bims-adipim 2023-08-06 papers

bims-adipim

Biomed News

on Adipose immunity and immunometabolism

Issue of 2023‒08‒06
twelve papers selected by
Matthew C. Sinton, University of Glasgow

Inhibition of the serotonin transporter induces dysfunction of human brown adipose tissue.
Ketolysis drives CD8+ T cell effector function through effects on histone acetylation.
Interleukin-17A Promotes Proliferation and Osteogenic Differentiation of Human Ligamentum Flavum Cells Through Regulation of β-Catenin Signaling.
RNA-Seq and ATAC-Seq analyses reveal a global transcriptional and chromatin accessibility profiling of γδ T17 differentiation from mouse spleen.
Lipocalin-2 promotes adipose-macrophage interactions to shape peripheral and central inflammatory responses in experimental autoimmune encephalomyelitis.
The serotonin transporter sustains human brown adipose tissue thermogenesis.
Lipid Metabolic Regulatory Crosstalk Between Cancer Cells and Tumor-Associated Macrophages.
Interleukin 17 signaling supports clinical benefit of dual CTLA-4 and PD-1 checkpoint inhibition in melanoma.
Type I interferons drive MAIT cell functions against bacterial pneumonia.
Interleukin-17-targeted treatment in patients with spondyloarthritis and associated cardiometabolic risk profile.
Mesenchymal stem cells modulate IL-17 and IL-9 production induced by Th17-inducing cytokine conditions in autoimmune arthritis: an explorative analysis.
Role of mitochondria-bound HK2 in rheumatoid arthritis fibroblast-like synoviocytes.

Nat Metab. 2023 Aug 03.

Inhibition of the serotonin transporter induces dysfunction of human brown adipose tissue.

DOI: https://doi.org/10.1038/s42255-023-00851-6
Immunity. 2023 Jul 20. pii: S1074-7613(23)00314-X. [Epub ahead of print]

Ketolysis drives CD8+ T cell effector function through effects on histone acetylation.

Katarzyna M Luda, Joseph Longo, Susan M Kitchen-Goosen, Lauren R Duimstra, Eric H Ma, McLane J Watson, Brandon M Oswald, Zhen Fu, Zachary Madaj, Ariana Kupai, Bradley M Dickson, Lisa M DeCamp, Michael S Dahabieh, Shelby E Compton, Robert Teis, Irem Kaymak, Kin H Lau, Daniel P Kelly, Patrycja Puchalska, Kelsey S Williams, Connie M Krawczyk, Dominique Lévesque, François-Michel Boisvert, Ryan D Sheldon, Scott B Rothbart, Peter A Crawford, Russell G Jones.

  Environmental nutrient availability influences T cell metabolism, impacting T cell function and shaping immune outcomes. Here, we identified ketone bodies (KBs)-including β-hydroxybutyrate (βOHB) and acetoacetate (AcAc)-as essential fuels supporting CD8+ T cell metabolism and effector function. βOHB directly increased CD8+ T effector (Teff) cell cytokine production and cytolytic activity, and KB oxidation (ketolysis) was required for Teff cell responses to bacterial infection and tumor challenge. CD8+ Teff cells preferentially used KBs over glucose to fuel the tricarboxylic acid (TCA) cycle in vitro and in vivo. KBs directly boosted the respiratory capacity and TCA cycle-dependent metabolic pathways that fuel CD8+ T cell function. Mechanistically, βOHB was a major substrate for acetyl-CoA production in CD8+ T cells and regulated effector responses through effects on histone acetylation. Together, our results identify cell-intrinsic ketolysis as a metabolic and epigenetic driver of optimal CD8+ T cell effector responses.

Keywords:  CD8(+) T cells; TCA cycle; acetyl-CoA; cancer immunology; effector function; epigenetics; ketolysis; ketone bodies; metabolism

DOI:  https://doi.org/10.1016/j.immuni.2023.07.002
Spine (Phila Pa 1976). 2023 Aug 04.

Interleukin-17A Promotes Proliferation and Osteogenic Differentiation of Human Ligamentum Flavum Cells Through Regulation of β-Catenin Signaling.

