bims-aditis Biomed News
on Adipose tissue, inflammation, immunometabolism
Issue of 2021–11–14
ten papers selected by
Matthew C. Sinton, University of Glasgow
  1. AdipoAtlas: Mapping out human white adipose tissue.
  2. Decreased Frequencies of Gamma/Delta T Cells Expressing Th1/Th17 Cytokine, Cytotoxic, and Immune Markers in Latent Tuberculosis-Diabetes/Pre-Diabetes Comorbidity.
  3. IL-17A injury to retinal ganglion cells is mediated by retinal Müller cells in diabetic retinopathy.
  4. AdipoAtlas: A reference lipidome for human white adipose tissue.
  5. Literature Overview of the IL-17 Inhibition from Psoriasis to COVID-19.
  6. Engineering a variant of IL-17RA with high binding affinity to IL-17A for optimized immunotherapy.
  7. Interleukin-10 improves stroke outcome by controlling the detrimental Interleukin-17A response.
  8. Mitochondria as a Cellular Hub in Infection and Inflammation.
  9. Mitochondrial respiration restricts Listeria monocytogenes infection by slowing down host cell receptor recycling.
  10. Glycogen involved in browning of adipocytes.
  1. Cell Rep Med. 2021 Oct 19. 2(10): 100429
    AdipoAtlas: Mapping out human white adipose tissue.
    Abhijit B Shinde, Elma Zaganjor.
      In this issue of Cell Reports Medicine, Lange and colleagues1 significantly improve lipid identification accuracy, detection, and quantification to provide AdipoAtlas, an in-depth lipidomic profile of human white adipose tissue (WAT). Importantly, they define obesity-mediated lipid alterations, which may provide insight into the etiology of associated diseases.
    DOI:  https://doi.org/10.1016/j.xcrm.2021.100429
  2. Front Cell Infect Microbiol. 2021 ;11 756854
    Decreased Frequencies of Gamma/Delta T Cells Expressing Th1/Th17 Cytokine, Cytotoxic, and Immune Markers in Latent Tuberculosis-Diabetes/Pre-Diabetes Comorbidity.
    Gokul Raj Kathamuthu, Nathella Pavan Kumar, Kadar Moideen, Pradeep A Menon, Subash Babu.
      Antigen-specific gamma-delta (γδ) T cells are important in exhibiting anti-mycobacterial immunity, but their role in latent tuberculosis (LTB) with diabetes mellitus (DM) or pre-DM (PDM) and non-DM comorbidities have not been studied. Thus, we have studied the baseline, mycobacterial (PPD, WCL), and positive control antigen-stimulated γδ T cells expressing Th1 (IFNγ, TNFα, IL-2) and Th17 (IL-17A, IL-17F, IL-22) cytokine as well as cytotoxic (perforin [PFN], granzyme [GZE B], granulysin [GNLSN]) and immune (GMCSF, PD-1, CD69) markers in LTB (DM, PDM, NDM) comorbidities by flow cytometry. In the unstimulated (UNS) condition, we did not observe any significant difference in the frequencies of γδ T cells expressing Th1 and Th17 cytokine, cytotoxic, and immune markers. In contrast, upon PPD antigen stimulation, the frequencies of γδ T cells expressing Th1 (IFNγ, TNFα) and Th17 (IL-17F, IL-22) cytokine, cytotoxic (PFN, GZE B, GNLSN), and immune (CD69) markers were significantly diminished in LTB DM and/or PDM individuals compared to LTB NDM individuals. Similarly, upon WCL antigen stimulation, the frequencies of γδ T cells expressing Th1 (TNFα) and Th17 (IL-17A, IL-22) cytokine, cytotoxic (PFN), and immune (PD-1, CD69) markers were significantly diminished in LTB DM and/or PDM individuals compared to LTB NDM individuals. Finally, upon P/I stimulation we did not observe any significant difference in the γδ T cell frequencies expressing cytokine, cytotoxic, and immune markers between the study populations. The culture supernatant levels of IFNγ, TNFα, and IL-17A cytokines were significantly increased in LTB DM and PDM after stimulation with Mtb antigens compared to LTB NDM individuals. Therefore, diminished γδ T cells expressing cytokine, cytotoxic, and other immune markers and elevated levels of cytokines in the supernatants is a characteristic feature of LTB PDM/DM co-morbidities.
