bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2021–12–19
twenty papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Analysis of Common Pathways and Markers From Non-Alcoholic Fatty Liver Disease to Immune-Mediated Diseases.
  2. ROCK2 inhibition attenuates profibrogenic immune cell function to reverse thioacetamide-induced liver fibrosis.
  3. Dual role of neutrophils in modulating liver injury and fibrosis during development and resolution of diet-induced murine steatohepatitis.
  4. Modeling human T1D-associated autoimmune processes.
  5. Dietary sugar restriction reduces hepatic de novo lipogenesis in adolescent boys with fatty liver disease.
  6. Smoking cessation reduces systemic inflammation and circulating endothelin-1.
  7. Dynamics of IL-15/IL-15Rα expression in response to HSV-1 infection reveal a novel mode of viral immune evasion counteracted by iNKT cells.
  8. Varied Relationship of Lipid and Lipoprotein Profiles to Liver Fat Content in Phenotypes of Metabolic Associated Fatty Liver Disease.
  9. BACH2 inhibition reverses β cell failure in type 2 diabetes models.
  10. Deletion of SA β-Gal+ cells using senolytics improves muscle regeneration in old mice.
  11. Type III Interferons: Emerging Roles in Autoimmunity.
  12. Enhanced hepatic respiratory capacity and altered lipid metabolism support metabolic homeostasis during short-term hypoxic stress.
  13. Marginal Zinc Deficiency Alters Essential Fatty Acid Metabolism in Healthy Men.
  14. Reduction of peripheral regulatory T cells in active rheumatoid arthritis patients with coronary artery disease.
  15. Dietary sugar restriction reduces hepatic de novo lipogenesis in boys with fatty liver disease.
  16. Soluble CD137 is a novel serum marker of liver cirrhosis in patients with hepatitis C and alcohol-associated disease etiology.
  17. Epigenetic regulation of natural killer cell memory.
  18. Tetracyclines Diminish In Vitro IFN-γ and IL-17-Producing Adaptive and Innate Immune Cells in Multiple Sclerosis.
  19. Recurrent Paravalvular Leak Following Mitral Valve Replacement.
  20. TOX4, an insulin receptor-independent regulator of hepatic glucose production, is activated in diabetic liver.
  1. Front Immunol. 2021 ;12 667354
    Analysis of Common Pathways and Markers From Non-Alcoholic Fatty Liver Disease to Immune-Mediated Diseases.
    Rocío Gallego-Durán, Rocío Montero-Vallejo, Douglas Maya-Miles, Ana Lucena, Franz Martin, Javier Ampuero, Manuel Romero-Gómez.
      Metabolic associated fatty liver disease (MAFLD) is the most prevalent form of liver disease worldwide, accounting for a high liver-related mortality and morbidity with extensive multi-organ involvement. This entity has displaced viral hepatitis as the main cause of severe forms of hepatic diseases, although the onset and transition of MAFLD stages still remains unclear. Nevertheless, innate and adaptive immune responses seem to play an essential role in the establishment and further progression of this disease. The immune system is responsible of safeguard and preserves organs and systems function, and might be altered under different stimuli. Thus, the liver suffers from metabolic and immune changes leading to different injuries and loss of function. It has been stablished that cell-cell crosstalk is a key process in the hepatic homeostasis maintenance. There is mounting evidence suggesting that MAFLD pathogenesis is determined by a complex interaction of environmental, genetic and host factors that leads to a full plethora of outcomes. Therefore, herein we will revisit and discuss the interplay between immune mechanisms and MAFLD, highlighting the potential role of immunological markers in an attempt to clarify its relationship.
    Keywords:  NAFLD; NASH; biomarkers; fibrosis; immunology
    DOI:  https://doi.org/10.3389/fimmu.2021.667354
  2. JHEP Rep. 2022 Jan;4(1): 100386
    ROCK2 inhibition attenuates profibrogenic immune cell function to reverse thioacetamide-induced liver fibrosis.
    Christina Nalkurthi, Wayne A Schroder, Michelle Melino, Katharine M Irvine, Melanie Nyuydzefe, Wei Chen, Jing Liu, Michele W L Teng, Geoffrey R Hill, Patrick Bertolino, Bruce R Blazar, Gregory C Miller, Andrew D Clouston, Alexandra Zanin-Zhorov, Kelli P A MacDonald.
       Background & Aims: Fibrosis, the primary cause of morbidity in chronic liver disease, is induced by pro-inflammatory cytokines, immune cell infiltrates, and tissue resident cells that drive excessive myofibroblast activation, collagen production, and tissue scarring. Rho-associated kinase 2 (ROCK2) regulates key pro-fibrotic pathways involved in both inflammatory reactions and altered extracellular matrix remodelling, implicating this pathway as a potential therapeutic target.
    Methods: We used the thioacetamide-induced liver fibrosis model to examine the efficacy of administration of the selective ROCK2 inhibitor KD025 to prevent or treat liver fibrosis and its impact on immune composition and function.