Jialiang Lin, Shuai Jiang, Qian Xiang, Yongzhao Zhao, Longjie Wang, Dongwei Fan, Woquan Zhong, Chuiguo Sun, Zhongqiang Chen, Weishi Li.

STUDY DESIGN: Basic experimental study.OBJECTIVE: To elucidate the role and mechanism of IL-17A in thoracic ossification of the ligamentum flavum (TOLF).
SUMMARY OF BACKGROUND DATA: TOLF is characterized by the replacement of the thoracic ligamentum flavum with ossified tissue and is one of the leading causes of thoracic spinal stenosis. IL-17A is an important member of the IL-17 family that has received widespread attention for its key contributions to the regulation of bone metabolism and heterotopic ossification. However, it is unclear whether IL-17A is involved in TOLF.
METHODS: Cell counting kit-8 assay and 5-Ethynyl-2'-deoxyuridine staining were performed to assess the proliferation of ligamentum flavum cells (LFCs). Alkaline phosphatase activity assay, Alizarin red staining, and protein level expression of osteogenic-related genes were used to evaluate the osteogenic differentiation potential of LFCs. The effect of IL-17A on the proliferation and osteogenic differentiation of LFCs was further assessed after silencing β-catenin by transfection with siRNA. In addition, the possible source of IL-17A was further demonstrated by co-culture assays of T helper 17 (Th17) cells with LFCs. Student's t test (t-test) was used for comparisons between groups and the one-way analysis of variance (ANOVA) followed by Tukey's post hoc test was used for comparison of more than two groups.
RESULTS: IL-17A was elevated in TOLF tissue compared to normal ligamentum flavum. IL-17A stimulation promoted the proliferation and osteogenic differentiation of LFCs derived from TOLF patients. We found that IL-17A promoted the proliferation and osteogenic differentiation of LFCs by regulating the β-catenin signaling. Co-culture of Th17 cells with LFCs enhanced β-catenin signaling-mediated proliferation and osteogenic differentiation of LFCs. However, these effects were markedly attenuated after the neutralization of IL-17A.
CONCLUSIONS: This is the first work we are aware of to highlight the importance of IL-17A in TOLF. IL-17A secreted by Th17 cells in the ligamentum flavum may be involved in ossification of the microenvironment by regulating β-catenin signaling to promote proliferation and osteogenic differentiation of LFCs.

DOI: https://doi.org/10.1097/BRS.0000000000004789
Immunobiology. 2023 Jul 05. pii: S0171-2985(23)03537-4. [Epub ahead of print]228(5): 152461

RNA-Seq and ATAC-Seq analyses reveal a global transcriptional and chromatin accessibility profiling of γδ T17 differentiation from mouse spleen.

Nanxi Shi, Yawen Zhang, Yunting Liang, Yiming Chen, Yu Huang, Xichun Xia, Zonghua Liu, Zhenhua Li, Fang Huang.

  IL-17A-producing γδ T cells (γδ T17) are known to play important roles in various autoimmune diseases. However, the molecular mechanisms of γδ T17 differentiation and their functions have not been clarified yet. Here, we sorted IL-17A+ Vγ4, IL-17A- Vγ4, and Vγ1 subsets from mouse spleen by in vitro priming of γδ T17 cells and investigated their differentially expressed genes (DEGs) and differentially accessible regions (DARs) using RNA-seq and ATAC-seq, respectively. Our results showed that DEGs-1 (upregulated genes: 677 and downregulated genes: 821) and DEGs-2 (upregulated genes: 1188 and downregulated genes: 1252) were most closely related to the function and differentiation of peripheral γδ T17. We identified key modules and MCODEs involved in the control of IL-17A+ Vγ4, IL-17A- Vγ4, and Vγ1 subsets using the WGCNA and Metascape analysis. Furthermore, 26 key transcription factors were enriched in three subsets, which contributed to deciphering the potential molecular mechanism driving γδ T17 differentiation. Simultaneously, we conducted chromatin accessibility profiling under γδ T17 differentiation by ATAC-seq. The top six candidate genes were screened for γδ T17 differentiation and function by integrating RNA-seq and ATAC-seq analysis, and the results were further confirmed using RT-qPCR, flow cytometry, and western blot. In addition, the association analysis of candidate genes with the RNA-seq database of psoriasis was performed to elucidate the functional relationship. Our findings provided a novel insight into understanding the molecular mechanisms of γδ T17 differentiation and function and may improve to the development of therapeutic approaches or drugs targeting γδ T17 for autoimmune diseases.

