bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2021‒12‒12
33 papers selected by
Fawaz Alzaïd
Sorbonne Université

  1. Clin Transl Sci. 2021 Dec 05.
      The roles that natural killer (NK) cells play in liver disease and transplantation remain ill-defined. Reports on the matter are often contradictory, and the mechanisms elucidated are complex and dependent on the context of the model tested. Moreover, NK cell attributes such as receptor protein expression and function differ among species, which makes study of primate or rodent transplant models challenging. Recent insights into NK function and NK-mediated therapy in the context of cancer therapy may prove applicable to transplantation. Of specific interest are immune checkpoint molecules and the mechanisms by which they modulate NK cells in the tumor micro-environment. In this review, we summarize NK cell populations in the peripheral blood and liver, and we explore the data regarding the expression and function of immune checkpoint molecules on NK cells. We also hypothesize about the roles they could play in liver transplantation and discuss how they might be harnessed therapeutically in transplant sciences.
    Keywords:  NK cell; immune checkpoint; liver; transplantation
  2. Dev Neurobiol. 2021 Dec 07.
      Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is an aggressive motor neuron degenerative disease characterized by selective loss of both upper and lower motor neurons. The mechanisms underlying disease initiation and progression are poorly understood. The involvement of non-motor neuraxis emphasizes the contribution of glia cells in disease progress. Microglia comprise a unique subset of glial cells and are the principal immune cells in the central nervous system (CNS). Triggering receptor expressed on myeloid cell 2 (TREM2) is a surface receptor that, within the CNS, is exclusively expressed on microglia and plays crucial roles in microglial proliferation, migration, activation, metabolism, and phagocytosis. Genetic evidence has linked TREM2 to neurodegenerative diseases including ALS, but its function in ALS pathogenesis is largely unknown. In this review, we summarize how microglial activation, with a specific focus on TREM2 function, affects ALS progression clinically and experimentally. Understanding microglial TREM2 function will help pinpoint the molecular target for ALS treatment. This article is protected by copyright. All rights reserved.
    Keywords:  TDP-43; TREM2; amyotrophic lateral sclerosis; disease-associated microglia; microglia
  3. Saudi J Biol Sci. 2021 Dec;28(12): 7012-7021
      This study evaluated the protective effect of astaxanthin (ASX) against high-fat diet (HFD)-induced cardiac damage and fibrosis in rats and examined if the mechanism of protection involves modulating SIRT1. Rat were divided into 5 groups (n = 10/group) as: 1) control: fed normal diet (3.82 kcal/g), 2) control + ASX (200 mg/kg/orally), 3) HFD: fed HFD (4.7 kcal/g), 4) HFD + ASX (200 mg/kg/orally), and HFD + ASX + EX-527 (1 mg/kg/i.p) (a selective SIRT1 inhibitor). All treatments were conducted for 14 weeks. Administration of ASX reduced cardiomyocyte damage, inhibited inflammatory cell infiltration, preserved cardiac fibers structure, prevented collagen deposition and protein levels of TGF-β 1 in the left ventricles (LVs) of HFD-fed rats. In the LVs of both the control and HFD-fed rat, ASX significantly reduced levels of reactive oxygen species (ROS), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and p-smad2/3 (Lys19) but increased the levels of glutathione (GSH), catalase, and manganese superoxide dismutase (MnSOD). Concomitantly, it increased the nuclear activity of Nrf2 and reduced that of NF-κB p65. Furthermore, administration of ASX to both the control and HFD-fed rats increased total and nuclear levels of SIRT1, stimulated the nuclear activity of SIRT1, and reduced the acetylation of Nrf2, NF-κB p65, and Smad3. All these cardiac beneficial effects of ASX in the HFD-fed rats were abolished by co-administration of EX-527. In conclusion, ASX stimulates antioxidants and inhibits markers of inflammation under basal and HFD conditions. The mechanism of protection involves, at least, activation SIRT1 signaling.