    Results: Prophylactic and therapeutic administration of KD025 effectively attenuated thioacetamide-induced liver fibrosis and promoted fibrotic regression. KD025 treatment inhibited liver macrophage tumour necrosis factor production and disrupted the macrophage niche within fibrotic septae. ROCK2 targeting in vitro directly regulated macrophage function through disruption of signal transducer and activator of transcription 3 (STAT3)/cofilin signalling pathways leading to the inhibition of pro-inflammatory cytokine production and macrophage migration. In vivo, KDO25 administration significantly reduced STAT3 phosphorylation and cofilin levels in the liver. Additionally, livers exhibited robust downregulation of immune cell infiltrates and diminished levels of retinoic acid receptor-related orphan receptor gamma (RORγt) and B-cell lymphoma 6 (Bcl6) transcription factors that correlated with a significant reduction in liver IL-17, splenic germinal centre numbers and serum IgG.
    Conclusions: As IL-17 and IgG-Fc binding promote pathogenic macrophage differentiation, together our data demonstrate that ROCK2 inhibition prevents and reverses liver fibrosis through direct and indirect effects on macrophage function and highlight the therapeutic potential of ROCK2 inhibition in liver fibrosis.
    Lay summary: By using a clinic-ready small-molecule inhibitor, we demonstrate that selective ROCK2 inhibition prevents and reverses hepatic fibrosis through its pleiotropic effects on pro-inflammatory immune cell function. We show that ROCK2 mediates increased IL-17 production, antibody production, and macrophage dysregulation, which together drive fibrogenesis in a model of chemical-induced liver fibrosis. Therefore, in this study, we not only highlight the therapeutic potential of ROCK2 targeting in chronic liver disease but also provide previously undocumented insights into our understanding of cellular and molecular pathways driving the liver fibrosis pathology.
    Keywords:  ALT, alanine aminotransferase; AST, aspartate aminotransferase; B cells; BMDM, bone marrow-derived macrophages; Bcl6, B-cell lymphoma 6; CLD, chronic liver disease; Col1a2, collagen type α1; DR, ductular reaction; ECM, extracellular matrix; GC, germinal centre; HCC, hepatocellular carcinoma; HSC, hepatic stellate cell; IHC, immunohistochemical; IL-17; Inflammation; LPS, lipopolysaccharide; Liver fibrosis; MMP, matrix metalloproteinase; Macrophages; NASH, non-alcoholic steatohepatitis; RAR, retinoic acid receptor; ROCK, Rho-associated coiled-coil forming protein kinases; ROCK2; ROCK2, Rho-associated kinase 2; RORγt, RAR-related orphan receptor gamma; SR, Sirius red; STAT3, signal transducer and activator of transcription 3; TAA, thioacetamide; TGF-β, transforming growth factor-beta; TNF, tumour necrosis factor; Tfh, T follicular helper; Th17, T helper 17; Therapy; cGVHD, chronic graft-vs-host disease; pCofilin, phosphorylated cofilin; pMac, peritoneal macrophages; pSTAT3, phosphorylated signal transducer and activator of transcription; qRT-PCR, quantitative real-time PCR; α-SMA, alpha smooth muscle actin
    DOI:  https://doi.org/10.1016/j.jhepr.2021.100386
  3. Sci Rep. 2021 Dec 17. 11(1): 24194
    Dual role of neutrophils in modulating liver injury and fibrosis during development and resolution of diet-induced murine steatohepatitis.
    Andrea D Kim, Sung Eun Kim, Aleksandra Leszczynska, Benedikt Kaufmann, Agustina Reca, Dong Joon Kim, Ariel E Feldstein.
      Inflammatory changes in the liver represent a key feature of non-alcoholic steatohepatitis (NASH), the progressive form of non-alcoholic fatty liver disease (NAFLD). Innate immune activation including hepatic neutrophilic infiltration acts as an important inflammatory trigger as well as a potential mediator of inflammation resolution. In this study, we dissected the effects of neutrophil depletion via anti-lymphocyte antigen 6 complex locus G6D (Ly6G) antibodies administration during ongoing high fat-fructose-cholesterol (FFC) diet-induced murine NASH and during inflammation resolution by switching into a low-fat control diet. During NASH progression, protective effects were shown as HSC activation, cell infiltration and activation of pro-inflammatory macrophages were ameliorated. Furthermore, these changes were contrasted with the effects observed when neutrophil depletion was performed during the resolution phase. Impaired resolving mechanisms, such as a failure to balance the pro and anti-inflammatory cytokines ratio, deficient macrophage phenotypic switch into a pro-restorative profile, and defective repair and remodeling processes were observed when neutrophils were depleted in this scenario. This study described phase-dependent contrasting roles of neutrophils as triggers and pro-resolutive mediators of liver injury and fibrosis associated with diet-induced NASH in mice. These findings have important translational implications at the time of designing NASH therapeutic strategies.
    DOI:  https://doi.org/10.1038/s41598-021-03679-w
  4. Mol Metab. 2021 Dec 10. pii: S2212-8778(21)00275-1. [Epub ahead of print] 101417
    Modeling human T1D-associated autoimmune processes.
    Mohsen Khosravi-Maharlooei, Rachel Madley, Chiara Borsotti, Leonardo M R Ferreira, Robert C Sharp, Michael A Brehm, Dale L Greiner, Audrey V Parent, Mark S Anderson, Megan Sykes, Remi J Creusot.