Keywords:  ATAC-seq; Autoimmune diseases; Psoriasis; RNA-seq; γδ T17

DOI:  https://doi.org/10.1016/j.imbio.2023.152461
Mol Metab. 2023 Jul 28. pii: S2212-8778(23)00117-5. [Epub ahead of print] 101783

Lipocalin-2 promotes adipose-macrophage interactions to shape peripheral and central inflammatory responses in experimental autoimmune encephalomyelitis.

Francesca Sciarretta, Veronica Ceci, Marta Tiberi, Fabio Zaccaria, Haoyun Li, Zhong-Yan Zhou, Qiyang Sun, Daniels Konja, Alessandro Matteocci, Anup Bhusal, Martina Verri, Diego Fresegna, Sara Balletta, Andrea Ninni, Marco Rosina, Kyoungho Suk, Diego Centonze, Yu Wang, Valerio Chiurchiù, Katia Aquilano, Daniele Lettieri-Barbato.

  Accumulating evidence suggests that dysfunctional adipose tissue (AT) plays a major role in the risk of developing multiple sclerosis (MS), the most common immune-mediated and demyelinating disease of the central nervous system. However, the contribution of adipose tissue to the etiology and progression of MS is still obscure. This study aimed at deciphering the responses of AT in experimental autoimmune encephalomyelitis (EAE), the best characterized animal model of MS. We observed a significant AT loss in EAE mice at the onset of disease, with a significant infiltration of M1-like macrophages and fibrosis in the AT, resembling a cachectic phenotype. Through an integrative and multilayered approach, we identified lipocalin2 (LCN2) as the key molecule released by dysfunctional adipocytes through redox-dependent mechanism. Adipose-derived LCN2 shapes the pro-inflammatory macrophage phenotype, and the genetic deficiency of LCN2 specifically in AT reduced weight loss as well as inflammatory macrophage infiltration in spinal cord in EAE mice. Mature adipocytes downregulating LCN2 reduced lipolytic response to inflammatory stimuli (e.g. TNFα) through an ATGL-mediated mechanism. Overall data highlighted a role LCN2 in exacerbating inflammatory phenotype in EAE model, suggesting a pathogenic role of dysfunctional AT in MS.

Keywords:  adipocyte; adipose tissue; cachexia; immune cells; lipid metabolism; macrophages; mitochondria

DOI:  https://doi.org/10.1016/j.molmet.2023.101783
Nat Metab. 2023 Aug 03.

The serotonin transporter sustains human brown adipose tissue thermogenesis.

Karla J Suchacki, Lynne E Ramage, T'ng Choong Kwok, Alexandra Kelman, Ben T McNeill, Stewart Rodney, Matthew Keegan, Calum Gray, Gillian MacNaught, Dilip Patel, Alison M Fletcher, Joanna P Simpson, Roderick N Carter, Robert K Semple, Natalie Z M Homer, Nicholas M Morton, Edwin J R van Beek, Sonia J Wakelin, Roland H Stimson.

Activation of brown adipose tissue (BAT) in humans is a strategy to treat obesity and metabolic disease. Here we show that the serotonin transporter (SERT), encoded by SLC6A4, prevents serotonin-mediated suppression of human BAT function. RNA sequencing of human primary brown and white adipocytes shows that SLC6A4 is highly expressed in human, but not murine, brown adipocytes and BAT. Serotonin decreases uncoupled respiration and reduces uncoupling protein 1 via the 5-HT2B receptor. SERT inhibition by the selective serotonin reuptake inhibitor (SSRI) sertraline prevents uptake of extracellular serotonin, thereby potentiating serotonin's suppressive effect on brown adipocytes. Furthermore, we see that sertraline reduces BAT activation in healthy volunteers, and SSRI-treated patients demonstrate no 18F-fluorodeoxyglucose uptake by BAT at room temperature, unlike matched controls. Inhibition of BAT thermogenesis may contribute to SSRI-induced weight gain and metabolic dysfunction, and reducing peripheral serotonin action may be an approach to treat obesity and metabolic disease.

