bims-aditis Biomed News
on Adipose tissue, inflammation, immunometabolism
Issue of 2021–10–17
nine papers selected by
Matthew C. Sinton, University of Glasgow
  1. CREG1 administration stimulates BAT thermogenesis and improves diet-induced obesity in mice.
  2. Neutralization of IL-17 and treatment with IL-2 protects septic arthritis by regulating free radical production and antioxidant enzymes in Th17 and Tregs: An immunomodulatory TLR2 versus TNFR response.
  3. REV-ERB agonist suppresses IL-17 production in γδT cells and improves psoriatic dermatitis in a mouse model.
  4. RORγt protein modifications and IL-17-mediated inflammation.
  5. IL-33 Enhances IFNγ and TNFα Production by Human MAIT Cells: A New Pro-Th1 Effect of IL-33.
  6. Metabolic Messengers: tumour necrosis factor.
  7. Adipokines as Immune Cell Modulators in Multiple Sclerosis.
  8. Proinflammatory cytokines promote TET2-mediated DNA demethylation during CD8 T cell effector differentiation.
  9. Excessive fat expenditure in cachexia is associated with dysregulated circadian rhythm: a review.
  1. J Biochem. 2021 Oct 14. pii: mvab106. [Epub ahead of print]
    CREG1 administration stimulates BAT thermogenesis and improves diet-induced obesity in mice.
    Tatsuya Kusudo, Tadashi Okada, Michihiro Hashimoto, Tamaki Takeuchi, Yuki Endo, Ayumi Niwa, Hitoshi Yamashita.
      Brown and beige adipocytes, which express thermogenic uncoupling protein-1 (UCP1), stimulate glucose and lipid metabolism, improving obesity and metabolic diseases such as type 2 diabetes and hyperlipidemia. Overexpression of cellular repressor of E1A-stimulated genes 1 (CREG1) promotes adipose tissue browning and inhibits diet-induced obesity (DIO) in mice. In this study, we investigated the effects of CREG1 administration on DIO inhibition and adipose browning. Subcutaneous administration of recombinant CREG1 protein to C57BL/6 mice stimulated UCP1 expression in interscapular brown adipose tissue (IBAT) and improved DIO, glucose tolerance, and fatty liver compared with those in PBS-treated mice. Injection of Creg1-expressing adenovirus into inguinal white adipose tissue (IWAT) significantly increased browning and mRNA expression of beige adipocyte marker genes compared with that in mice injected with control virus. The effect of Creg1 induction on beige adipocyte differentiation was supported in primary culture using preadipocytes isolated from IWAT of Creg1-transgenic mice compared with that of wild-type mice. Our results indicate a therapeutic effect of CREG1 on obesity and its associated pathology and a potential of CREG1 to stimulate brown/beige adipocyte formation.
    Keywords:  BAT; CREG1; UCP1; beige adipocyte; obesity
    DOI:  https://doi.org/10.1093/jb/mvab106
  2. Cell Immunol. 2021 Sep 20. pii: S0008-8749(21)00160-X. [Epub ahead of print]370 104441
    Neutralization of IL-17 and treatment with IL-2 protects septic arthritis by regulating free radical production and antioxidant enzymes in Th17 and Tregs: An immunomodulatory TLR2 versus TNFR response.
    Rituparna Ghosh, Rajen Dey, Ritasha Sawoo, Biswadev Bishayi.
      Septic arthritis is a destructive joint disease caused by Staphylococcus aureus. Synovial inflammation involved Th17 proliferation and down regulation of Treg population, thus resolution of inflammation targeting IL-17 may be important to control arthritis. Endogenous inhibition of IL-17 to regulate arthritic inflammation correlating with Th17/Treg cells TLR2 and TNFRs are not done. The role of SOD, CAT and GRx in relation to ROS production during arthritis along with expression of TLR2, TNFR1/TNFR2 in Th17/Treg cells of mice treated with IL-17A Ab/ IL-2 were studied. Increased ROS, reduced antioxidant enzyme activity was found in Th17 cells of SA infected mice whereas Treg cells of IL-17A Ab/ IL-2 treated group showed opposite effects. Neutralization of IL-17 after arthritis cause decreased TNFR1 and increased TNFR2 expression in Treg cells. Thus, neutralization of IL-17 or IL-2 treatment regulates septic arthritis by enhancing anti-inflammatory properties of Treg via antioxidant balance and modulating TLR2/TNFR response.