       BACKGROUND: Type 1 diabetes (T1D) is an autoimmune disease characterized by impaired immune tolerance to β-cell antigens and progressive destruction of insulin-producing β-cells. Animal models have provided valuable insights in understanding the etiology and pathogenesis of this disease, but they fall short of reflecting the extensive heterogeneity of the disease in humans, which is contributed by various combinations of risk gene alleles and unique environmental factors. Collectively, these factors have been used to define subgroups of patients, termed endotypes, with distinct predominating disease characteristics.
    SCOPE OF REVIEW: Here, we review the gaps filled by these models in understanding the intricate involvement and regulation of the immune system in human T1D pathogenesis. We describe the various models developed so far and the scientific questions that have been addressed using them. Finally, we discuss the limitations of these models, primarily ascribed to hosting a human immune system in a xenogeneic recipient, and what remains to be done to improve their physiological relevance.
    MAJOR CONCLUSIONS: To understand the role of genetic and environmental factors or evaluate immune-modifying therapies in humans, it is critical to develop and apply models in which human cells can be manipulated and their functions studied under conditions that recapitulate as closely as possible the physiological conditions of the human body. While microphysiological systems and living tissue slices provide some of these conditions, human immune system mice enable more extensive analyses using in vivo systems.
    Keywords:  Autoimmunity; Beta cell destruction; Disease modeling; Humanized mice; In vitro models; Type 1 diabetes
    DOI:  https://doi.org/10.1016/j.molmet.2021.101417
  5. J Clin Invest. 2021 Dec 15. pii: e150996. [Epub ahead of print]131(24):
    Dietary sugar restriction reduces hepatic de novo lipogenesis in adolescent boys with fatty liver disease.
    Catherine C Cohen, Kelvin W Li, Adina L Alazraki, Carine Beysen, Carissa A Carrier, Rebecca L Cleeton, Mohamad Dandan, Janet Figueroa, Jack Knight-Scott, Cynthia J Knott, Kimberly P Newton, Edna M Nyangau, Claude B Sirlin, Patricia A Ugalde-Nicalo, Jean A Welsh, Marc K Hellerstein, Jeffrey B Schwimmer, Miriam B Vos.
      BACKGROUNDHepatic de novo lipogenesis (DNL) is elevated in nonalcoholic fatty liver disease (NAFLD). Improvements in hepatic fat by dietary sugar reduction may be mediated by reduced DNL, but data are limited, especially in children. We examined the effects of 8 weeks of dietary sugar restriction on hepatic DNL in adolescents with NAFLD and correlations between DNL and other metabolic outcomes.METHODSAdolescent boys with NAFLD (n = 29) participated in an 8-week, randomized controlled trial comparing a diet low in free sugars versus their usual diet. Hepatic DNL was measured as percentage contribution to plasma triglyceride palmitate using a 7-day metabolic labeling protocol with heavy water. Hepatic fat was measured by magnetic resonance imaging-proton density fat fraction.RESULTSHepatic DNL was significantly decreased in the treatment group (from 34.6% to 24.1%) versus the control group (33.9% to 34.6%) (adjusted week 8 mean difference: -10.6% [95% CI: -19.1%, -2.0%]), which was paralleled by greater decreases in hepatic fat (25.5% to 17.9% vs. 19.5% to 18.8%) and fasting insulin (44.3 to 34.7 vs. 35.5 to 37.0 μIU/mL). Percentage change in DNL during the intervention correlated significantly with changes in free-sugar intake (r = 0.48, P = 0.011), insulin (r = 0.40, P = 0.047), and alanine aminotransferase (ALT) (r = 0.39, P = 0.049), but not hepatic fat (r = 0.13, P = 0.532).CONCLUSIONOur results suggest that dietary sugar restriction reduces hepatic DNL and fasting insulin, in addition to reductions in hepatic fat and ALT, among adolescents with NAFLD. These results are consistent with the hypothesis that hepatic DNL is a critical metabolic abnormality linking dietary sugar and NAFLD.TRIAL REGISTRYClinicalTrials.gov NCT02513121.FUNDINGThe Nutrition Science Initiative (made possible by gifts from the Laura and John Arnold Foundation, Ambrose Monell Foundation, and individual donors), the UCSD Altman Clinical and Translational Research Institute, the NIH, Children's Healthcare of Atlanta and Emory University's Children's Clinical and Translational Discovery Core, Children's Healthcare of Atlanta and Emory University Pediatric Biostatistical Core, the Georgia Clinical and Translational Science Alliance, and the NIH National Institute of Diabetes, Digestive, and Kidney Disease.
    Keywords:  Carbohydrate metabolism; Hepatology; Insulin; Metabolism; Obesity
    DOI:  https://doi.org/10.1172/JCI150996
  6. Sci Rep. 2021 Dec 16. 11(1): 24122
    Smoking cessation reduces systemic inflammation and circulating endothelin-1.
    Cassandra C Derella, Martha S Tingen, Anson Blanks, Samantha J Sojourner, Matthew A Tucker, Jeffrey Thomas, Ryan A Harris.
