bims-aditis Biomed News
on Adipose tissue, inflammation, immunometabolism
Issue of 2022‒05‒29
fourteen papers selected by
Matthew C. Sinton, University of Glasgow
  1. Adipocytes behaving like immune cells.
  2. Nutrients and the Circadian Clock: A Partnership Controlling Adipose Tissue Function and Health.
  3. The Yin and Yang of IL-17 in Systemic Sclerosis.
  4. Real-Time Measurement of Energy Metabolism Over Circadian Time Using Indirect Calorimetry-Enabled Metabolic Cages.
  5. Serine and arginine rich splicing factor 1 deficiency alters pathways involved in IL-17A expression and is implicated in human psoriasis.
  6. Fatty Acid Metabolism and T Cells in Multiple Sclerosis.
  7. A Mechanistic Insight into the Pathogenic Role of Interleukin 17A in Systemic Autoimmune Diseases.
  8. Differential metabolic requirement governed by transcription factor c-Maf dictates innate γδT17 effector functionality in mice and humans.
  9. Epigenetic regulation of T cell exhaustion.
  10. Circadian rhythm of lipid metabolism.
  11. γδ T cells license immature B cells to produce a broad range of polyreactive antibodies.
  12. IL-17A Is the Critical Cytokine for Liver and Spleen Amyloidosis in Inflammatory Skin Disease.
  13. Metabolic regulation of type 2 immune response during tissue repair and regeneration.
  14. Cumulative host energetic costs of soil-transmitted helminth infection.
  1. Nat Immunol. 2022 May 27.
    Adipocytes behaving like immune cells.
    Nicholas J Bernard.
      
    DOI:  https://doi.org/10.1038/s41590-022-01236-9
  2. Nutrients. 2022 May 16. pii: 2084. [Epub ahead of print]14(10):
    Nutrients and the Circadian Clock: A Partnership Controlling Adipose Tissue Function and Health.
    Aleix Ribas-Latre, Kristin Eckel-Mahan.
      White adipose tissue (WAT) is a metabolic organ with flexibility to retract and expand based on energy storage and utilization needs, processes that are driven via the coordination of different cells within adipose tissue. WAT is comprised of mature adipocytes (MA) and cells of the stromal vascular cell fraction (SVF), which include adipose progenitor cells (APCs), adipose endothelial cells (AEC) and infiltrating immune cells. APCs have the ability to proliferate and undergo adipogenesis to form MA, the main constituents of WAT being predominantly composed of white, triglyceride-storing adipocytes with unilocular lipid droplets. While adiposity and adipose tissue health are controlled by diet and aging, the endogenous circadian (24-h) biological clock of the body is highly active in adipose tissue, from adipocyte progenitor cells to mature adipocytes, and may play a unique role in adipose tissue health and function. To some extent, 24-h rhythms in adipose tissue rely on rhythmic energy intake, but individual circadian clock proteins are also thought to be important for healthy fat. Here we discuss how and why the clock might be so important in this metabolic depot, and how temporal and qualitative aspects of energy intake play important roles in maintaining healthy fat throughout aging.
    Keywords:  adipose progenitor cells; adipose tissue; circadian rhythms
    DOI:  https://doi.org/10.3390/nu14102084
  3. Front Immunol. 2022 ;13 885609
    The Yin and Yang of IL-17 in Systemic Sclerosis.
    Lanxuan Wei, David Abraham, Voon Ong.
      IL-17 (IL-17A) is a pro-inflammatory cytokine produced by a sub-set of T helper cells termed Th17 cells primarily in response to cytokines like TGF-β and IL-23 and play an important role in host defense. IL-17 signals via the IL-17RA/RC heterodimer and the adaptor protein Act1 to activate both canonical and non-canonical pathways inducing transcriptional activation and stabilization of mRNAs. IL-17 appears to act not directly on immune cells but stimulates stromal cells such as endothelial and epithelial cells and fibroblasts to secrete other immunomodulatory factors. Fibroblast activated by IL-17 can support the growth and differentiation of immune cells. Studies have begun to uncover a dual role for IL-17; on one hand enhancing immune reactions and promoting inflammatory diseases and on the other decreasing responses and immune activity in established disease settings. The balance of double-edged sword effect of IL-17 and autoimmunity is illustrated in a variety of human diseases and experimental models of diseases. Specifically, the emerging interest in autoimmunity in systemic sclerosis (Scleroderma, SSc) has led to potential role of IL-17A as a target therapy in this disease.