    Keywords:  Astaxanthin; Fibrosis; Heart; High fat diet; Inflammation; Oxidative stress; Rats; SIRT1
  4. Toxicol Lett. 2021 Dec 01. pii: S0378-4274(21)00898-5. [Epub ahead of print]355 116-126
      Microglia is the innate immune cell in central nervous system (CNS) and plays an important role in neuroinflammation. Microglia mediated neuroinflammation is the key factor affecting the development of neurodegenerative diseases. Although there was evidence that paraquat (PQ) could induce inflammatory response, its mechanism was not clear. The present study investigated the mechanisms of PQ-induced inflammatory responses in BV-2 microglia cells, and tried to reveal the role of ROS/Akt1 pathway. The results showed that the cell activation markers (iNOS and CD206) of BV-2 cells were increased after PQ treatment, suggesting that BV-2 microglia were activated. PQ induced the reactive oxygen species (ROS) and inhibited the AKT1 phosphorylation in BV-2 cells. Besides, the M1 markers expression (IL-6, TNF-α and IL-1β) were significantly increased after PQ treatment, which suggested that PQ induced the increase of M1 phenotype of BV-2 microglia. Pre-treated with NAC (ROS scavenger), the M1 phenotype was decreased while the p-Akt1 was restored compared to PQ stimulation. Furthermore, we built an Akt1(S473E)-overexpression BV-2 cell line. The Akt1 (S473E) partially attenuated the PQ induced increase in M1 phenotype, while ROS did not significantly change. These results indicated that PQ induced BV-2 microglia activation by increased ROS mediated Akt1 activation inhibition, leading to neuroinflammation.
    Keywords:  Akt1; BV-2 microglia; M1/M2 phenotype; Paraquat; ROS
  5. Curr Issues Mol Biol. 2021 Nov 16. 43(3): 2022-2035
      Hepatitis C virus (HCV)-induced liver disease contributes to chronic hepatitis. The immune factors identified in HCV include changes in the innate and adaptive immune system. The inflammatory mediators, known as "inflammasome", are a consequence of the metabolic products of cells and commensal or pathogenic bacteria and viruses. The only effective strategy to prevent disease progression is eradication of the viral infection. Immune cells play a pivotal role during liver inflammation, triggering fibrogenesis. The present paper discusses the potential role of markers in cell death and the inflammatory cascade leading to the severity of liver damage. We aim to present the clinical parameters and laboratory data in a cohort of 88 HCV-infected non-cirrhotic and 25 HCV cirrhotic patients, to determine the characteristic light microscopic (LM) and transmission electron microscopic (TEM) changes in their liver biopsies and to present the link between the severity of liver damage and the serum levels of cytokines and caspases. A matched HCV non-infected cohort was used for the comparison of serum inflammatory markers. We compared the inflammation in HCV individuals with a control group of 280 healthy individuals. We correlated the changes in inflammatory markers in different stages of the disease and the histology. We concluded that the serum levels of cytokine, chemokine, and cleaved caspase markers reveal the inflammatory status in HCV. Based upon the information provided by the changes in biomarkers the clinician can monitor the severity of HCV-induced liver damage. New oral well-tolerated treatment regimens for chronic hepatitis C patients can achieve cure rates of over 90%. Therefore, using the noninvasive biomarkers to monitor the evolution of the liver damage is an effective personalized medicine procedure to establish the severity of liver injury and its repair.
    Keywords:  apoptosome; chemokines; cytokines; electron microscopy; fibrosis; inflammasome; tumor necrosis factor alpha; viral hepatitis C
  6. Curr Hypertens Rep. 2021 Dec 09. 23(12): 45
      PURPOSE OF REVIEW: In this article, we summarize the current literature supporting metabolic and redox signaling pathways as important mechanisms underlying T cell activation in the context of hypertension.RECENT FINDINGS: T cell immunometabolism undergoes dramatic remodeling in order to meet the demands of T cell activation, differentiation, and proliferation. Recent evidence demonstrates that the T cell oxidation-reduction (redox) system also undergoes significant changes upon activation, which can itself modulate metabolic processes and T cell function. Dysregulation of these signaling pathways can lead to aberrant T cell activation and inappropriate ROS production, both of which are linked to pathological conditions like hypertension. While the contribution of T cells to the progression of hypertension has been thoroughly investigated, how T cell metabolism and redox signaling changes, both separately and together, is an area of study that remains largely untouched. This review presents evidence from our own laboratory as well as others to highlight the importance of these two mechanisms in the study of hypertension.