    Keywords:  Th1/Th17 cytokines; cytotoxic and immune markers; diabetes mellitus; latent tuberculosis; pre-diabetes; γδ T cells
    DOI:  https://doi.org/10.3389/fcimb.2021.756854
  3. Cell Death Dis. 2021 Nov 08. 12(11): 1057
    IL-17A injury to retinal ganglion cells is mediated by retinal Müller cells in diabetic retinopathy.
    Ao-Wang Qiu, Da-Rui Huang, Bin Li, Yuan Fang, Wei-Wei Zhang, Qing-Huai Liu.
      Diabetic retinopathy (DR), the most common and serious ocular complication, recently has been perceived as a neurovascular inflammatory disease. However, role of adaptive immune inflammation driven by T lymphocytes in DR is not yet well elucidated. Therefore, this study aimed to clarify the role of interleukin (IL)-17A, a proinflammatory cytokine mainly produced by T lymphocytes, in retinal pathophysiology particularly in retinal neuronal death during DR process. Ins2Akita (Akita) diabetic mice 12 weeks after the onset of diabetes were used as a DR model. IL-17A-deficient diabetic mice were obtained by hybridization of IL-17A-knockout (IL-17A-KO) mouse with Akita mouse. Primarily cultured retinal Müller cells (RMCs) and retinal ganglion cells (RGCs) were treated with IL-17A in high-glucose (HG) condition. A transwell coculture of RGCs and RMCs whose IL-17 receptor A (IL-17RA) gene had been silenced with IL-17RA-shRNA was exposed to IL-17A in HG condition and the cocultured RGCs were assessed on their survival. Diabetic mice manifested increased retinal microvascular lesions, RMC activation and dysfunction, as well as RGC apoptosis. IL-17A-KO diabetic mice showed reduced retinal microvascular impairments, RMC abnormalities, and RGC apoptosis compared with diabetic mice. RMCs expressed IL-17RA. IL-17A exacerbated HG-induced RMC activation and dysfunction in vitro and silencing IL-17RA gene in RMCs abolished the IL-17A deleterious effects. In contrast, RGCs did not express IL-17RA and IL-17A did not further alter HG-induced RGC death. Notably, IL-17A aggravated HG-induced RGC death in the presence of intact RMCs but not in the presence of RMCs in which IL-17RA gene had been knocked down. These findings establish that IL-17A is actively involved in DR pathophysiology and particularly by RMC mediation it promotes RGC death. Collectively, we propose that antagonizing IL-17RA on RMCs may prevent retinal neuronal death and thereby slow down DR progression.
    DOI:  https://doi.org/10.1038/s41419-021-04350-y
  4. Cell Rep Med. 2021 Oct 19. 2(10): 100407
    AdipoAtlas: A reference lipidome for human white adipose tissue.
    Mike Lange, Georgia Angelidou, Zhixu Ni, Angela Criscuolo, Jürgen Schiller, Matthias Blüher, Maria Fedorova.
      Obesity, characterized by expansion and metabolic dysregulation of white adipose tissue (WAT), has reached pandemic proportions and acts as a primer for a wide range of metabolic disorders. Remodeling of WAT lipidome in obesity and associated comorbidities can explain disease etiology and provide valuable diagnostic and prognostic markers. To support understanding of WAT lipidome remodeling at the molecular level, we provide in-depth lipidomics profiling of human subcutaneous and visceral WAT of lean and obese individuals. We generate a human WAT reference lipidome by performing tissue-tailored preanalytical and analytical workflows, which allow accurate identification and semi-absolute quantification of 1,636 and 737 lipid molecular species, respectively. Deep lipidomic profiling allows identification of main lipid (sub)classes undergoing depot-/phenotype-specific remodeling. Previously unanticipated diversity of WAT ceramides is now uncovered. AdipoAtlas reference lipidome serves as a data-rich resource for the development of WAT-specific high-throughput methods and as a scaffold for systems medicine data integration.
    Keywords:  LC-MS/MS; ceramides; human white adipose tissue; lipid identification; lipid metabolism; lipidomics; obesity; plasmalogens; semi-absolute lipid quantification; sphingolipids; subcutaneous white adipose tissue; triacylglycerols; visceral white adipose tissue
    DOI:  https://doi.org/10.1016/j.xcrm.2021.100407
  5. J Inflamm Res. 2021 ;14 5611-5618
    Literature Overview of the IL-17 Inhibition from Psoriasis to COVID-19.
