bims-adipim Biomed News
on Adipose immunity and immunometabolism
Issue of 2023–07–23
eight papers selected by
Matthew C. Sinton, University of Glasgow
  1. Differential effects of sugar and fat on adipose tissue inflammation.
  2. γδ T cell dichotomy with opposing cytotoxic and wound healing functions in human solid tumors.
  3. Obesity accelerates age defects in B cells, and weight loss improves B cell function.
  4. Obesity-induced dysregulation of skin-resident PPARγ+ Treg cells promotes IL-17A-mediated psoriatic inflammation.
  5. An autonomous activation of interleukin-17 receptor signaling sustains inflammation and promotes disease progression.
  6. Bcl-2 supports survival and metabolic fitness of quiescent tissue-resident ILC3.
  7. Tricarboxylic acid (TCA) cycle, sphingolipid, and phosphatidylcholine metabolism are dysregulated in T. gondii infection-induced cachexia.
  8. Infiltrated IL-17A-producing gamma delta T cells play a protective role in sepsis-induced liver injury and are regulated by CCR6 and gut commensal microbes.
  1. iScience. 2023 Jul 21. 26(7): 107163
    Differential effects of sugar and fat on adipose tissue inflammation.
    Tracey Avequin, Kin H Lau, Althea N Waldhart, Hannah Guak, Holly Dykstra, Connie Krawczyk, Ning Wu.
      Obese individuals experience low grade inflammation initiated within their adipose tissue. However, the early events that lead to the release of these inflammatory factors from adipose tissue are poorly characterized. To separate glucose effects from lipid effects on adipose tissue, we used an adipose-specific TXNIP knockout model where excess basal glucose influx into adipocytes led to modest increase in adiposity without using high fat diet. We found an uncoupling of two events that are generally presumed to be coregulated: (1) an increase of adipose tissue macrophage (ATM) number; and (2) pro-inflammatory activation of ATMs. These two events are associated with different triggering signals: elevated free fatty acids output and extracellular matrix remodeling with increased ATM number, whereas decreased adiponectin level with activated ATM. This separation reflects non-overlapping pathways regulated by glucose and lipids in adipocytes, and neither group alone is sufficient to elicit the full inflammatory response in adipose tissue.
    Keywords:  Cell biology; Endocrinology; Immunology
    DOI:  https://doi.org/10.1016/j.isci.2023.107163
  2. Nat Cancer. 2023 Jul 20.
    γδ T cell dichotomy with opposing cytotoxic and wound healing functions in human solid tumors.
    Cathal Harmon, Alexandra Zaborowski, Haim Moore, Pamela St Louis, Karen Slattery, Danielle Duquette, John Scanlan, Harry Kane, Britta Kunkemoeller, Claire L McIntyre, Aine Ni Scannail, Bruce Moran, Ana C Anderson, Des Winter, Donal Brennan, Michael A Brehm, Lydia Lynch.
      γδ T cells are important tissue-resident, innate T cells that are critical for tissue homeostasis. γδ cells are associated with positive prognosis in most tumors; however, little is known about their heterogeneity in human cancers. Here, we phenotyped innate and adaptive cells in human colorectal (CRC) and endometrial cancer. We found striking differences in γδ subsets and function in tumors compared to normal tissue, and in the γδ subsets present in tumor types. In CRC, an amphiregulin (AREG)-producing subset emerges, while endometrial cancer is infiltrated by cytotoxic cells. In humanized CRC models, tumors induced this AREG phenotype in Vδ1 cells after adoptive transfer. To exploit the beneficial roles of γδ cells for cell therapy, we developed an expansion method that enhanced cytotoxic function and boosted metabolic flexibility, while eliminating AREG production, achieving greater tumor infiltration and tumor clearance. This method has broad applications in cellular therapy as an 'off-the-shelf' treatment option.