    Keywords:  Hypertension; Immune cells; Immunometabolism; Redox signaling; T cells
  7. Metabol Open. 2021 Dec;12 100151
      Background and aims: Nanoparticles could represent a therapeutic approach for the treatment of various diseases. It has been reported that cerium oxide nanoparticles (CeO2 NPs) have potential useful effects. Therefore, we aimed to examine the protective effects of the CeO2 NPs in two models of liver injury, non-alcoholic fatty liver disease (NAFLD) and carbon tetrachloride (CCl4)-induced liver fibrosis, in rats.Methods: In this experimental study, male rats were randomly divided into different experimental groups including: Experiment 1; group1: healthy rats received normal saline, 2: CCl4 group, 3: CCl4 + nanoparticle. Experiment 2; group1: healthy rats received chow diet, 2: NAFLD group, 3: NAFLD + nanoparticle. The oxidative stress markers were determined in the liver and intestine. Tumor necrosis factor-α (TNF-α) levels were measured by ELISA. Histopathological changes of liver and intestine were evaluated by light microspore.
    Results: Total antioxidant capacity (TAC) and glutathione (GSH) levels significantly decreased, while malondialdehyde (MDA) and total oxidant status (TOS) were significantly increased in the liver, and intestine of the NAFLD and CCl4 group compared with control rats. However, the use of nanoparticles significantly normalized these markers. The levels of the TNF-α were significantly reduced in the nanoparticle group as compared with NAFLD model and CCl4-treated rats. CeO2 NPs also normalized the liver and intestinal histological changes.
    Conclusions: Our finding revealed that CeO2 NPs has potential protective effects by increasing antioxidant activity, and reducing inflammation.
    Keywords:  Carbon tetrachloride; Cerium oxide nanoparticles; Inflammation; Liver injury; Rats
  8. Front Endocrinol (Lausanne). 2021 ;12 794437
      Earlier studies investigating the pathogenesis of chronic vascular inflammation associated with atherosclerosis described pro-inflammatory and vascular barrier disruptive effects of lipid oxidation products accumulated in the sites of vascular lesion and atherosclerotic plaque. However, accumulating evidence including studies from our group suggests potent barrier protective and anti-inflammatory properties of certain oxidized phospholipids (OxPLs) in the lung vascular endothelium. Among these OxPLs, oxidized 1-palmitoyl-2-arachdonyl-sn-glycero-3-phosphocholine (OxPAPC) causes sustained enhancement of lung endothelial cell (EC) basal barrier properties and protects against vascular permeability induced by a wide variety of agonists ranging from bacterial pathogens and their cell wall components, endotoxins, thrombin, mechanical insults, and inflammatory cytokines. On the other hand, truncated OxPLs cause acute endothelial barrier disruption and potentiate inflammation. It appears that multiple signaling mechanisms triggering cytoskeletal remodeling are involved in OxPLs-mediated regulation of EC barrier. The promising vascular barrier protective and anti-inflammatory properties exhibited by OxPAPC and its particular components that have been established in the cellular and animal models of sepsis and acute lung injury has prompted consideration of OxPAPC as a prototype therapeutic molecule. In this review, we will summarize signaling and cytoskeletal mechanisms involved in OxPLs-mediated damage, rescue, and restoration of endothelial barrier in various pathophysiological settings and discuss a future potential of OxPAPC in treating lung disorders associated with endothelial barrier dysfunction.