    Yulin Zou, Zudong Meng.
      The COVID-19 pandemic has posed a serious problem for drug anti-viral efficacy in combatting the cytokine storm triggered by SARS-CoV-2. From dermato-epidemiological studies conducted on psoriatic and other rheumatological patients, IL-17 inhibitors seem to attenuate or even prevent the cytokine storm and thus ICU referral. Furthermore, both in-vivo and in-vitro experiments suggest that IL-17 plays a key role in SARS-CoV-2 infection progression. Due to this evidence, we decided to summarize the literature findings on IL-17 inhibitors and COVID-19, maintaining psoriasis as the referral disease to better understand the extent of drug effects on the immune system.
    Keywords:  COVID-19; IL-17; biologics; psoriasis; therapy
    DOI:  https://doi.org/10.2147/JIR.S329252
  6. Biotechnol Rep (Amst). 2021 Dec;32 e00682
    Engineering a variant of IL-17RA with high binding affinity to IL-17A for optimized immunotherapy.
    Fatemeh Armaghan, Zahra Hajihassan.
      Immunotherapy is one of the most recently used treatments for numerous cancer types and also some autoimmune and inflammatory diseases. One of the valuable targets for immunotherapy is Interleukin-17A (IL-17A) or its receptor (IL-17RA) because overexpression of IL-17A as a pro-inflammatory cytokine is associated with several inflammatory, autoimmune and cancer diseases. In this study, the extracellular domain of IL-17RA involved in binding to IL-17A was mutated by using R software to achieve a variant with increased binding affinity to IL-17A. The ∆∆G value of -30.89 kcal/mol was calculated for the best variant (385) with point mutations of R265N, N91T, and W31K using the FoldX module. Also, the KD for its interaction with IL-17A was calculated 0.06 nM by surface plasmon resonance (SPR) technique. Our results indicated that variant 385 could bind to IL-17A with higher binding affinity than wild-type one, so, it can be a good therapeutic candidate for blocking IL-17A.
    Keywords:  E. coli; IL-17A; Immunotherapy; Protein expression
    DOI:  https://doi.org/10.1016/j.btre.2021.e00682
  7. J Neuroinflammation. 2021 Nov 13. 18(1): 265
    Interleukin-10 improves stroke outcome by controlling the detrimental Interleukin-17A response.
    Marius Piepke, Bettina H Clausen, Peter Ludewig, Jonas H Vienhues, Tanja Bedke, Ehsan Javidi, Björn Rissiek, Larissa Jank, Leonie Brockmann, Inga Sandrock, Karoline Degenhardt, Alina Jander, Vanessa Roth, Ines S Schädlich, Immo Prinz, Richard A Flavell, Yasushi Kobayashi, Thomas Renné, Christian Gerloff, Samuel Huber, Tim Magnus, Mathias Gelderblom.
       BACKGROUND: Lymphocytes have dichotomous functions in ischemic stroke. Regulatory T cells are protective, while IL-17A from innate lymphocytes promotes the infarct growth. With recent advances of T cell-subtype specific transgenic mouse models it now has become possible to study the complex interplay of T cell subpopulations in ischemic stroke.
    METHODS: In a murine model of experimental stroke we analyzed the effects of IL-10 on the functional outcome for up to 14 days post-ischemia and defined the source of IL-10 in ischemic brains based on immunohistochemistry, flow cytometry, and bone-marrow chimeric mice. We used neutralizing IL-17A antibodies, intrathecal IL-10 injections, and transgenic mouse models which harbor a deletion of the IL-10R on distinct T cell subpopulations to further explore the interplay between IL-10 and IL-17A pathways in the ischemic brain.