    Keywords:  IL-17; IL-17A; fibrosis; inflammation; systemic sclerosis
    DOI:  https://doi.org/10.3389/fimmu.2022.885609
  4. Methods Mol Biol. 2022 ;2482 301-310
    Real-Time Measurement of Energy Metabolism Over Circadian Time Using Indirect Calorimetry-Enabled Metabolic Cages.
    Kevin B Koronowski, Paolo Sassone-Corsi.
      Indirect calorimetry probes the relationship between fuel consumed and energy produced, and in doing so provides an estimation of whole-body energy expenditure and fuel preference. When assayed continuously in real-time, rhythms appear and illuminate the temporal regulation of energy metabolism by the circadian clock. Here we describe a method for recording circadian energy metabolism in mice using indirect calorimetry-enabled metabolic cages, encompassing mouse entrainment, experimental design, data acquisition and analysis, troubleshooting of common problems, and important considerations. This method is adaptable to the end user's equipment and serves as an effective tool to study, for example, mutant mice, dietary interventions, drug treatments, or circadian disruption.
    Keywords:  Circadian clock; Circadian rhythm; Energy metabolism; In vivo recording; Indirect calorimetry; Metabolic cage; Real-time recording
    DOI:  https://doi.org/10.1007/978-1-0716-2249-0_20
  5. Clin Immunol. 2022 May 22. pii: S1521-6616(22)00122-X. [Epub ahead of print] 109041
    Serine and arginine rich splicing factor 1 deficiency alters pathways involved in IL-17A expression and is implicated in human psoriasis.
    Shi Su, Xanthi-Lida Katopodi, Yered H Pita-Juarez, Emanual Maverakis, Ioannis S Vlachos, Iannis E Adamopoulos.
      Serine and Arginine Rich Splicing Factor 1 (SRSF1) is a splicing factor that binds to exonic enhancers and stimulates splicing and is previously implicated with autoimmunity. Herein, we investigate the role of SRSF1 in regulating innate immune functions that are pertinent in the pathogenesis of auto-inflammatory diseases. Specifically, we show that conditional deletion of SRSF1 in mature lymphocytes resulted in higher expression of il-17a and il-17 f and an expansion of IL17A+ CD8 T cells. Mechanistically, the aberrant expression of IL-17A in SRSF1 cKO mice could not be attributed to alternative splicing of il-17a or il-17 f genes but possibly to defective CD11B+LY6C+ myeloid derived suppressor function in the spleen. Finally, meta-analysis of RNA-Seq collected from psoriasis patients demonstrate a clear correlation between SRSF1 and psoriasis that suggests a putative role of SRSF1 in IL-17A-induced psoriasis.
    Keywords:  Alternative splicing; Autoimmunity; Il-17; Psoriasis; SRSF1
    DOI:  https://doi.org/10.1016/j.clim.2022.109041
  6. Front Immunol. 2022 ;13 869197
    Fatty Acid Metabolism and T Cells in Multiple Sclerosis.
    Saige L Pompura, David A Hafler, Margarita Dominguez-Villar.
      Cellular metabolic remodeling is intrinsically linked to the development, activation, differentiation, function, and survival of T cells. T cells transition from a catabolic, naïve state to an anabolic effector state upon T cell activation. Subsequently, specialization of T cells into T helper (Th) subsets, including regulatory T cells (Treg), requires fine-tuning of metabolic programs that better support and optimize T cell functions for that particular environment. Increasingly, studies have shown that changes in nutrient availability at both the cellular and organismal level during disease states can alter T cell function, highlighting the importance of better characterizing metabolic-immune axes in both physiological and disease settings. In support of these data, a growing body of evidence is emerging that shows specific lipid species are capable of altering the inflammatory functional phenotypes of T cells. In this review we summarize the metabolic programs shown to support naïve and effector T cells, and those driving Th subsets. We then discuss changes to lipid profiles in patients with multiple sclerosis, and focus on how the presence of specific lipid species can alter cellular metabolism and function of T cells.