      Smoking increases systemic inflammation and circulating endothelin-1 (ET-1), both of which contribute to an elevated risk of cardiovascular disease (CVD). The present study sought to test the hypothesis that a 12-week smoking cessation intervention would contribute to a long-term reduction in circulating ET-1, tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6). 30 individuals participated in a 12-week evidence-based smoking cessation program at Augusta University. Serum cotinine, plasma inflammatory cytokines, and plasma ET-1 were determined at baseline, immediately after the 12-week cessation program (end of treatment, EOT), and 12-months (12M) following the cessation program. Serum cotinine was significantly reduced (p < 0.001) at EOT and 12M following the smoking cessation program. Compared to BL (7.0 ± 1.6 pg/mL), TNF-α was significantly reduced at EOT (6.3 ± 1.5 pg/mL, p = 0.001) and 12M (5.2 ± 2.7 pg/mL, p < 0.001). ET-1 was significantly lower at EOT (1.9 ± 0.6 pg/mL, p = 0.013) and at 12M (2.0 ± 0.8 pg/mL, p = 0.091) following smoking cessation compared with BL (2.3 ± 0.6 pg/mL). BL concentrations of cotinine were significantly associated with basal ET-1 (r = 0.449, p = 0.013) and the change in cotinine at 12M following smoking cessation was significantly associated with the change in plasma ET-1 at 12M (r = 0.457, p = 0.011). Findings from the present pilot investigation demonstrate that a 12-week smoking cessation program reduces circulating concentrations of ET-1 and TNF-α for at least a year. The reduction in serum cotinine was associated with the decrease in circulating ET-1. The attenuation in ET-1 and inflammation may in part, contribute to the lower risk of CVD that is observed with smoking cessation.
    DOI:  https://doi.org/10.1038/s41598-021-03476-5
  7. Eur J Immunol. 2021 Dec 15.
    Dynamics of IL-15/IL-15Rα expression in response to HSV-1 infection reveal a novel mode of viral immune evasion counteracted by iNKT cells.
    Michał J Sobkowiak, Dominic Paquin-Proulx, Lidija Bosnjak, Markus Moll, Margaret Sällberg Chen, Johan K Sandberg.
      Herpes simplex virus type 1 (HSV-1) infects and persists in most of the human population. Interleukin-15 (IL-15) has an important role in the activation of cell-mediated immune responses and acts in complex with IL-15 receptor alpha (IL-15Rα) through cell surface trans-presentation. Here, we have examined the IL-15/IL-15Rα complex response dynamics during HSV-1 infection in human keratinocytes. Surface expression of the IL-15/IL-15Rα complex rapidly increased in response to HSV-1, reaching a peak around 12 hours after infection. This response was dependent on detection of viral replication by TLR3, and enhancement of IL15 and IL15RA gene expression. Beyond the peak of expression, levels of IL-15 and IL-15Rα gradually declined, reaching a profound loss of surface expression beyond 24 hours of infection. This involved the loss of IL15 and IL15RA transcription. Interestingly, invariant natural killer T (iNKT) cells inhibited the viral interference with IL-15/IL-15Rα complex expression in an IFNγ-dependent manner. These results indicate that rapid upregulation of the IL-15/IL-15Rα complex occurs in HSV-1 infected keratinocytes, and that this response is targeted by viral interference. Shutdown of the IL-15 axis represents a novel mode of HSV-1 immune evasion, which can be inhibited by the host iNKT cell response. This article is protected by copyright. All rights reserved.
    Keywords:  CD1d; HSV-1; IL-15; Keratinocyte; TLR3; iNKT cells
    DOI:  https://doi.org/10.1002/eji.202149287
  8. Front Endocrinol (Lausanne). 2021 ;12 691556
    Varied Relationship of Lipid and Lipoprotein Profiles to Liver Fat Content in Phenotypes of Metabolic Associated Fatty Liver Disease.
    Tingfeng Wu, Junzhao Ye, Congxiang Shao, Fuxi Li, Yansong Lin, Qianqian Ma, Wei Wang, Shiting Feng, Bihui Zhong.
       Background: Progressive overloads of intrahepatic triglycerides are related to metabolic dysregulation of multiple lipid and lipoprotein profiles, but whether similar dose effects are found in each subtype of metabolic associated fatty liver disease (MAFLD) remains unclear. We aimed to characterize the lipid profiles associated with liver fat content (LFC) in MAFLD patients who were overweight, lean/normal weight, or had diabetes.
    Methods: We conducted a cross-sectional study enrolling 1,182 consecutive participants (144 non-MAFLD and 1,038 MAFLD) who underwent MRI proton density fat fraction measurement (MRI-PDFF) from 2011 to 2020. Lipid and apolipoprotein profiles, free fatty acid (FFA), liver and metabolism parameters, and anthropometric measurements were also assessed.
    Results: MAFLD patients with type 2 diabetes or overweight/obesity had a higher proportion of abnormal lipid and lipoprotein profiles than those who were lean/normal weight. The degree of LFC had a positive correlation with total cholesterol, triglyceride, ApoB, and ApoE in patients with overweight/obesity and type 2 diabetes. In those with overweight/obesity, there were dose-response relationships between moderate-to-severe steatosis and total cholesterol, triglyceride, HDL-c, LDL-c, ApoB, ApoE, and Lp(a). A similar trend was observed for triglyceride in those with type 2 diabetes and for HDL-c in patients who were lean/normal weight (all p for trend <0.05). The combined model of relative lipid-related markers performed well in the prediction of moderate-to-severe steatosis (AUC: 0.762 for overweight/obesity; 0.742 for lean/normal weight).
    Conclusion: LFC was associated with lipid profiles, including triglyceride, LDL-c, ApoB, ApoE, and FFA. These relationships were varied by the phenotype of MAFLD according to its diagnostic flow.