    RESULTS: We demonstrate that IL-10 deficient mice exhibit significantly increased infarct sizes on days 3 and 7 and enlarged brain atrophy and impaired neurological outcome on day 14 following tMCAO. In ischemic brains IL-10 producing immune cells included regulatory T cells, macrophages, and microglia. Neutralization of IL-17A following stroke reversed the worse outcome in IL-10 deficient mice and intracerebral treatment with recombinant IL-10 revealed that IL-10 controlled IL-17A positive lymphocytes in ischemic brains. Importantly, IL-10 acted differentially on αβ and γδ T cells. IL-17A producing CD4+ αβ T cells were directly controlled via their IL-10-receptor (IL-10R), whereas IL-10 by itself had no direct effect on the IL-17A production in γδ T cells. The control of the IL-17A production in γδ T cells depended on an intact IL10R signaling in regulatory T cells (Tregs).
    CONCLUSIONS: Taken together, our data indicate a key function of IL-10 in restricting the detrimental IL-17A-signaling in stroke and further supports that IL-17A is a therapeutic opportunity for stroke treatment.
    Keywords:  Inflammation; Interleukin-10; Interleukin-17; Ischemia; Stroke; T cells
    DOI:  https://doi.org/10.1186/s12974-021-02316-7
  8. Int J Mol Sci. 2021 Oct 20. pii: 11338. [Epub ahead of print]22(21):
    Mitochondria as a Cellular Hub in Infection and Inflammation.
    Pauline Andrieux, Christophe Chevillard, Edecio Cunha-Neto, João Paulo Silva Nunes.
      Mitochondria are the energy center of the cell. They are found in the cell cytoplasm as dynamic networks where they adapt energy production based on the cell's needs. They are also at the center of the proinflammatory response and have essential roles in the response against pathogenic infections. Mitochondria are a major site for production of Reactive Oxygen Species (ROS; or free radicals), which are essential to fight infection. However, excessive and uncontrolled production can become deleterious to the cell, leading to mitochondrial and tissue damage. Pathogens exploit the role of mitochondria during infection by affecting the oxidative phosphorylation mechanism (OXPHOS), mitochondrial network and disrupting the communication between the nucleus and the mitochondria. The role of mitochondria in these biological processes makes these organelle good targets for the development of therapeutic strategies. In this review, we presented a summary of the endosymbiotic origin of mitochondria and their involvement in the pathogen response, as well as the potential promising mitochondrial targets for the fight against infectious diseases and chronic inflammatory diseases.
    Keywords:  infection; infection disease; inflammation; inflammatory disease; mitochondria; mitochondria dysfunction; mitochondrial bioenergetics
    DOI:  https://doi.org/10.3390/ijms222111338
  9. Cell Rep. 2021 Nov 09. pii: S2211-1247(21)01468-6. [Epub ahead of print]37(6): 109989
    Mitochondrial respiration restricts Listeria monocytogenes infection by slowing down host cell receptor recycling.
    Anna Spier, Michael G Connor, Thomas Steiner, Filipe Carvalho, Pascale Cossart, Wolfgang Eisenreich, Timothy Wai, Fabrizia Stavru.
      Mutations in mitochondrial genes impairing energy production cause mitochondrial diseases (MDs), and clinical studies have shown that MD patients are prone to bacterial infections. However, the relationship between mitochondrial (dys)function and infection remains largely unexplored, especially in epithelial cells, the first barrier to many pathogens. Here, we generate an epithelial cell model for one of the most common mitochondrial diseases, Leigh syndrome, by deleting surfeit locus protein 1 (SURF1), an assembly factor for respiratory chain complex IV. We use this genetic model and a complementary, nutrient-based approach to modulate mitochondrial respiration rates and show that impaired mitochondrial respiration favors entry of the human pathogen Listeria monocytogenes, a well-established bacterial infection model. Reversely, enhanced mitochondrial energy metabolism decreases infection efficiency. We further demonstrate that endocytic recycling is reduced in mitochondrial respiration-dependent cells, dampening L. monocytogenes infection by slowing the recycling of its host cell receptor c-Met, highlighting a previously undescribed role of mitochondrial respiration during infection.
    Keywords:  (13)C isotopologue profiling; Listeria monocytogenes; Rab11; endocytic recycling; infection; metabolism; mitochondria; mitochondrial disease; respiration
    DOI:  https://doi.org/10.1016/j.celrep.2021.109989
  10. Nat Rev Endocrinol. 2021 Nov 10.
    Glycogen involved in browning of adipocytes.
    Claire Greenhill.
      
    DOI:  https://doi.org/10.1038/s41574-021-00599-7
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