology

The DOI matches its Crossref record; 149 of the 150 references it cites were found in a registry or an index.

The Alterations in and the Role of the Th17/Treg Balance in Metabolic Diseases

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Zhang, Siwen, Gang, Xiaokun, Yang, Shuo, Cui, Mengzhao, Sun, Lin, Li, Zhuo, Wang, Guixia·2021·Frontiers in Immunology
DOI 10.3389/fimmu.2021.678355PMC PMC8311559
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Abstract

Chronic inflammation plays an important role in the development of metabolic diseases. These include obesity, type 2 diabetes mellitus, and metabolic dysfunction-associated fatty liver disease. The proinflammatory environment maintained by the innate immunity, including macrophages and related cytokines, can be influenced by adaptive immunity. The function of T helper 17 (Th17) and regulatory T (Treg) cells in this process has attracted attention. The Th17/Treg balance is regulated by inflammatory cytokines and various metabolic factors, including those associated with cellular energy metabolism. The possible underlying mechanisms include metabolism-related signaling pathways and epigenetic regulation. Several studies conducted on human and animal models have shown marked differences in and the important roles of Th17/Treg in chronic inflammation associated with obesity and metabolic diseases. Moreover, Th17/Treg seems to be a bridge linking the gut microbiota to host metabolic disorders. In this review, we have provided an overview of the alterations in and the functions of the Th17/Treg balance in metabolic diseases and its role in regulating immune response-related glucose and lipid metabolism.