    DOI:  https://doi.org/10.1038/s43018-023-00589-w
  3. Immun Ageing. 2023 Jul 17. 20(1): 35
    Obesity accelerates age defects in B cells, and weight loss improves B cell function.
    Daniela Frasca, Maria Romero, Alain Diaz, Bonnie B Blomberg.
       BACKGROUND: We have previously shown that obesity accelerates age-associated defects in B cell function and antibody production leading to decreased secretion of protective antibodies and increased autoimmunity. We wanted to evaluate if obese adults enrolled in a voluntary weight reduction program had higher protective and lower autoimmune antibody responses similar to those observed in lean adults.
    METHODS: Experiments were performed using blood isolated from an established cohort of female lean adult and elderly individuals, as well as from the blood of female adults with obesity, before and after a voluntary weight reduction program in which their Body Mass Index (BMI) was reduced 10-34% in 12 months. All participants were vaccinated with the Trivalent Inactivated Influenza vaccine. Serum samples were evaluated for the presence of pro-inflammatory cytokines and adipokines, vaccine-specific antibodies and autoimmune antibodies. We evaluated the composition of the B cell pool by flow cytometry, the expression of RNA for class switch transcription factors and pro-inflammatory markers by qPCR, the in vitro secretion of pro- and anti-inflammatory cytokines and their capacity to induce pro-inflammatory T cells.
    RESULTS: Obesity, similar to aging, induced increased serum levels of pro-inflammatory cytokines and autoimmune antibodies, while vaccine-specific antibodies were reduced. In agreement with the serum results, the B cell pool of obese adults and elderly individuals was enriched in pro-inflammatory B cell subsets and was characterized by higher expression of markers associated with cell senescence, higher levels of T-bet, the transcription factor for autoimmune antibodies and lower levels of E47, the transcription factor associated with protective responses to the influenza vaccine. B cells from obese adults and elderly individuals were also able to secrete inflammatory cytokines and support the generation of inflammatory T cells. All these pro-inflammatory characteristics of B cells from obese individuals were significantly attenuated, but not completely reversed, by weight loss.
    CONCLUSIONS: Although the results from our small observational study show that obesity-induced dysfunctional B cell responses, similar to those occurring during aging, are ameliorated in some but not all obese individuals after weight loss, the effects of body weight loss on mechanistic pathways are largely missing and deserve further investigation.
    Keywords:  Aging; B cells; Humoral immunity; Influenza vaccination; Obesity
    DOI:  https://doi.org/10.1186/s12979-023-00361-9
  4. Immunity. 2023 Jul 14. pii: S1074-7613(23)00278-9. [Epub ahead of print]
    Obesity-induced dysregulation of skin-resident PPARγ+ Treg cells promotes IL-17A-mediated psoriatic inflammation.
    Pulavendran Sivasami, Cody Elkins, Pamela P Diaz-Saldana, Kyndal Goss, Amy Peng, Michael Hamersky, Jennifer Bae, Miaoer Xu, Brian P Pollack, Edwin M Horwitz, Christopher D Scharer, Lindsey Seldin, Chaoran Li.
      Obesity is a major risk factor for psoriasis, but how obesity disrupts the regulatory mechanisms that keep skin inflammation in check is unclear. Here, we found that skin was enriched with a unique population of CD4+Foxp3+ regulatory T (Treg) cells expressing the nuclear receptor peroxisome proliferation-activated receptor gamma (PPARγ). PPARγ drove a distinctive transcriptional program and functional suppression of IL-17A+ γδ T cell-mediated psoriatic inflammation. Diet-induced obesity, however, resulted in a reduction of PPARγ+ skin Treg cells and a corresponding loss of control over IL-17A+ γδ T cell-mediated inflammation. Mechanistically, PPARγ+ skin Treg cells preferentially took up elevated levels of long-chain free fatty acids in obese mice, which led to cellular lipotoxicity, oxidative stress, and mitochondrial dysfunction. Harnessing the anti-inflammatory properties of these PPARγ+ skin Treg cells could have therapeutic potential for obesity-associated inflammatory skin diseases.