DOI: https://doi.org/10.1038/s42255-023-00839-2
DNA Cell Biol. 2023 Aug 03.

Lipid Metabolic Regulatory Crosstalk Between Cancer Cells and Tumor-Associated Macrophages.

Shu Liu, Ying Ying Shen, Li Yang Yin, Jianghua Liu, Xuyu Zu.

  In the tumor microenvironment, tumor-associated macrophages (TAMs) are one of the most abundant cell populations, playing key roles in tumorigenesis, chemoresistance, immune evasion, and metastasis. There is an important interaction between TAMs and cancer cells: on the one hand, tumors control the function of infiltrating macrophages, contributing to reprogramming of TAMs, and on the other hand, TAMs affect the growth of cancer cells. This review focuses on lipid metabolism changes in the complex relationship between cancer cells and TAMs. We discuss how lipid metabolism in cancer cells affects macrophage phenotypic and metabolic changes and, subsequently, how altered lipid metabolism of TAMs influences tumor progression. Identifying the metabolic changes that influence the complex interaction between tumor cells and TAMs is also an important step in exploring new therapeutic approaches that target metabolic reprogramming of immune cells to enhance their tumoricidal potential and bypass therapy resistance. Our work may provide new targets for antitumor therapies.

Keywords:  cancer cells; lipid metabolism; targeting therapy; tumor-associated macrophages

DOI:  https://doi.org/10.1089/dna.2023.0071
Nat Cancer. 2023 Jul 31.

Interleukin 17 signaling supports clinical benefit of dual CTLA-4 and PD-1 checkpoint inhibition in melanoma.

Renáta Váraljai, Lisa Zimmer, Yahya Al-Matary, Paulien Kaptein, Lea J Albrecht, Batool Shannan, Jan C Brase, Daniel Gusenleitner, Teresa Amaral, Nina Wyss, Jochen Utikal, Lukas Flatz, Florian Rambow, Hans Christian Reinhardt, Jenny Dick, Daniel R Engel, Susanne Horn, Selma Ugurel, Wiebke Sondermann, Elisabeth Livingstone, Antje Sucker, Annette Paschen, Fang Zhao, Jan M Placke, Jasmin M Klose, Wolfgang P Fendler, Daniela S Thommen, Iris Helfrich, Dirk Schadendorf, Alexander Roesch.

Recent studies suggest that BRAFV600-mutated melanomas in particular respond to dual anti-programmed cell death protein 1 (PD-1) and anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4) immune checkpoint inhibition (ICI). Here we identified an over-representation of interleukin (IL)-17-type 17 helper T (TH17) gene expression signatures (GES) in BRAFV600-mutated tumors. Moreover, high baseline IL-17 GES consistently predicted clinical responses in dual-ICI-treated patient cohorts but not in mono anti-CTLA-4 or anti-PD-1 ICI cohorts. High IL-17 GES corresponded to tumor infiltration with T cells and neutrophils. Accordingly, high neutrophil infiltration correlated with clinical response specifically to dual ICI, and tumor-associated neutrophils also showed strong IL-17-TH17 pathway activity and T cell activation capacity. Both the blockade of IL-17A and the depletion of neutrophils impaired dual-ICI response and decreased T cell activation. Finally, high IL-17A levels in the blood of patients with melanoma indicated a higher global TH17 cytokine profile preceding clinical response to dual ICI but not to anti-PD-1 monotherapy, suggesting a future role as a biomarker for patient stratification.

DOI: https://doi.org/10.1038/s43018-023-00610-2
J Exp Med. 2023 10 02. pii: e20230037. [Epub ahead of print]220(10):

Type I interferons drive MAIT cell functions against bacterial pneumonia.

Juan Carlos López-Rodríguez, Steven J Hancock, Kelin Li, Stefania Crotta, Christopher Barrington, Alejandro Suárez-Bonnet, Simon L Priestnall, Jeffrey Aubé, Andreas Wack, Paul Klenerman, Jose A Bengoechea, Patricia Barral.