    Keywords:  OxPAPC; Rho GTPases; endothelial barrier; inflammation; lung injury; oxidized phospholipids; receptor
  9. Autoimmunity. 2021 Dec 09. 1-14
      Progressive destruction of pancreatic islet β-cells by immune cells is a primary feature of type 1 diabetes (T1D) and therapies that can restore the functional β-cell mass are needed to alleviate disease progression. Here, we report the use of mesenchymal stromal/stem cells (MSCs) for the production and delivery of Gastrin, a peptide hormone that is produced by intestinal cells and foetal islets and can increase β-Cell mass, to promote protection from T1D. A single injection of syngeneic MSCs that were engineered to express Gastrin (Gastrin-MSCs) caused a significant delay in hyperglycaemia in non-obese diabetic (NOD) mice compared to engineered control-MSCs. Similar treatment of early-hyperglycaemic mice caused the restoration of euglycemia for a considerable duration, and these therapeutic effects were associated with the protection of, and/or higher frequencies of, insulin-producing islets and less severe insulitis. While the overall immune cell phenotype was not affected profoundly upon treatment using Gastrin-MSCs or upon in vitro culture, pancreatic lymph node cells from Gastrin-MSC treated mice, upon ex vivo challenge with self-antigen, showed a Th2 and Th17 bias, and diminished the diabetogenic property in NOD-Rag1 deficient mice suggesting a disease protective immune modulation under Gastrin-MSC treatment associated protection from hyperglycaemia. Overall, this study shows the potential of production and delivery of Gastrin in vivo, by MSCs, in protecting insulin-producing β-cells and ameliorating the disease progression in T1D.
    Keywords:  Mesenchymal stem cells; autoimmunity; gastrin; immune modulation; insulitis; type 1 diabetes
  10. J Immunol. 2021 Dec 10. pii: ji2001389. [Epub ahead of print]
      SAMHD1 is a potent HIV-1 restriction factor that blocks reverse transcription in monocytes, dendritic cells and resting CD4+ T cells by decreasing intracellular dNTP pools. However, SAMHD1 may diminish innate immune sensing and Ag presentation, resulting in a weaker adaptive immune response. To date, the role of SAMHD1 on antiretroviral immunity remains unclear, as mouse SAMHD1 had no impact on murine retrovirus replication in prior in vivo studies. Here, we show that SAMHD1 significantly inhibits acute Friend retrovirus infection in mice. Pretreatment with LPS, a significant driver of inflammation during HIV-1 infection, further unmasked a role for SAMHD1 in influencing immune responses. LPS treatment in vivo doubled the intracellular dNTP levels in immune compartments of SAMHD1 knockout but not wild-type mice. SAMHD1 knockout mice exhibited higher plasma infectious viremia and proviral DNA loads than wild-type mice at 7 d postinfection (dpi), and proviral loads inversely correlated with a stronger CD8+ T cell response. SAMHD1 deficiency was also associated with weaker NK, CD4+ T and CD8+ T cell responses by 14 dpi and weaker neutralizing Ab responses by 28 dpi. Intriguingly, SAMHD1 influenced these cell-mediated immune (14 dpi) and neutralizing Ab (28 dpi) responses in male but not female mice. Our findings formally demonstrate SAMHD1 as an antiretroviral factor in vivo that could promote adaptive immune responses in a sex-dependent manner. The requirement for LPS to unravel the SAMHD1 immunological phenotype suggests that comorbidities associated with a "leaky" gut barrier may influence the antiviral function of SAMHD1 in vivo.
  11. J Clin Med. 2021 Nov 26. pii: 5529. [Epub ahead of print]10(23):
      Hepatis virus C (HCV) infection causes liver cirrhosis and hepatocellular carcinoma (HCC) worldwide. The objective of our study was to examine the effects of the HCV nonstructural protein (NS) 3/4A inhibitor glecaprevir/NS5A inhibitor pibrentasvir on real-world HCV patients in the northern part of Tokyo, Japan. Although 106 patients were consecutively included, a total of 102 HCV-infected patients with chronic hepatitis or compensated cirrhosis, who received 8- or 12-week combination treatment with glecaprevir/pibrentasvir and were followed up to week 12 after the end of treatment were analyzed retrospectively. Only three patients discontinued treatment due to adverse events; however, they achieved a sustained virologic response at 12 weeks (SVR12). Finally, SVR rates were 99.0% (101/102). Only one patient without liver cirrhosis was a treatment relapser who received hepatic resection for HCC approximately two years after commencement of the 8-week combination treatment with glecaprevir/pibrentasvir. After the exclusion of patients with HCV genotype 1b and P32 deletion in the HCV NS5A region, a 12-week combination of glecaprevir/pibrentasvir led to SVR12 in all nine direct-acting antiviral-experienced patients. Glecaprevir/pibrentasvir had a high efficacy and an acceptable safety profile for real-world HCV patients in a single hospital in Japan.