    Keywords:  apolipoprotein; free fatty acid (FFA); lipids - blood; liver fat content; metabolic associated fatty liver disease (MAFLD)
    DOI:  https://doi.org/10.3389/fendo.2021.691556
  9. J Clin Invest. 2021 Dec 15. pii: e153876. [Epub ahead of print]131(24):
    BACH2 inhibition reverses β cell failure in type 2 diabetes models.
    Jinsook Son, Hongxu Ding, Thomas B Farb, Alexander M Efanov, Jiajun Sun, Julie L Gore, Samreen K Syed, Zhigang Lei, Qidi Wang, Domenico Accili, Andrea Califano.
      Type 2 diabetes (T2D) is associated with defective insulin secretion and reduced β cell mass. Available treatments provide a temporary reprieve, but secondary failure rates are high, making insulin supplementation necessary. Reversibility of β cell failure is a key translational question. Here, we reverse engineered and interrogated pancreatic islet-specific regulatory networks to discover T2D-specific subpopulations characterized by metabolic inflexibility and endocrine progenitor/stem cell features. Single-cell gain- and loss-of-function and glucose-induced Ca2+ flux analyses of top candidate master regulatory (MR) proteins in islet cells validated transcription factor BACH2 and associated epigenetic effectors as key drivers of T2D cell states. BACH2 knockout in T2D islets reversed cellular features of the disease, restoring a nondiabetic phenotype. BACH2-immunoreactive islet cells increased approximately 4-fold in diabetic patients, confirming the algorithmic prediction of clinically relevant subpopulations. Treatment with a BACH inhibitor lowered glycemia and increased plasma insulin levels in diabetic mice, and restored insulin secretion in diabetic mice and human islets. The findings suggest that T2D-specific populations of failing β cells can be reversed and indicate pathways for pharmacological intervention, including via BACH2 inhibition.
    Keywords:  Beta cells; Diabetes; Endocrinology; Metabolism
    DOI:  https://doi.org/10.1172/JCI153876
  10. Aging Cell. 2021 Dec 13. e13528
    Deletion of SA β-Gal+ cells using senolytics improves muscle regeneration in old mice.
    Cory M Dungan, Kevin A Murach, Christopher J Zdunek, Zuo Jian Tang, Georgia L VonLehmden, Camille R Brightwell, Zachary Hettinger, Davis A Englund, Zheng Liu, Christopher S Fry, Antonio Filareto, Michael Franti, Charlotte A Peterson.
      Systemic deletion of senescent cells leads to robust improvements in cognitive, cardiovascular, and whole-body metabolism, but their role in tissue reparative processes is incompletely understood. We hypothesized that senolytic drugs would enhance regeneration in aged skeletal muscle. Young (3 months) and old (20 months) male C57Bl/6J mice were administered the senolytics dasatinib (5 mg/kg) and quercetin (50 mg/kg) or vehicle bi-weekly for 4 months. Tibialis anterior (TA) was then injected with 1.2% BaCl2 or PBS 7- or 28 days prior to euthanization. Senescence-associated β-Galactosidase positive (SA β-Gal+) cell abundance was low in muscle from both young and old mice and increased similarly 7 days following injury in both age groups, with no effect of D+Q. Most SA β-Gal+ cells were also CD11b+ in young and old mice 7- and 14 days following injury, suggesting they are infiltrating immune cells. By 14 days, SA β-Gal+/CD11b+ cells from old mice expressed senescence genes, whereas those from young mice expressed higher levels of genes characteristic of anti-inflammatory macrophages. SA β-Gal+ cells remained elevated in old compared to young mice 28 days following injury, which were reduced by D+Q only in the old mice. In D+Q-treated old mice, muscle regenerated following injury to a greater extent compared to vehicle-treated old mice, having larger fiber cross-sectional area after 28 days. Conversely, D+Q blunted regeneration in young mice. In vitro experiments suggested D+Q directly improve myogenic progenitor cell proliferation. Enhanced physical function and improved muscle regeneration demonstrate that senolytics have beneficial effects only in old mice.
    Keywords:  regeneration; satellite cells; senescence; senolytics; skeletal muscle
    DOI:  https://doi.org/10.1111/acel.13528
  11. Front Immunol. 2021 ;12 764062
    Type III Interferons: Emerging Roles in Autoimmunity.
    Sindhu Manivasagam, Robyn S Klein.
      Type III interferons (IFNs) or the lambda IFNs (IFNLs or IFN-λs) are antimicrobial cytokines that play key roles in immune host defense at endothelial and epithelial barriers. IFNLs signal via their heterodimeric receptor, comprised of two subunits, IFNLR1 and interleukin (IL)10Rβ, which defines the cellular specificity of the responses to the cytokines. Recent studies show that IFNL signaling regulates CD4+ T cell differentiation, favoring Th1 cells, which has led to the identification of IFNL as a putative therapeutic target for autoimmune diseases. Here, we summarize the IFNL signaling pathways during antimicrobial immunity, IFNL-mediated immunomodulation of both innate and adaptive immune cells, and induction of autoimmunity.
    Keywords:  IFNLR; Th1 cells; autoimmune diseases; interferon lambda; neuroimmunology and neuropathology
    DOI:  https://doi.org/10.3389/fimmu.2021.764062
  12. BMC Biol. 2021 Dec 15. 19(1): 265
    Enhanced hepatic respiratory capacity and altered lipid metabolism support metabolic homeostasis during short-term hypoxic stress.