Mucosal-associated invariant T (MAIT) cells are abundant in the lung and contribute to host defense against infections. During bacterial infections, MAIT cell activation has been proposed to require T cell receptor (TCR)-mediated recognition of antigens derived from the riboflavin synthesis pathway presented by the antigen-presenting molecule MR1. MAIT cells can also be activated by cytokines in an MR1-independent manner, yet the contribution of MR1-dependent vs. -independent signals to MAIT cell functions in vivo remains unclear. Here, we use Klebsiella pneumoniae as a model of bacterial pneumonia and demonstrate that MAIT cell activation is independent of MR1 and primarily driven by type I interferons (IFNs). During Klebsiella infection, type I IFNs stimulate activation of murine and human MAIT cells, induce a Th1/cytotoxic transcriptional program, and modulate MAIT cell location within the lungs. Consequently, adoptive transfer or boosting of pulmonary MAIT cells protect mice from Klebsiella infection, with protection being dependent on direct type I IFN signaling on MAIT cells. These findings reveal type I IFNs as new molecular targets to manipulate MAIT cell functions during bacterial infections.

DOI: https://doi.org/10.1084/jem.20230037
Front Immunol. 2023 ;14 1203372

Interleukin-17-targeted treatment in patients with spondyloarthritis and associated cardiometabolic risk profile.

Rubén Queiro, Elena Aurrecoechea, Sara Alonso Castro, Ignacio Villa Blanco, Anahy Brandy-Garcia, Raquel Linge.

  Spondyloarthritis is a group of immune-mediated rheumatic disorders that significantly impact patients' physical function and quality of life. Patients with spondyloarthritis experience a greater prevalence of cardiometabolic disorders, such as obesity, hypertension, dyslipidemia and diabetes mellitus, and these comorbidities are associated with increased spondyloarthritis disease activity and risk of cardiovascular events. This narrative review summarizes the evidence for a physiological link between inflammatory status and cardiometabolic comorbidities in spondyloarthritis, as well as the impact of interleukin (IL)-17 blockade versus other molecular mechanisms in patients with cardiometabolic conditions. The IL-23/IL-17 axis plays a pivotal role in the pathophysiology of spondyloarthritis by promoting inflammation and tissue remodeling at the affected joints and entheses. The importance of the IL-23/IL-17 signaling cascade in underlying sub-clinical inflammation in common cardiometabolic disorders suggests the existence of shared pathways between these processes and spondyloarthritis pathophysiology. Thus, a bidirectional relationship exists between the effects of biologic drugs and patients' cardiometabolic profile, which must be considered during treatment decision making. Biologic therapy may induce changes in patients' cardiometabolic status and cardiometabolic conditions may conversely impact the clinical response to biologic therapy. Available evidence regarding the impact of IL-17 blockade with secukinumab on cardiometabolic parameters suggests this drug does not interfere with traditional cardiovascular risk markers and could be associated with a decreased risk of cardiovascular events. Additionally, the efficacy and retention rates of secukinumab do not appear to be negatively affected by obesity, with some studies reporting a positive impact on clinical outcomes, contrary to that described with other approaches, such as tumor necrosis factor blockade. In this article, we also review evidence for this bidirectional association with other treatments for spondyloarthritis. Current evidence suggests that IL-17-targeted therapy with secukinumab is highly effective in spondyloarthritis patients with cardiometabolic comorbidities and may provide additional cardiometabolic benefits.

Keywords:  biologic therapy; cardiometabolic comorbidities; interleukin-17A; metabolic syndrome; obesity; psoriatic arthritis; secukinumab; spondyloarthritis

DOI:  https://doi.org/10.3389/fimmu.2023.1203372
Adv Rheumatol. 2023 Jul 31. 63(1): 37

Mesenchymal stem cells modulate IL-17 and IL-9 production induced by Th17-inducing cytokine conditions in autoimmune arthritis: an explorative analysis.

Maximilian Riekert, Giovanni Almanzar, Marc Schmalzing, Norbert Schütze, Franz Jakob, Martina Prelog.