    Keywords:  Anti-oxidant enzymes; IL-17 antibody; IL-2; Reactive oxygen species, S. aureus arthritis; T helper 17; T regulatory cells; TLR2 versus TNFR response
    DOI:  https://doi.org/10.1016/j.cellimm.2021.104441
  3. Biomed Pharmacother. 2021 Oct 07. pii: S0753-3322(21)01067-2. [Epub ahead of print]144 112283
    REV-ERB agonist suppresses IL-17 production in γδT cells and improves psoriatic dermatitis in a mouse model.
    Shangyi Wang, Mina Kozai, Hironobu Mita, Zimeng Cai, Md Abdul Masum, Osamu Ichii, Kensuke Takada, Mutsumi Inaba.
      Psoriasis is a chronic inflammatory skin disease characterized by epidermal hyperplasia and cellular infiltration. Studies have shown that disease development depends on proinflammatory cytokines, such as interleukin (IL)-23 and IL-17. It has been suggested that IL-23 produced by innate immune cells, such as macrophages, stimulates a subset of helper T cells to release IL-17, promoting neutrophil recruitment and keratinocyte proliferation. However, recent studies have revealed the crucial role of γδT cells in psoriasis pathogenesis as the primary source of dermal IL-17. The nuclear receptors REV-ERBs are ligand-dependent transcription factors recognized as circadian rhythm regulators. REV-ERBs negatively regulate IL-17-producing helper T cells, whereas the involvement of REV-ERBs in regulating IL-17-producing γδT (γδT17) cells remains unclear. Here we revealed the regulatory mechanism involving γδT17 cells through REV-ERBs. γδT17 cell levels were remarkably elevated in the secondary lymphoid organs of mice that lacked an isoform of REV-ERBs. A synthetic REV-ERB agonist, SR9009, suppressed γδT17 cells in vitro and in vivo. Topical application of SR9009 to the skin reduced the inflammatory symptoms of psoriasiform dermatitis in mice. The results of this study provide a novel therapeutic approach for psoriasis targeting REV-ERBs in γδT17 cells.
    Keywords:  IL-17; Nuclear receptor; Psoriasis; REV-ERB; γδT cells
    DOI:  https://doi.org/10.1016/j.biopha.2021.112283
  4. Trends Immunol. 2021 Oct 09. pii: S1471-4906(21)00181-2. [Epub ahead of print]
    RORγt protein modifications and IL-17-mediated inflammation.
    Ritesh Kumar, Arianne L Theiss, K Venuprasad.
      RORγt, the master transcription factor for cytokine interleukin (IL)-17, is expressed explicitly in Th17 cells, γδT cells, and type 3 innate lymphoid cells in mice and humans. Since dysregulated IL-17 expression is strongly linked to several human inflammatory diseases, the RORγt-IL-17 axis has been the focus of intense research. Recently, several studies have shown that RORγt is modified by multiple post-translational mechanisms, including ubiquitination, acetylation, SUMOylation, and phosphorylation. This review discusses how post-translational modifications modulate RORγt function and its turnover to regulate IL-17-driven inflammation. Broad knowledge of these pathways is crucial for a clear understanding of the pathogenic role of RORγt+IL-17+ cells and for the development of putative therapeutic strategies to target IL-17-driven diseases such as multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, and inflammatory bowel disease.
    Keywords:  IL-17; RORγt; Th17; autoimmune diseases; post-translational modifications
    DOI:  https://doi.org/10.1016/j.it.2021.09.005
  5. Int J Mol Sci. 2021 Sep 30. pii: 10602. [Epub ahead of print]22(19):
    IL-33 Enhances IFNγ and TNFα Production by Human MAIT Cells: A New Pro-Th1 Effect of IL-33.