    Katie A O'Brien, Ben D McNally, Alice P Sowton, Antonio Murgia, James Armitage, Luke W Thomas, Fynn N Krause, Lucas A Maddalena, Ian Francis, Stefan Kavanagh, Dominic P Williams, Margaret Ashcroft, Julian L Griffin, Jonathan J Lyon, Andrew J Murray.
       BACKGROUND: Tissue hypoxia is a key feature of several endemic hepatic diseases, including alcoholic and non-alcoholic fatty liver disease, and organ failure. Hypoxia imposes a severe metabolic challenge on the liver, potentially disrupting its capacity to carry out essential functions including fuel storage and the integration of lipid metabolism at the whole-body level. Mitochondrial respiratory function is understood to be critical in mediating the hepatic hypoxic response, yet the time-dependent nature of this response and the role of the respiratory chain in this remain unclear.
    RESULTS: Here, we report that hepatic respiratory capacity is enhanced following short-term exposure to hypoxia (2 days, 10% O2) and is associated with increased abundance of the respiratory chain supercomplex III2+IV and increased cardiolipin levels. Suppression of this enhanced respiratory capacity, achieved via mild inhibition of mitochondrial complex III, disrupted metabolic homeostasis. Hypoxic exposure for 2 days led to accumulation of plasma and hepatic long chain acyl-carnitines. This was observed alongside depletion of hepatic triacylglycerol species with total chain lengths of 39-53 carbons, containing palmitic, palmitoleic, stearic, and oleic acids, which are associated with de novo lipogenesis. The changes to hepatic respiratory capacity and lipid metabolism following 2 days hypoxic exposure were transient, becoming resolved after 14 days in line with systemic acclimation to hypoxia and elevated circulating haemoglobin concentrations.
    CONCLUSIONS: The liver maintains metabolic homeostasis in response to shorter term hypoxic exposure through transient enhancement of respiratory chain capacity and alterations to lipid metabolism. These findings may have implications in understanding and treating hepatic pathologies associated with hypoxia.
    Keywords:  De novo lipogenesis; Hepatic mitochondria; Hypoxia; Mitochondrial respiratory chain; Mitochondrial supercomplexes
    DOI:  https://doi.org/10.1186/s12915-021-01192-0
  13. J Nutr. 2021 Dec 17. pii: nxab425. [Epub ahead of print]
    Marginal Zinc Deficiency Alters Essential Fatty Acid Metabolism in Healthy Men.
    Jung H Suh, Sarah J Zyba, Mark Shigenaga, Christine M McDonald, Janet C King.
       BACKGROUND: Rice biofortification with Zinc (Zn) can improve the Zn status of rice-consuming populations. However, the metabolic impact in humans consuming Zn biofortified rice is unknown.
    OBJECTIVE: To determine the effects of Zn biofortified rice on lipid metabolism in normolipidemic men.
    DESIGN: The men consumed a rice-based diet containing 6 mg Zn/d and 1.5 g phytate (phytate:Zn ratio = 44) for 2 weeks (wk) followed by a 10 mg Zn/d diet without phytate for 4 wk. An ad libitum diet supplemented with 25 mg Zn/d was then fed for 3 wk. Fasting blood samples were taken at baseline and at the end of each metabolic period for measuring plasma zinc, glucose, insulin, triglyceride (TG), low- and high-density lipoprotein-cholesterol, fatty acids, oxylipins, and fatty acid desaturase activities. Statistical differences were assessed by linear mixed model.
    RESULTS: FADS1 activity decreased by 29.1% (P = 0.007) when the 6 mg Zn/d diet was consumed for 2 wk. This change was associated with significant decreases in HDL-c and LDL-c. The alterations in FADS1, HDL-c and TG remained unchanged when Zn intakes were increased to 10 mg/d for 4 wk. Supplementation with 25 mg Zn/d for 3 wk normalized these metabolic changes and significantly increased LDL-c at the end of this metabolic period compared to baseline. FADS1 activity was inversely correlated with FADS2 (rmcorr = -0.52; P = 0.001) and TG (rmcorr = -0.55; P = 0.001) at all timepoints.
    CONCLUSION: A low zinc, high phytate rice-based diet reduced plasma HDL-c concentrations and altered fatty acid profiles in healthy men within 2 wk. Consuming 10 mg Zn/d without phytate for 4 wk did not improve the lipid profiles, but a 25 mg Zn/d supplement corrects these alterations in lipid metabolism within 3 wk. Registration: Clinical Trials.gov: NCT02861352.
    Keywords:  Low-density lipoprotein cholesterol; fatty acid desaturase; fatty acid metabolism; high-density lipoprotein cholesterol; lipids; oxylipins; phytate; zinc; zinc biofortification
    DOI:  https://doi.org/10.1093/jn/nxab425
  14. BMC Immunol. 2021 Dec 16. 22(1): 76
    Reduction of peripheral regulatory T cells in active rheumatoid arthritis patients with coronary artery disease.
    Yanyan Wang, Rui Su, Baochen Li, Qiaoling Guo, Fangyuan Hu, Xiaopu Yu, Mingxia Ma, Lizhi Wang, Chong Gao, Xiaofeng Li, Caihong Wang.