    Keywords:  IL-17A; PPARγ; Treg; free fatty acid; high-fat diet; immunometabolism; obesity; psoriasis; skin; γδ T cell
    DOI:  https://doi.org/10.1016/j.immuni.2023.06.021
  5. Immunity. 2023 Jul 13. pii: S1074-7613(23)00269-8. [Epub ahead of print]
    An autonomous activation of interleukin-17 receptor signaling sustains inflammation and promotes disease progression.
    Qiong Luo, Yijun Liu, Ke Shi, Xuecheng Shen, Yaqi Yang, Xuejiao Liang, Liangliang Lu, Wenxuan Qiao, Airu Chen, Dongmei Hong, Yang Sun, Qiang Xu.
      Anti-interleukin-17 (IL-17) therapy has been used in various autoimmune diseases. However, the efficacy is unexpectedly limited in several IL-17-associated diseases, and the mechanism of limited efficacy remains unclear. Here, we show that a molecular complex containing the adaptor molecule Act1 and tyrosine phosphatase SHP2 mediated autonomous IL-17R signaling that accelerated and sustained inflammation. SHP2, aberrantly augmented in various autoimmune diseases, was induced by IL-17A itself in astrocytes and keratinocytes, sustaining chemokine production even upon anti-IL-17 therapies. Mechanistically, SHP2 directly interacted with and dephosphorylated Act1, which replaced Act1-TRAF5 complexes and induced IL-17-independent activation of IL-17R signaling. Genetic or pharmacologic inactivation of SHP2, or blocking Act1-SHP2 interaction, paralyzed both IL-17-induced and IL-17-independent signaling and attenuated primary or relapsing experimental autoimmune encephalomyelitis. Therefore, Act1-SHP2 complexes mediate an alternative pathway for autonomous activation of IL-17R signaling, targeting which could be a therapeutic option for IL-17-related diseases in addition to current antibody therapies.
    Keywords:  Act1; IL-17-related autoimmune diseases; IL-17R signaling; SHP2; dephosphorylation
    DOI:  https://doi.org/10.1016/j.immuni.2023.06.012
  6. Mucosal Immunol. 2023 Jul 13. pii: S1933-0219(23)00053-3. [Epub ahead of print]
    Bcl-2 supports survival and metabolic fitness of quiescent tissue-resident ILC3.
    James I King, Felipe Melo-Gonzalez, Bert Malengier-Devlies, Roser Tachó-Piñot, Marlene S Magalhaes, Suzanne H Hodge, Xavier Romero Ros, Rebecca Gentek, Matthew R Hepworth.
      Group 3 innate lymphoid cells (ILC3) are potent effector cells with critical roles in enforcing immunity, barrier integrity and tissue homeostasis along the gastrointestinal tract. ILC3 are considered primarily tissue-resident cells, seeding the gastrointestinal tract during embryonic stages and early life. However, the mechanisms through which mature ILC3 are maintained within adult tissues are poorly understood. Here, we report that LTi-like ILC3 exhibit minimal turnover in the healthy adult intestinal tract, persist for extended periods of time, and display a quiescent phenotype. Strikingly, during enteric bacterial infection LTi-like ILC3 also exhibit negligible hematopoietic replenishment and remain non-proliferative, despite robustly producing cytokines. Survival of LTi-like ILC3 was found to be dependent upon the balance of the metabolic activity required to drive effector function and anti-apoptotic programs. Notably, the pro-survival protein Bcl-2 was required for the survival of LTi-like ILC3 ex vivo but was rendered partially dispensable if mitochondrial respiration was inhibited. Together we demonstrate LTi-like ILC3 are a tissue-resident, quiescent population that persist independently of haematopoietic replenishment to survive within the intestinal microenvironment.