    Mourad Azzout, Céline Dietrich, François Machavoine, Pauline Gastineau, Alix Bottier, Guillaume Lezmi, Maria Leite-de-Moraes.
      Mucosal-associated invariant T (MAIT) cells represent a distinct T cell population restricted by the MHC-class-I-related molecule, MR1, which recognizes microbial-derived vitamin B2 (riboflavin) metabolites. Their abundance in humans, together with their ability to promptly produce distinct cytokines including interferon γ (IFNγ) and tumor necrosis factor α (TNFα), are consistent with regulatory functions in innate as well as adaptive immunity. Here, we tested whether the alarmin interleukin 33 (IL-33), which is secreted following inflammation or cell damage, could activate human MAIT cells. We found that MAIT cells stimulated with IL-33 produced high levels of IFNγ, TNFα and Granzyme B (GrzB). The action of IL-33 required IL-12 but was independent of T cell receptor (TCR) cross-linking. MAIT cells expressed the IL-33 receptor ST2 (suppression of tumorigenicity 2) and upregulated Tbet (T-box expressed in T cells) in response to IL-12 or IL-33. Electronically sorted MAIT cells also upregulated the expression of CCL3 (Chemokine C-C motif ligand 3), CD40L (CD40 Ligand), CSF-1 (Colony Stimulating Factor 1), LTA (Lymphotoxin-alpha) and IL-2RA (IL-2 receptor alpha chain) mRNAs in response to IL-33 plus IL-12. In conclusion, IL-33 combined with IL-12 can directly target MAIT cells to induce their activation and cytokine production. This novel mechanism of IL-33 activation provides insight into the mode of action by which human MAIT cells can promote inflammatory responses in a TCR-independent manner.
    Keywords:  IL-12; IL-33; MAIT cells; inflammation; innate-like T cells
    DOI:  https://doi.org/10.3390/ijms221910602
  6. Nat Metab. 2021 Oct 14.
    Metabolic Messengers: tumour necrosis factor.
    Jaswinder K Sethi, Gökhan S Hotamisligil.
      Tumour necrosis factor (TNF) is a classical, pleiotropic pro-inflammatory cytokine. It is also the first 'adipokine' described to be produced from adipose tissue, regulated in obesity and proposed to contribute to obesity-associated metabolic disease. In this review, we provide an overview of TNF in the context of metabolic inflammation or metaflammation, its discovery as a metabolic messenger, its sites and mechanisms of action and some critical considerations for future research. Although we focus on TNF and the studies that elucidated its immunometabolic actions, we highlight a conceptual framework, generated by these studies, that is equally applicable to the complex network of pro-inflammatory signals, their biological activity and their integration with metabolic regulation, and to the field of immunometabolism more broadly.
    DOI:  https://doi.org/10.1038/s42255-021-00470-z
  7. Int J Mol Sci. 2021 Oct 07. pii: 10845. [Epub ahead of print]22(19):
    Adipokines as Immune Cell Modulators in Multiple Sclerosis.
    Merel Rijnsburger, Niek Djuric, Inge A Mulder, Helga E de Vries.
      Multiple sclerosis (MS), a chronic inflammatory and demyelinating disease of the central nervous system (CNS), is a major clinical and societal problem, which has a tremendous impact on the life of patients and their proxies. Current immunomodulatory and anti-inflammatory therapies prove to be relatively effective; however, they fail to concomitantly stop ongoing neurological deterioration and do not reverse acquired disability. The proportion to which genetic and environmental factors contribute to the etiology of MS is still incompletely understood; however, a recent association between MS etiology and obesity was shown, with obesity greatly increasing the risk of developing MS. An altered balance of adipokines, which are white adipose tissue (WAT) hormones, plays an important role in the low-grade chronic inflammation during obesity by their pervasive modification of local and systemic inflammation. Vice versa, inflammatory factors secreted by immune cells affect adipokine function. To explore the role of adipokines in MS pathology, we will here review the reciprocal effects of adipokines and immune cells and summarize alterations in adipokine levels in MS patient cohorts. Finally, we will discuss proof-of-concept studies demonstrating the therapeutic potential of adipokines to target both neuroinflammation and neurodegeneration processes in MS.