    Keywords:  T cell; T regulatory (Treg) cell; fatty acids; immunometabolism; multiple sclerosis
    DOI:  https://doi.org/10.3389/fimmu.2022.869197
  7. Mediators Inflamm. 2022 ;2022 6600264
    A Mechanistic Insight into the Pathogenic Role of Interleukin 17A in Systemic Autoimmune Diseases.
    Radjesh Bisoendial, Erik Lubberts.
      Interleukin 17A (IL-17A) has been put forward as a strong ally in our fight against invading pathogens across exposed epithelial surfaces by serving an antimicrobial immunosurveillance role in these tissues to protect the barrier integrity. Amongst other mechanisms that prevent tissue injury mediated by potential microbial threats and promote restoration of epithelial homeostasis, IL-17A attracts effector cells to the site of inflammation and support the host response by driving the development of ectopic lymphoid structures. Accumulating evidence now underscores an integral role of IL-17A in driving the pathophysiology and clinical manifestations in three potentially life-threatening autoimmune diseases, namely, systemic lupus erythematosus, Sjögren's syndrome, and systemic sclerosis. Available studies provide convincing evidence that the abundance of IL-17A in target tissues and its prime source, which is T helper 17 cells (Th17) and double negative T cells (DNT), is not an innocent bystander but in fact seems to be prerequisite for organ pathology. In this regard, IL-17A has been directly implicated in critical steps of autoimmunity. This review reports on the synergistic interactions of IL-17A with other critical determinants such as B cells, neutrophils, stromal cells, and the vasculature that promote the characteristic immunopathology of these autoimmune diseases. The summary of observations provided by this review may have empowering implications for IL-17A-based strategies to prevent clinical manifestations in a broad spectrum of autoimmune conditions.
    DOI:  https://doi.org/10.1155/2022/6600264
  8. Sci Adv. 2022 May 27. 8(21): eabm9120
    Differential metabolic requirement governed by transcription factor c-Maf dictates innate γδT17 effector functionality in mice and humans.
    Xu Chen, Yihua Cai, Xiaoling Hu, Chuanlin Ding, Liqing He, Xiang Zhang, Fuxiang Chen, Jun Yan.
      Cellular metabolism has been proposed to govern distinct γδ T cell effector functions, but the underlying molecular mechanisms remain unclear. We show that interleukin-17 (IL-17)-producing γδ T (γδT17) and interferon-γ (IFN-γ)-producing γδ T (γδT1) cells have differential metabolic requirements and that the rate-limiting enzyme isocitrate dehydrogenase 2 (IDH2) acts as a metabolic checkpoint for their effector functions. Intriguingly, the transcription factor c-Maf regulates γδT17 effector function through direct regulation of IDH2 promoter activity. Moreover, mTORC2 affects the expression of c-Maf and IDH2 and subsequent IL-17 production in γδ T cells. Deletion of c-Maf in γδ T cells reduces metastatic lung cancer development, suggesting c-Maf as a potential target for cancer immune therapy. We show that c-Maf also controls IL-17 production in human γδ T cells from peripheral blood and in oral cancers. These results demonstrate a critical role of the transcription factor c-Maf in regulating γδT17 effector function through IDH2-mediated metabolic reprogramming.
    DOI:  https://doi.org/10.1126/sciadv.abm9120
  9. Nat Immunol. 2022 May 27.
    Epigenetic regulation of T cell exhaustion.
    Julia A Belk, Bence Daniel, Ansuman T Satpathy.