    Keywords:  Bcl-2; Innate lymphoid cell; intestine; metabolism; survival
    DOI:  https://doi.org/10.1016/j.mucimm.2023.07.001
  7. Heliyon. 2023 Jul;9(7): e17411
    Tricarboxylic acid (TCA) cycle, sphingolipid, and phosphatidylcholine metabolism are dysregulated in T. gondii infection-induced cachexia.
    Tzu-Yu Feng, Stephanie J Melchor, Xiao-Yu Zhao, Haider Ghumman, Mark Kester, Todd E Fox, Sarah E Ewald.
      Cachexia is a life-threatening disease characterized by chronic, inflammatory muscle wasting and systemic metabolic impairment. Despite its high prevalence, there are no efficacious therapies for cachexia. Mice chronically infected with the protozoan parasite Toxoplasma gondii represent a novel animal model recapitulating the chronic kinetics of cachexia. To understand how perturbations to metabolic tissue homeostasis influence circulating metabolite availability we used mass spectrometry analysis. Despite the significant reduction in circulating triacylglycerides, non-esterified fatty acids, and glycerol, sphingolipid long-chain bases and a subset of phosphatidylcholines (PCs) were significantly increased in the sera of mice with T. gondii infection-induced cachexia. In addition, the TCA cycle intermediates α-ketoglutarate, 2-hydroxyglutarate, succinate, fumarate, and malate were highly depleted in cachectic mouse sera. Sphingolipids and their de novo synthesis precursors PCs are the major components of the mitochondrial membrane and regulate mitochondrial function consistent with a causal relationship in the energy imbalance driving T. gondii-induced chronic cachexia.
    Keywords:  Cachexia; Ceramides; Lipid rebound; Liver atrophy; Sphingolipids; TCA cycle; Toxoplasma gondii
    DOI:  https://doi.org/10.1016/j.heliyon.2023.e17411
  8. Front Cell Infect Microbiol. 2023 ;13 1149506
    Infiltrated IL-17A-producing gamma delta T cells play a protective role in sepsis-induced liver injury and are regulated by CCR6 and gut commensal microbes.
    Jian Wan, Qian Zhang, Yilong Hao, Zhang Tao, Wei Song, Song Chen, Long Qin, Weidong Song, Yi Shan.
       Introduction: Sepsis is a common but serious disease in intensive care units, which may induce multiple organ dysfunctions such as liver injury. Previous studies have demonstrated that gamma delta (γδ) T cells play a protective role in sepsis. However, the function and mechanism of γδ T cells in sepsis-induced liver injury have not been fully elucidated. IL-17A-producing γδ T cells are a newly identified cell subtype.
    Methods: We utilized IL-17A-deficient mice to investigate the role of IL-17A-producing γδ T cells in sepsis using the cecum ligation and puncture (CLP) model.
    Results: Our findings suggested that these cells were the major source of IL-17A and protected against sepsis-induced liver injury. Flow cytometry analysis revealed that these γδ T cells expressed Vγ4 TCR and migrated into liver from peripheral post CLP, in a CCR6-dependent manner. When CLP mice were treated with anti-CCR6 antibody to block CCR6-CCL20 axis, the recruitment of Vγ4+ γδ T cells was abolished, indicating a CCR6-dependent manner of migration. Interestingly, pseudo germ-free CLP mice treated with antibiotics showed that hepatic IL-17A+ γδ T cells were regulated by gut commensal microbes. E. coli alone were able to restore the protective effect in pseudo germ-free mice by rescuing hepatic IL-17A+ γδ T cell population.
    Conclusion: Our research has shown that Vγ4+ IL-17A+ γδ T cells infiltrating into the liver play a crucial role in protecting against sepsis-induced liver injury. This protection was contingent upon the recruitment of CCR6 and regulated by gut commensal microbes.
    Keywords:  CCR6; IL-17A; gamma delta T cells; liver injury; microbiota; sepsis
    DOI:  https://doi.org/10.3389/fcimb.2023.1149506
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