    Keywords:  adipokines; demyelination; immunology; multiple sclerosis; neurodegeneration; neuroinflammation; obesity
    DOI:  https://doi.org/10.3390/ijms221910845
  8. Cell Rep. 2021 Oct 12. pii: S2211-1247(21)01256-0. [Epub ahead of print]37(2): 109796
    Proinflammatory cytokines promote TET2-mediated DNA demethylation during CD8 T cell effector differentiation.
    Caitlin C Zebley, Hossam A Abdelsamed, Hazem E Ghoneim, Shanta Alli, Charmaine Brown, Dalia Haydar, Tian Mi, Tarsha Harris, Maureen A McGargill, Giedre Krenciute, Ben Youngblood.
      To gain insight into the signaling determinants of effector-associated DNA methylation programming among CD8 T cells, we explore the role of interleukin (IL)-12 in the imprinting of IFNg expression during CD8 T cell priming. We observe that anti-CD3/CD28-mediated stimulation of human naive CD8 T cells is not sufficient to induce substantial demethylation of the IFNg promoter. However, anti-CD3/CD28 stimulation in the presence of the inflammatory cytokine, IL-12, results in stable demethylation of the IFNg locus that is commensurate with IFNg expression. IL-12-associated demethylation of the IFNg locus is coupled to cell division through TET2-dependent demethylation in an ex vivo human chimeric antigen receptor T cell model system and an in vivo immunologically competent murine system. Collectively, these data illustrate that IL-12 signaling promotes TET2-mediated effector DNA demethylation programming in CD8 T cells and serve as proof of concept that cytokines can guide induction of epigenetically regulated traits for T cell-based immunotherapies.
    Keywords:  cytokines; effector CD8 T cells; epigenetics; inflammation
    DOI:  https://doi.org/10.1016/j.celrep.2021.109796
  9. Nutr Metab (Lond). 2021 Oct 09. 18(1): 89
    Excessive fat expenditure in cachexia is associated with dysregulated circadian rhythm: a review.
    Dufang Ma, Xiao Li, Yongcheng Wang, Lu Cai, Yong Wang.
      Cachexia is a progressive metabolic disorder characterized by the excessive depletion of adipose tissue. This hypermetabolic condition has catastrophic impacts on the survival and quality of life for patients suffering from critical illness. However, efficient therapies to prevent adipose expenditure have not been discovered. It has been established that the circadian clock plays an important role in modulating fat metabolic processes. Recently, an increasing number of studies had provided evidence showing that disrupted circadian rhythm leads to insulin resistance and obesity; however, studies analyzing the relationship between circadian misalignment and adipose tissue expenditure in cachexia are scarce. In the present review, we cover the involvement of the circadian clocks in the regulation of adipogenesis, lipid metabolism and thermogenesis as well as inflammation in white and brown adipose tissue. According to the present review, we conclude that circadian clock disruption is associated with lipid metabolism imbalance and elevated adipose tissue inflammation. Moreover, under cachexia conditions, lipid synthesis and storage processes lost rhythm and decreased, while lipolysis and thermogenesis activities remained high for 24 h. Therefore, disordered circadian clock may be responsible for fat expenditure in cachexia by adversely influencing lipid synthesis/ storage/lipolysis/utilization. Further study needs to be performed to explore the direct interaction between circadian clock and fat expenditure in cachexia, it will likely provide potential efficient drugs for the treatment of fat expenditure in cachexia.
    Keywords:  Adipose tissue expenditure; Brown adipose tissue; Cachexia; Circadian clock; Inflammation; White adipose tissue
    DOI:  https://doi.org/10.1186/s12986-021-00616-6
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