    Keywords:  DAA failure; HCV; NS5A P32 deletion mutant; chronic kidney disease; hemodialysis
  12. FEBS J. 2021 Dec 06.
      Microglial homeostasis has emerged as a critical mediator of health and disease in the central nervous system. In their neuroprotective role as the predominant immune cells of the brain, microglia surveil the microenvironment for debris and pathogens, while also promoting neurogenesis and performing maintenance on synapses. Chronological aging, disease onset, or traumatic injury promotes irreparable damage or deregulated signaling to reinforce neurotoxic phenotypes in microglia. These insults may include cellular senescence, a stable growth arrest often accompanied by the production of a distinctive pro-inflammatory secretory phenotype, which may contribute to age- or disease-driven decline in neuronal health and cognition and is a potential novel therapeutic target. Despite this increased scrutiny, unanswered questions remain about what distinguishes senescent microglia and non-senescent microglia reacting to insults occurring in aging, disease, and injury, and how central the development of senescence is in their pivot from guardian to assailant. To intelligently design future studies to untangle senescent microglia from other primed and reactionary states, specific criteria must be developed that define this population and allow for comparisons between different model systems. Comparing microglial activity seen in homeostasis, aging, disease, and injury allows for a more coherent understanding of when and how senescent and other harmful microglial subpopulations should be targeted.
    Keywords:  TBI; aging; microglia; neurodegenerative disease; senescence
  13. Front Immunol. 2021 ;12 777788
      T cell receptors (TCRs) are unique markers that define antigen specificity for a given T cell. With the evolution of sequencing and computational analysis technologies, TCRs are now prime candidates for the development of next-generation non-cell based T cell biomarkers, which provide a surrogate measure to assess the presence of antigen-specific T cells. Type 1 diabetes (T1D), the immune-mediated form of diabetes, is a prototypical organ specific autoimmune disease in which T cells play a pivotal role in targeting pancreatic insulin-producing beta cells. While the disease is now predictable by measuring autoantibodies in the peripheral blood directed to beta cell proteins, there is an urgent need to develop T cell markers that recapitulate T cell activity in the pancreas and can be a measure of disease activity. This review focuses on the potential and challenges of developing TCR biomarkers for T1D. We summarize current knowledge about TCR repertoires and clonotypes specific for T1D and discuss challenges that are unique for autoimmune diabetes. Ultimately, the integration of large TCR datasets produced from individuals with and without T1D along with computational 'big data' analysis will facilitate the development of TCRs as potentially powerful biomarkers in the development of T1D.
    Keywords:  HLA; MHC; T cells; TCR sequencing; autoimmunity; type 1 diabetes
  14. Nat Commun. 2021 Dec 09. 12(1): 7172
      Complement receptor of immunoglobulin superfamily (CRIg) is expressed on liver macrophages and directly binds complement component C3b or Gram-positive bacteria to mediate phagocytosis. CRIg plays important roles in several immune-mediated diseases, but it is not clear how its pathogen recognition and phagocytic functions maintain homeostasis and prevent disease. We previously associated cytolysin-positive Enterococcus faecalis with severity of alcohol-related liver disease. Here, we demonstrate that CRIg is reduced in liver tissues from patients with alcohol-related liver disease. CRIg-deficient mice developed more severe ethanol-induced liver disease than wild-type mice; disease severity was reduced with loss of toll-like receptor 2. CRIg-deficient mice were less efficient than wild-type mice at clearing Gram-positive bacteria such as Enterococcus faecalis that had translocated from gut to liver. Administration of the soluble extracellular domain CRIg-Ig protein protected mice from ethanol-induced steatohepatitis. Our findings indicate that ethanol impairs hepatic clearance of translocated pathobionts, via decreased hepatic CRIg, which facilitates progression of liver disease.