       OBJECTIVE: To identify lymphocyte and CD4 + T cell subset characteristics, particularly regulatory T cells (Tregs), in active rheumatoid arthritis (RA) patients with coronary artery disease (CAD).
    METHODS: A total of 54 RA patients with CAD (RA-CAD group), 43 RA patients without CAD (pure RA group), and 43 healthy controls (HC group) were enrolled. The absolute number and frequency of lymphocyte subpopulations and CD4 + T cell subsets were analyzed by flow cytometry. Serum levels of cytokines were analyzed using a cytometric bead array. Clinical and laboratory data were collected retrospectively and their correlation with CD4 + T subsets were analyzed.
    RESULTS: There was a significant decrease in the absolute number of Treg cells (CD4 + CD25 + Foxp3 + T cells) in the RA-CAD group compared to the pure RA group (p < 0.001). Similarly, both the absolute number (p = 0.001) and frequency (p = 0.011) of Tregs in the RA-CAD group were decreased compared to the HCs, causing a Th17/Treg imbalance (p = 0.044). No difference was found in the absolute number and frequency of Treg cells between the pure RA and HC groups. However, the absolute Th17 cell count was increased in the pure RA group (p = 0.032). The serum level of cytokine IL-17 was lower in the RA-CAD group than in the pure RA group (p = 0.023). In the RA-CAD group, the Treg number was negatively correlated with the RA disease activity score and ESR value, and LDL and ApoB100 levels were negatively correlated with the number of Th17 cells.
    CONCLUSIONS: Active RA patients with CAD sustain more severe immune tolerance damage and Th17/Treg disorder. Monitoring of lymphocyte and CD4 + T cell subsets, particularly Treg cells, is crucial to understanding immune status in this group. Focusing on RA activity and CAD risk control, immune-regulatory therapy based on the Treg level may be more beneficial for RA patients with CAD.
    Keywords:  Coronary artery disease; Lymphocyte; Regulatory T cell; Rheumatoid arthritis; Th17/Treg
    DOI:  https://doi.org/10.1186/s12865-021-00466-0
  15. J Clin Invest. 2021 Dec 15. pii: e154645. [Epub ahead of print]131(24):
    Dietary sugar restriction reduces hepatic de novo lipogenesis in boys with fatty liver disease.
    Stephanie T Chung, Sheela N Magge.
      Nonalcoholic fatty liver disease (NAFLD) in children resulting from the obesity epidemic is widespread and increasing. Although the complexities of pediatric NAFLD are recognized, screening and therapies in children remain limited. Moreover, pediatric NAFLD diagnosis fails to consider insulin resistance and metabolic dysfunction as important determinants. In this issue of the JCI, Cohen et al. explored the contribution of dietary factors to the pathogenesis of NAFLD in adolescent boys with biopsy-proven NAFLD and control participants. Notably, dietary sugar restriction over 8 weeks decreased de novo lipogenesis (DNL) and hepatic fat. The change in DNL correlated with changes in insulin and weight, but not with changes in hepatic fat, supporting the relevance of metabolic dysfunction to NAFLD. These results confirm the pathological link between excessive dietary sugar intake and NAFLD in children and support recent recommendations to change the nomenclature of NAFLD to metabolic associated fatty liver disease (MAFLD).
    DOI:  https://doi.org/10.1172/JCI154645
  16. Eur J Immunol. 2021 Dec 16.
    Soluble CD137 is a novel serum marker of liver cirrhosis in patients with hepatitis C and alcohol-associated disease etiology.
    Kilian Weigand, Georg Peschel, Jonathan Grimm, Khang Luu, Doris Schacherer, Reiner Wiest, Martina Müller, Herbert Schwarz, Christa Buechler.
      Defective T-cell functions play a role in the persistence of hepatitis C virus (HCV) infection. Activated T-cells express CD137, which co-stimulates anti-virus T-cell responses, and this activity is antagonized by soluble CD137 (sCD137). Here, we show that in sera of 81 patients with chronic HCV, sCD137 levels did not correlate with measures of viral infection, and did not decline after virus eradication using direct-acting antivirals. Thus, serum sCD137 was similar in patients infected with HCV and in uninfected controls. Of note, in HCV patients with liver cirrhosis and patients with mostly alcohol associated liver cirrhosis, sCD137 was increased. A negative association of sCD137 and albumin existed in both cohorts. sCD137 concentrations were similar in hepatic and portal vein blood excluding the liver as origin of higher levels. Recombinant sCD137 reduced T-helper (Th) 1 and Th2 but not Th17 cell polarization in-vitro, and accordingly lowered interferon-γ, tumor necrosis factor (TNF) and interleukin-13 in cell media. Serum sCD137 is associated with inflammatory states, and positively correlated with serum TNF in cirrhotic HCV patients following virus eradication. Our study argues against a role of sCD137 in HCV infection and suggests a function of sCD137 in liver cirrhosis, which yet has to be defined. This article is protected by copyright. All rights reserved.
    Keywords:  Direct-acting antivirals; Foxp3; MELD score; TNF; liver cirrhosis
    DOI:  https://doi.org/10.1002/eji.202149488
  17. Immunol Rev. 2021 Dec 14.
    Epigenetic regulation of natural killer cell memory.
    Colleen M Lau, Gabriela M Wiedemann, Joseph C Sun.