  BACKGROUND: The importance of proinflammatory T-cells and their cytokine production in patients with autoimmune arthritis has been widely described. Due to their immunomodulatory properties, mesenchymal stem cells (MSCs) have come into focus as a potential therapeutic concept. The aim of this study was to investigate the influence of MSCs on the phenotype, cytokine profile, and functionality of naive and non-naive CD4+ T-cells from healthy donors (HD) and patients with autoimmune arthritis under Th17-cytokine polarizing conditions in an explorative way using a transwell system prohibiting any cell-cell-contact.METHODS: Magnetically isolated naive and non-naive CD4+ T-cells were stimulated under Th17-polarizing proinflammatory cytokine conditions in presence and absence of bone marrow derived mesenchymal stromal cells (MSCs). After an incubation period of 6 days, the proportions of the T-cell subpopulations TEMRA (CD45RA+CD27-), memory (CD45RA-CD27+), effector (CD45RA-CD27-) and naive cells (CD45RA+CD27+) were determined. Quantitative immunofluorescence intensity was used as a measure for IL-9, IL-17 and IFN-γ production in each subpopulation.
RESULTS: In isolated naive CD4+ T-cells from HD and patients, MSCs suppressed the differentiation of naive towards an effector phenotype while memory and naive cells showed higher percentages in culture with MSCs. In patients, MSCs significantly decreased the proportion of IL-9 and IL-17 producing effector T-cells. MSCs also reduced IFN-γ production in the naive and memory phenotype from HD.
CONCLUSION: The results of the study indicate significant immunomodulatory properties of MSCs, as under Th17-polarizing conditions MSCs are still able to control T-cell differentiation and proinflammatory cytokine production in both HD and patients with autoimmune arthritis.

Keywords:  Arthritis; Mesenchymal stem cell; T lymphocytes

DOI:  https://doi.org/10.1186/s42358-023-00317-z
Front Immunol. 2023 ;14 1103231

Role of mitochondria-bound HK2 in rheumatoid arthritis fibroblast-like synoviocytes.

Alyssa Torres, Sarah Kang, Christopher B Mahony, Martha Cedeño, Patricia G Oliveira, Marta Fernandez-Bustamante, Samuel Kemble, Teresina Laragione, Percio S Gulko, Adam P Croft, Elsa Sanchez-Lopez, Shigeki Miyamoto, Monica Guma.

  Background: Glucose metabolism, specifically, hexokinase 2 (HK2), has a critical role in rheumatoid arthritis (RA) fibroblast-like synoviocyte (FLS) phenotype. HK2 localizes not only in the cytosol but also in the mitochondria, where it protects mitochondria against stress. We hypothesize that mitochondria-bound HK2 is a key regulator of RA FLS phenotype.Methods: HK2 localization was evaluated by confocal microscopy after FLS stimulation. RA FLSs were infected with Green fluorescent protein (GFP), full-length (FL)-HK2, or HK2 lacking its mitochondrial binding motif (HK2ΔN) expressing adenovirus (Ad). RA FLS was also incubated with methyl jasmonate (MJ; 2.5 mM), tofacitinib (1 µM), or methotrexate (1 µM). RA FLS was tested for migration and invasion and gene expression. Gene associations with HK2 expression were identified by examining single-cell RNA sequencing (scRNA-seq) data from murine models of arthritis. Mice were injected with K/BxN serum and given MJ. Ad-FLHK2 or Ad-HK2ΔN was injected into the knee of wild-type mice.
Results: Cobalt chloride (CoCl2) and platelet-derived growth factor (PDGF) stimulation induced HK2 mitochondrial translocation. Overexpression of the HK2 mutant and MJ incubation reversed the invasive and migrative phenotype induced by FL-HK2 after PDGF stimulation, and MJ also decreased the expression of C-X-C Motif Chemokine Ligand 1 (CXCL1) and Collagen Type I Alpha 1 Chain (COL1A1). Of interest, tofacitinib but not methotrexate had an effect on HK2 dissociation from the mitochondria. In murine models, MJ treatment significantly decreased arthritis severity, whereas HK2FL was able to induce synovial hypertrophy as opposed to HK2ΔN.
Conclusion: Our results suggest that mitochondrial HK2 regulates the aggressive phenotype of RA FLS. New therapeutic approaches to dissociate HK2 from mitochondria offer a safer approach than global glycolysis inhibition.

Keywords:  FLS; glucose metabolism; hexokinase; mitochondria; rheumatoid arthritis

DOI:  https://doi.org/10.3389/fimmu.2023.1103231