  15. Mol Metab. 2021 Dec 07. pii: S2212-8778(21)00270-2. [Epub ahead of print] 101412
      OBJECTIVE: Multiple GWAS have identified SNPs in the 8q24 locus near TRIB1 that significantly associate with plasma lipids and other markers of cardiometabolic health, and prior studies have uncovered roles for hepatic and myeloid Trib1 in plasma lipid regulation and atherosclerosis. The same 8q24 SNPs additionally associate with plasma adiponectin levels in humans, implicating TRIB1 in adipocyte biology. Here, we hypothesize that TRIB1 in adipose tissue regulates plasma adiponectin, lipids, and metabolic health.METHODS: We investigate the metabolic phenotype of adipocyte-specific Trib1 knockout mice (Trib1_ASKO) on chow and high fat diet. Through secretomics of adipose tissue explants and RNA-seq of adipocytes and livers from these mice, we further investigate the mechanism of TRIB1 in adipose tissue.
    RESULTS: Trib1_ASKO mice have an improved metabolic phenotype with increased plasma adiponectin levels, improved glucose tolerance, and decreased plasma lipids. Trib1_ASKO adipocytes have increased adiponectin production and secretion independent of the known TRIB1 function of regulating proteasomal degradation. RNA-seq analysis of adipocytes and livers from Trib1_ASKO mice suggests that alterations in adipocyte function underlie the observed plasma lipid changes. Adipose tissue explant secretomics further reveals that Trib1_ASKO adipose tissue has decreased ANGPTL4 production, and we demonstrate an accompanying increase in LPL activity that likely underlies the triglyceride phenotype.
    CONCLUSION: Adipocyte Trib1 regulates multiple aspects of metabolic health, confirming previously observed genetic associations in humans and shedding light on further mechanisms by which TRIB1 regulates plasma lipids and metabolic health.
    Keywords:  Adipose; GWAS; Lipoproteins; Metabolic Syndrome; Pseudokinases; Tribbles
  16. Proc Natl Acad Sci U S A. 2021 Dec 14. pii: e2109972118. [Epub ahead of print]118(50):
      TNF, produced largely by T and innate immune cells, is potently proinflammatory, as are cytokines such as IFN-γ and IL-17 produced by Th1 and Th17 cells, respectively. Here, we asked if TNF is upstream of Th skewing toward inflammatory phenotypes. Exposure of mouse CD4+ T cells to TNF and TGF-β generated Th17 cells that express low levels of IL-17 (ROR-γt+IL-17lo) and high levels of inflammatory markers independently of IL-6 and STAT3. This was mediated by the nondeath TNF receptor TNFR2, which also contributed to the generation of inflammatory Th1 cells. Single-cell RNA sequencing of central nervous system-infiltrating CD4+ T cells in mouse experimental autoimmune encephalomyelitis (EAE) found an inflammatory gene expression profile similar to cerebrospinal fluid-infiltrating CD4+ T cells from patients with multiple sclerosis. Notably, TNFR2-deficient CD4+ T cells produced fewer inflammatory mediators and were less pathogenic in EAE and colitis. IL-1β, a Th17-skewing cytokine, induced TNF and proinflammatory granulocyte-macrophage colony-stimulating factor (GM-CSF) in T cells, which was inhibited by disruption of TNFR2 signaling, demonstrating IL-1β can function indirectly via the production of TNF. Thus, TNF is not just an effector but also an initiator of inflammatory Th differentiation.