      Chronic antigen stimulation during viral infections and cancer can lead to T cell exhaustion, which is characterized by reduced effector function and proliferation, and the expression of inhibitory immune checkpoint receptors. Recent studies have demonstrated that T cell exhaustion results in wholescale epigenetic remodeling that confers phenotypic stability to these cells and prevents T cell reinvigoration by checkpoint blockade. Here, we review foundational technologies to profile the epigenome at multiple scales, including mapping the locations of transcription factors and histone modifications, DNA methylation and three-dimensional genome conformation. We discuss how these technologies have elucidated the development and epigenetic regulation of exhausted T cells and functional implications across viral infection, cancer, autoimmunity and engineered T cell therapies. Finally, we cover emerging multi-omic and genome engineering technologies, current and upcoming opportunities to apply these to T cell exhaustion, and therapeutic opportunities for T cell engineering in the clinic.
    DOI:  https://doi.org/10.1038/s41590-022-01224-z
  10. Biochem Soc Trans. 2022 May 23. pii: BST20210508. [Epub ahead of print]
    Circadian rhythm of lipid metabolism.
    Flore Sinturel, Weronika Spaleniak, Charna Dibner.
      Lipids comprise a diverse group of metabolites that are indispensable as energy storage molecules, cellular membrane components and mediators of inter- and intra-cellular signaling processes. Lipid homeostasis plays a crucial role in maintaining metabolic health in mammals including human beings. A growing body of evidence suggests that the circadian clock system ensures temporal orchestration of lipid homeostasis, and that perturbation of such diurnal regulation leads to the development of metabolic disorders comprising obesity and type 2 diabetes. In view of the emerging role of circadian regulation in maintaining lipid homeostasis, in this review, we summarize the current knowledge on lipid metabolic pathways controlled by the mammalian circadian system. Furthermore, we review the emerging connection between the development of human metabolic diseases and changes in lipid metabolites that belong to major classes of lipids. Finally, we highlight the mechanisms underlying circadian organization of lipid metabolic rhythms upon the physiological situation, and the consequences of circadian clock dysfunction for dysregulation of lipid metabolism.
    Keywords:  T2D; circadian clock; lipid metabolism; lipidomics; metabolic disorders
    DOI:  https://doi.org/10.1042/BST20210508
  11. Cell Rep. 2022 May 24. pii: S2211-1247(22)00627-1. [Epub ahead of print]39(8): 110854
    γδ T cells license immature B cells to produce a broad range of polyreactive antibodies.
    Francesca Rampoldi, Elisa Donato, Leon Ullrich, Malte Deseke, Anika Janssen, Abdi Demera, Inga Sandrock, Anja Bubke, Anna-Lena Juergens, Maxine Swallow, Tim Sparwasser, Christine Falk, Likai Tan, Andreas Trumpp, Immo Prinz.
      Immature autoreactive B cells are present in all healthy individuals, but it is unclear which signals are required for their maturation into antibody-producing cells. Inducible depletion of γδ T cells show that direct interaction between γδ T cells and immature B cells in the spleen support an "innate" transition to mature B cells with a broad range of antigen specificities. IL-4 production of γδ T cells and cell-to-cell contact via CD30L support B cell maturation and induce genes of the unfolded protein response and mTORC1 signaling. Eight days after in vivo depletion of γδ T cells, increased numbers of B cells are already stuck in the transitional phase and express increased levels of IgD and CD21. Absence of γδ T cells leads also to reduced levels of serum anti-nuclear autoantibodies, making γδ T cells an attractive target to treat autoimmunity.
    Keywords:  CP: Immunology; IL-4; autoimmunity; innate help; polyreactive antibodies; transitional B cells; γδ T cells
    DOI:  https://doi.org/10.1016/j.celrep.2022.110854
  12. Int J Mol Sci. 2022 May 20. pii: 5726. [Epub ahead of print]23(10):
    IL-17A Is the Critical Cytokine for Liver and Spleen Amyloidosis in Inflammatory Skin Disease.
    Shohei Iida, Takehisa Nakanishi, Fumiyasu Momose, Masako Ichishi, Kento Mizutani, Yoshiaki Matsushima, Ai Umaoka, Makoto Kondo, Koji Habe, Yoshifumi Hirokawa, Masatoshi Watanabe, Yoichiro Iwakura, Yoshihiro Miyahara, Yasutomo Imai, Keiichi Yamanaka.