      Immunological memory is the underlying mechanism by which the immune system remembers previous encounters with pathogens to produce an enhanced secondary response upon re-encounter. It stands as the hallmark feature of the adaptive immune system and the cornerstone of vaccine development. Classic recall responses are executed by conventional T and B cells, which undergo somatic recombination and modify their receptor repertoire to ensure recognition of a vast number of antigens. However, recent evidence has challenged the dogma that memory responses are restricted to the adaptive immune system, which has prompted a reevaluation of what delineates "immune memory." Natural killer (NK) cells of the innate immune system have been at the forefront of these pushed boundaries, and have proved to be more "adaptable" than previously thought. Like T cells, we now appreciate that their "natural" abilities actually require a myriad of signals for optimal responses. In this review, we discuss the many signals required for effector and memory NK cell responses and the epigenetic mechanisms that ultimately endow their enhanced features.
    Keywords:  epigenetic regulation; immune memory; natural killer cells; viral infection
    DOI:  https://doi.org/10.1111/imr.13031
  18. Front Immunol. 2021 ;12 739186
    Tetracyclines Diminish In Vitro IFN-γ and IL-17-Producing Adaptive and Innate Immune Cells in Multiple Sclerosis.
    Despoina T Florou, Athanasios Mavropoulos, Efthymios Dardiotis, Vana Tsimourtou, Vasileios Siokas, Athina-Maria Aloizou, Christos Liaskos, Christina Tsigalou, Christina Katsiari, Lazaros I Sakkas, Georgios Hadjigeorgiou, Dimitrios P Bogdanos.
       Introduction: Limited data from clinical trials in multiple sclerosis (MS) reported that minocycline, a widely used antibiotic belonging to the family of tetracyclines (TCs), exerts a beneficial short-lived clinical effect A similar anti-inflammatory effect of minocycline attributed to a deviation from Th1 to Th2 immune response has been reported in experimental models of MS. Whether such an immunomodulatory mechanism is operated in the human disease remains largely unknown.
    Aim: To assess the in vitro immunomodulatory effect of tetracyclines, and in particular minocycline and doxycycline, in naïve and treated patients with MS.
    Material and Methods: Peripheral blood mononuclear cells from 45 individuals (35 MS patients, amongst which 15 naïve patients and 10 healthy controls, HCs) were cultured with minocycline or doxycycline and conventional stimulants (PMA/Ionomycin or IL-12/IL-18). IFN-γ and IL-17 producing T-, NK- and NKT cells were assessed by flow cytometry. The effect of TCs on cell viability and apoptosis was further assessed by flow cytometry with Annexin V staining.
    Results: Both tetracyclines significantly decreased, in a dose dependent manner, IFN-γ production in NKT and CD4+ T lymphocytes from MS patients (naïve or treated) stimulated with IL-12/IL-18 but did not decrease IFN-γ producing CD8+ T cells from naive MS or treated RRMS patients. They also decreased IL-17+ T and NKT cells following PMA and Ionomycin-stimulation. Tetracyclines did not affect the viability of cell subsets.
    Conclusion: Tetracyclines can in vitro suppress IFN-γ and IL-17- producing cells from MS patients, and this may explain their potential therapeutic effect in vivo.
    Keywords:  NKT cells; doxycycline; interferon-γ; interleukin-17; minocycline; multiple sclerosis; proinflammatory
    DOI:  https://doi.org/10.3389/fimmu.2021.739186
  19. JAMA Cardiol. 2021 Dec 01. 6(12): e213737
    Recurrent Paravalvular Leak Following Mitral Valve Replacement.
    Badar Patel, Musa A Sharkawi, Pinak B Shah.
      
    DOI:  https://doi.org/10.1001/jamacardio.2021.3737
  20. Cell Metab. 2021 Dec 09. pii: S1550-4131(21)00541-6. [Epub ahead of print]
    TOX4, an insulin receptor-independent regulator of hepatic glucose production, is activated in diabetic liver.
    Liheng Wang, Junjie Yu, Qiuzhong Zhou, Xiaobo Wang, Maria Mukhanova, Wen Du, Lei Sun, Utpal B Pajvani, Domenico Accili.
      Increased hepatic glucose production (HGP) contributes to hyperglycemia in type 2 diabetes. Hormonal regulation of this process is primarily, but not exclusively, mediated by the AKT-FoxO1 pathway. Here, we show that cAMP and dexamethasone regulate the high-mobility group superfamily member TOX4 to mediate HGP, independent of the insulin receptor/FoxO1 pathway. TOX4 inhibition decreases glucose production in primary hepatocytes and liver and increases glucose tolerance. Combined genetic ablation of TOX4 and FoxO1 in liver has additive effects on glucose tolerance and gluconeogenesis. Moreover, TOX4 ablation fails to reverse the metabolic derangement brought by insulin receptor knockout. TOX4 expression is increased in livers of patients with steatosis and diabetes and in diet-induced obese and db/db mice. In the latter two murine models, knockdown Tox4 decreases glycemia and improves glucose tolerance. We conclude that TOX4 is an insulin receptor-independent regulator of HGP and a candidate contributor to the pathophysiology of diabetes.
    Keywords:  TOX2, transcription regulation, HGP, type 2 diabetes
    DOI:  https://doi.org/10.1016/j.cmet.2021.11.013
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