    Keywords:  GM-CSF; TNFR2; Th skewing; inflammatory disease
  17. Nat Med. 2021 Dec 09.
      Intracranial aneurysm (IA) rupture leads to subarachnoid hemorrhage, a sudden-onset disease that often causes death or severe disability. Although genome-wide association studies have identified common genetic variants that increase IA risk moderately, the contribution of variants with large effect remains poorly defined. Using whole-exome sequencing, we identified significant enrichment of rare, deleterious mutations in PPIL4, encoding peptidyl-prolyl cis-trans isomerase-like 4, in both familial and index IA cases. Ppil4 depletion in vertebrate models causes intracerebral hemorrhage, defects in cerebrovascular morphology and impaired Wnt signaling. Wild-type, but not IA-mutant, PPIL4 potentiates Wnt signaling by binding JMJD6, a known angiogenesis regulator and Wnt activator. These findings identify a novel PPIL4-dependent Wnt signaling mechanism involved in brain-specific angiogenesis and maintenance of cerebrovascular integrity and implicate PPIL4 gene mutations in the pathogenesis of IA.
  18. Immunol Cell Biol. 2021 Dec 09.
      Regulatory T cells (Tregs) are a specialised immune cell type that plays important roles in regulating immune responses. However, those found in adipose tissue, particularly visceral adipose tissue (VAT), have also been shown to exert metabolic regulatory functions. In this study, we investigate the requirement of the miR-17~92a cluster of microRNAs in VAT Tregs and the impact on blood glucose. This cluster of microRNAs is one that we previously showed to be important for the fitness of Tregs found in secondary lymphoid organs. We found that male mice with Treg-specific miR-17~92a deficiency are resistant to impaired glucose tolerance induced by a high-fat diet. However, high-fat feeding still impaired glucose tolerance in female mice with Treg-specific miR-17~92a deficiency. There was an increase in KLRG1- naïve Tregs and a loss of KLRG1+ terminally differentiated Tregs in the VAT of Treg-specific miR-17~92a deficient male mice but not female mice. The protection of male mice from high-fat feeding was also associated with increased IL-10 and reduced IFNγ expression by conventional CD4+ T cells and reduced IL-2 expression by both CD4+ and CD8+ T cells in the VAT. Together this suggests that expression of miR-17~92a by VAT Tregs regulates the effector phenotype of conventional T cells and in turn the metabolic function of adipose tissue and blood glucose homeostasis.
    Keywords:  MicroRNA; adipose tissue; blood glucose; regulatory T cells
  19. J Inflamm Res. 2021 ;14 6477-6489
      Purpose: Methylglyoxal (MGO) is a highly reactive dicarbonyl species implicated in diabetic-associated diseases. Acute lung injury (ALI) symptoms and prognosis are worsened by diabetes and obesity. Here, we hypothesized that elevated MGO levels aggravate ALI, which can be prevented by metformin. Therefore, this study evaluated the lung inflammation in lipopolysaccharide (LPS)-exposed mice pretreated with MGO.Methods: C57Bl/6 male mice treated or not with MGO for 12 weeks were intranasally instilled with LPS (30 µg) to induce ALI, and metformin (300 mg/kg) was given as gavage in the last two weeks of treatment. After 6 h, bronchoalveolar lavage fluid (BALF) and lung tissues were collected to quantify the cell infiltration, cytokine levels, reactive-oxygen species (ROS) production, and RAGE expression.
    Results: LPS exposure markedly increased the neutrophil infiltration in BALF and lung tissue, which was accompanied by higher levels of IFN-γ, TNF-α and IL-1β compared with untreated group. MGO treatment significantly increased the airways neutrophil infiltration and mRNA expressions of TNF-α and IL-1β, whereas COX-2 expression remained unchanged. In lung tissues of LPS-exposed mice, MGO treatment significantly increased the immunostaining and mRNA expression of RAGE, and the ROS levels. Serum MGO concentration achieved after 12-week intake was 9.2-fold higher than control mice, which was normalized by metformin treatment. Metformin also reduced the inflammatory markers in response to MGO.
    Conclusion: MGO intake potentiates the LPS-induced ALI, increases RAGE expression and ROS generation, which is normalized by metformin. MGO scavengers may be a good adjuvant therapy to reduce ALI in patients with cardiometabolic diseases.