      Systemic amyloidosis is recognized as a serious complication of rheumatoid arthritis or inflammatory bowel disease, but also of inflammatory skin disease. However, the detailed molecular mechanism of amyloidosis associated with cutaneous inflammation remains unclear, and therapeutic approaches are limited. Here, we investigated the pathophysiology of amyloidosis secondary to cutaneous inflammation and the therapeutic effects of Janus kinase (JAK) inhibitors by examining a mouse model of spontaneous dermatitis (KCASP1Tg mice). Moreover, KCASP1Tg mice were crossed with interleukin-17A (IL-17A) knockout mice to generate IL-17A-/KCASP1Tg and examine the role of IL-17A in amyloidosis under cutaneous inflammation. KCASP1Tg mice showed severe amyloid deposition in the liver and spleen. Increased serum-neutral fat levels and decreased lymphocyte production were observed in the spleen. Overproduction of amyloidosis was partially ameliorated by the administration of JAK inhibitors and was further improved in IL-17A-/KCASP1Tg mice. IL-17A-producing cells included CD4, gamma delta, and CD8 T cells. In summary, our results from the analysis of a mouse model of dermatitis revealed that skin-derived inflammatory cytokines can induce amyloid deposition in the liver and spleen, and that the administration of JAK inhibitors and, even more, IL-17A ablation, reduced amyloidosis. This study demonstrates that active control of skin inflammation is essential to prevent internal organ amyloidosis.
    Keywords:  IL-17A; JAK inhibitor; amyloidosis; cytokine; dermatitis; inflammatory skin; mouse model
    DOI:  https://doi.org/10.3390/ijms23105726
  13. J Leukoc Biol. 2022 May 23.
    Metabolic regulation of type 2 immune response during tissue repair and regeneration.
    Tian Ding, Shaohua Ge.
      Type 2 immune responses are mediated by the cytokines interleukin (IL)-4, IL-5, IL-10, and IL-13 and associated cell types, including T helper (Th)2 cells, group 2 innate lymphoid cells (ILC2s), basophils, mast cells, eosinophils, and IL-4- and IL-13-activated macrophages. It can suppress type 1-driven autoimmune diseases, promote antihelminth immunity, maintain cellular metabolic homeostasis, and modulate tissue repair pathways following injury. However, when type 2 immune responses become dysregulated, they can be a significant pathogenesis of many allergic and fibrotic diseases. As such, there is an intense interest in studying the pathways that modulate type 2 immune response so as to identify strategies of targeting and controlling these responses for tissue healing. Herein, we review recent literature on the metabolic regulation of immune cells initiating type 2 immunity and immune cells involved in the effector phase, and talk about how metabolic regulation of immune cell subsets contribute to tissue repair. At last, we discuss whether these findings can provide a novel prospect for regenerative medicine.
    Keywords:  immune cell; immunomodulation; metabolic regulation; tissue repair; type 2 immunity
    DOI:  https://doi.org/10.1002/JLB.3MR0422-665R
  14. Trends Parasitol. 2022 May 19. pii: S1471-4922(22)00103-9. [Epub ahead of print]
    Cumulative host energetic costs of soil-transmitted helminth infection.
    Theresa E Gildner, Tara J Cepon-Robins, Samuel S Urlacher.
      The health consequences of soil-transmitted helminth (STH) infections are often attributed to parasite-caused tissue damage and nutrient loss, combined with immune energy costs. However, this view overlooks additional pathways by which infection can alter host energetics. Here, we take a first step toward defining this suite of energetic pathways and clarifying their cumulative impact on health. We consider how STH characteristics and human variation influence host-parasite interactions, as well as the initial and downstream energetic costs of infection. We conclude by discussing how complex biological, cultural, and temporal factors may affect host energetics, and explore promising avenues for future research. Our goal is to provide an integrative framework for more comprehensively measuring and addressing the energetic consequences of STH infection.
    Keywords:  energy expenditure; energy trade-offs; intestinal worms; metabolism; parasitic disease
    DOI:  https://doi.org/10.1016/j.pt.2022.04.007
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