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Figure 1 Th17/Treg balance regulated by the cytokine microenvironment and cellular metabolic signaling pathways. Naïve CD4+ T cells may differentiate into T helper cells (proinflammatory Th17 or anti-inflammatory Treg cells) according to specific cytokine profiles. Th17 cell differentiation can be induced by IL-6, IL-21, IL-23, IL-1β, and TGF-β. The proinflammatory cytokines IL-6, IL-21, and IL-23 activate STAT3 to induce RORC gene expression and stimulate T cells towards Th17 cell differentiation. RORγt promotes the expression of specific genes (e.g., CCR6, CD161, IL17a, IL17f, and IL23r) to maintain the phenotype and function of Th17 cells. mTOR is activated by PI3K/Akt signaling after T cell receptor activation and co-stimulation along with naïve T cells. mTOR stimulates HIF-1 to support glycolysis and is indispensable for driving the Th17 phenotype. Additionally, the fatty acid biosynthetic pathway has been shown to regulate Th17 cell differentiation and function. The reverse is true for Treg cell differentiation. IL-2 and TGF-β promote Treg cell differentiation during the development of Treg cells, for which Foxp3 is indispensable. AMPK inhibits mTOR activity and promotes Foxp3-induced OXPHOS and FAO, which allow Treg cells to produce ATP and to generate energy. TGF-β is a developmental factor shared by Th17 and Treg cells and its function is dependent on the coexisting cytokines. Th17, T helper 17; Treg, regulatory T; APC, antigen-presenting cell; IL, interleukin; TGF, transforming growth factor; TCR, T cell receptor; PPP, pentose phosphate pathway; PEP, phosphoenolpyruvate; Lac, lactate; Pyr, pyruvate; α-KG, alpha ketoglutarate; TCA, tricarboxylic acid; FA, fatty acid; PI3K, phosphatidylinositol 3-kinase; Akt, protein kinase B; STAT3, signal transducer and activator of transcription 3; RORγt, retinoid acid-related orphan receptor γt; mTOR, mammalian target of rapamycin; HIF-1, hypoxia inducible factor 1; Foxp3, forkhead box protein P3; AMPK, AMP-activated protein kinase; OXPHOS, oxidative phosphorylation; FAO, fatty acid oxidation.
Figure 1 Th17/Treg balance regulated by the cytokine microenvironment and cellular metabolic signaling pathways. Naïve CD4+ T cells may differentiate into T helper cells (proinflammatory Th17 or anti-inflammatory Treg cells) according to specific cytokine profiles. Th17 cell differentiation can be induced by IL-6, IL-21, IL-23, IL-1β, and TGF-β. The proinflammatory cytokines IL-6, IL-21, and IL-23 activate STAT3 to induce RORC gene expression and stimulate T cells towards Th17 cell differentiation. RORγt promotes the expression of specific genes (e.g., CCR6, CD161, IL17a, IL17f, and IL23r) to maintain the phenotype and function of Th17 cells. mTOR is activated by PI3K/Akt signaling after T cell receptor activation and co-stimulation along with naïve T cells. mTOR stimulates HIF-1 to support glycolysis and is indispensable for driving the Th17 phenotype. Additionally, the fatty acid biosynthetic pathway has been shown to regulate Th17 cell differentiation and function. The reverse is true for Treg cell differentiation. IL-2 and TGF-β promote Treg cell differentiation during the development of Treg cells, for which Foxp3 is indispensable. AMPK inhibits mTOR activity and promotes Foxp3-induced OXPHOS and FAO, which allow Treg cells to produce ATP and to generate energy. TGF-β is a developmental factor shared by Th17 and Treg cells and its function is dependent on the coexisting cytokines. Th17, T helper 17; Treg, regulatory T; APC, antigen-presenting cell; IL, interleukin; TGF, transforming growth factor; TCR, T cell receptor; PPP, pentose phosphate pathway; PEP, phosphoenolpyruvate; Lac, lactate; Pyr, pyruvate; α-KG, alpha ketoglutarate; TCA, tricarboxylic acid; FA, fatty acid; PI3K, phosphatidylinositol 3-kinase; Akt, protein kinase B; STAT3, signal transducer and activator of transcription 3; RORγt, retinoid acid-related orphan receptor γt; mTOR, mammalian target of rapamycin; HIF-1, hypoxia inducible factor 1; Foxp3, forkhead box protein P3; AMPK, AMP-activated protein kinase; OXPHOS, oxidative phosphorylation; FAO, fatty acid oxidation.CC BY · PubMed Central
Figure 2 The alterations in and the roles of the Th17/Treg balance in metabolic disorders. Excess nutrition can result in the development of obesity and metabolic dysfunction-associated fatty liver disease, and this phenomenon is reportedly influenced by the gut microbiota. This results in the development of insulin resistance, diabetes, metabolic syndrome, and related cardiovascular complications (their relationships were showed by blue arrows). In obesity, adipocytes can secrete proinflammatory cytokines, including IL-6, to increase the number of Th17 cells. Th17 cells stimulate macrophages towards an inflammatory signaling cascade. IL-17 secreted by Th17 cells targets adipocytes and participates in the proinflammatory signaling. IL-21 secreted by Th17 cells can inhibit Treg cell differentiation and function. The decreased number of Treg cells in visceral adipose tissues is inversely correlated with the body mass index and plasma leptin levels. Increased release of free fatty acids by white adipose tissue causes hepatocyte injury and leads to the synthesis of proinflammatory cytokines. IL-17A increases cytokine production in hepatocytes and macrophages, thereby inducing steatosis and fibrosis. M1 macrophages can inhibit the function of Treg cells via ROS-induced apoptosis. TGF-β and IL-10 secreted by Treg cells are involved in the exertion of anti-inflammatory effects. The intestinal microbiota is essential for the development of obesity and plays an important role in regulating NAFLD progression. Translocation of bacteria and bacterial products activates inflammasomes and stimulates proinflammatory cytokines to cause a shift in the Th17/Treg balance. Lactobacillus reuteri, Bacteroides fragilis, Bacteroides thetaiotaomicron, Clostridium, and Faecalibacterium prausnitzii promote Treg cell differentiation. Segmented filamentous bacteria are necessary for the development of the gut Th17 cells. SCFAs, as metabolites of microbes such as acetate-, propionate-, and butyrate-producing microbes, can limit Th17 cell and promote Treg cell differentiation. Bile acid transformation mediated by the gut bacteria can increase Foxp3 expression in Treg cells. Th17, T helper 17; Treg, regulatory T; IL, interleukin; TGF, transforming growth factor; SCFA, short-chain fatty acid; PSA, polysaccharide A; HDAC, histone deacetylase; JNK, c-Jun N-terminal kinase; FAS, fatty acid synthesis; TNF-α, tumor necrosis factor alpha; IR, insulin resistance; T2DM, type 2 diabetes mellitus; NAFLD, non-alcoholic fatty liver disease; ROS, reactive oxygen species; IFN-γ, interferon gamma.
Figure 2 The alterations in and the roles of the Th17/Treg balance in metabolic disorders. Excess nutrition can result in the development of obesity and metabolic dysfunction-associated fatty liver disease, and this phenomenon is reportedly influenced by the gut microbiota. This results in the development of insulin resistance, diabetes, metabolic syndrome, and related cardiovascular complications (their relationships were showed by blue arrows). In obesity, adipocytes can secrete proinflammatory cytokines, including IL-6, to increase the number of Th17 cells. Th17 cells stimulate macrophages towards an inflammatory signaling cascade. IL-17 secreted by Th17 cells targets adipocytes and participates in the proinflammatory signaling. IL-21 secreted by Th17 cells can inhibit Treg cell differentiation and function. The decreased number of Treg cells in visceral adipose tissues is inversely correlated with the body mass index and plasma leptin levels. Increased release of free fatty acids by white adipose tissue causes hepatocyte injury and leads to the synthesis of proinflammatory cytokines. IL-17A increases cytokine production in hepatocytes and macrophages, thereby inducing steatosis and fibrosis. M1 macrophages can inhibit the function of Treg cells via ROS-induced apoptosis. TGF-β and IL-10 secreted by Treg cells are involved in the exertion of anti-inflammatory effects. The intestinal microbiota is essential for the development of obesity and plays an important role in regulating NAFLD progression. Translocation of bacteria and bacterial products activates inflammasomes and stimulates proinflammatory cytokines to cause a shift in the Th17/Treg balance. Lactobacillus reuteri, Bacteroides fragilis, Bacteroides thetaiotaomicron, Clostridium, and Faecalibacterium prausnitzii promote Treg cell differentiation. Segmented filamentous bacteria are necessary for the development of the gut Th17 cells. SCFAs, as metabolites of microbes such as acetate-, propionate-, and butyrate-producing microbes, can limit Th17 cell and promote Treg cell differentiation. Bile acid transformation mediated by the gut bacteria can increase Foxp3 expression in Treg cells. Th17, T helper 17; Treg, regulatory T; IL, interleukin; TGF, transforming growth factor; SCFA, short-chain fatty acid; PSA, polysaccharide A; HDAC, histone deacetylase; JNK, c-Jun N-terminal kinase; FAS, fatty acid synthesis; TNF-α, tumor necrosis factor alpha; IR, insulin resistance; T2DM, type 2 diabetes mellitus; NAFLD, non-alcoholic fatty liver disease; ROS, reactive oxygen species; IFN-γ, interferon gamma.CC BY · PubMed Central

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Metadata

Authors
Zhang, S., Gang, X., Yang, S., Cui, M., Sun, L., Li, Z., & Wang, G.
Affiliations
First Hospital of Jilin University (CN)
Corresponding author
  • Li, Zhuo
  • Wang, Guixia
ORCID
Venue
Frontiers in Immunology
Publisher
Frontiers Media SA
Published
2021-07-12
Volume
12
Pages
678355-678355
ISSN
1664-3224 (ISSN-L)
DOI
10.3389/fimmu.2021.678355
PMC
PMC8311559
OpenAlex
W3178963741
Cited by
263
References
150
Citations by year
2026: 49 · 2025: 97 · 2024: 46 · 2023: 43 · 2022: 26 · 2021: 2
FWCI
4.48
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Immunology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • People's Government of Jilin Province
  • Department of Science and Technology of Jilin Province (20170623005TC)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
  • Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Keywords
Th17/Treg balance, regulatory T cells, Th17 cells, chronic inflammation, metabolic disorders, obesity, type 2 diabetes, non-alcoholic fatty liver disease, innate immunity, macrophages, inflammatory cytokines, energy metabolism, epigenetic regulation, gut microbiota, glucose metabolism, lipid metabolism
MeSH terms
Animals, Disease Susceptibility, Humans, Inflammation, Lymphocyte Activation, Metabolic Diseases, Signal Transduction, Biomarkers, Cytokines, Lymphocyte Count, Adipogenesis, T-Lymphocytes, Regulatory, Th17 Cells, Cellular Microenvironment

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