    Keywords:  advanced glycated end products; airways; immunohistochemistry; neutrophil
  20. Front Immunol. 2021 ;12 777860
      Despite long-term mass drug administration programmes, approximately 220 million people are still infected with filariae in endemic regions. Several research studies have characterized host immune responses but a major obstacle for research on human filariae has been the inability to obtain adult worms which in turn has hindered analysis on infection kinetics and immune signalling. Although the Litomosoides sigmodontis filarial mouse model is well-established, the complex immunological mechanisms associated with filarial control and disease progression remain unclear and translation to human infections is difficult, especially since human filarial infections in rodents are limited. To overcome these obstacles, we performed adoptive immune cell transfer experiments into RAG2IL-2Rγ-deficient C57BL/6 mice. These mice lack T, B and natural killer cells and are susceptible to infection with the human filaria Loa loa. In this study, we revealed a long-term release of L. sigmodontis offspring (microfilariae) in RAG2IL-2Rγ-deficient C57BL/6 mice, which contrasts to C57BL/6 mice which normally eliminate the parasites before patency. We further showed that CD4+ T cells isolated from acute L. sigmodontis-infected C57BL/6 donor mice or mice that already cleared the infection were able to eliminate the parasite and prevent inflammation at the site of infection. In addition, the clearance of the parasites was associated with Th17 polarization of the CD4+ T cells. Consequently, adoptive transfer of immune cell subsets into RAG2IL-2Rγ-deficient C57BL/6 mice will provide an optimal platform to decipher characteristics of distinct immune cells that are crucial for the immunity against rodent and human filarial infections and moreover, might be useful for preclinical research, especially about the efficacy of macrofilaricidal drugs.
    Keywords:  CD4+ and CD8+ T cells; Filariae; Litomosoides sigmodontis; Th17 polarization ; adoptive transfer; anti-filarial immunity
  21. Front Immunol. 2021 ;12 783882
      It has been reported that several immune cells can release chromatin and granular proteins into extracellular space in response to the stimulation, forming extracellular traps (ETs). The cells involved in the extracellular trap formation are recognized including neutropils, macrophages, basophils, eosinophils, and mast cells. With the development of research related to central nervous system, the role of ETs has been valued in neuroinflammation, blood-brain barrier, and other fields. Meanwhile, it has been found that microglial cells as the resident immune cells of the central nervous system can also release ETs, updating the original understanding. This review aims to clarify the role of the ETs in the central nervous system, especially in neuroinflammation and blood-brain barrier.
    Keywords:  CNS; blood–brain barrier (BBB); extracellular traps; neurodegenaration; neuroinflammation; stroke
  22. Front Immunol. 2021 ;12 718359
      Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with widespread inflammation, immune dysregulation, and is associated with the generation of destructive anti-DNA autoantibodies. We have shown previously the immune modulatory properties of pCons peptide in the induction of both CD4+ and CD8+ regulatory T cells which can in turn suppress development of the autoimmune disease in (NZB/NZW) F1 (BWF1) mice, an established model of lupus. In the present study, we add novel protein information and further demonstrate the molecular and cellular phenotypes of pCons-induced CD4+ and CD8+ Treg subsets. Flow cytometry analyses revealed that pCons induced CD8+ Treg cells with the following cell surface molecules: CD25highCD28high and low subsets (shown earlier), CD62Lhigh, CD122low, PD1low, CTLA4low, CCR7low and 41BBhigh. Quantitative real-time PCR (qRT-PCR) gene expression analyses revealed that pCons-induced CD8+ Treg cells downregulated the following several genes: Regulator of G protein signaling (RGS2), RGS16, RGS17, BAX, GPT2, PDE3b, GADD45β and programmed cell death 1 (PD1). Further, we confirmed the down regulation of these genes by Western blot analyses at the protein level. To our translational significance, we showed herein that pCons significantly increased the percentage of CD8+FoxP3+ T cells and further increased the mean fluorescence intensity (MFI) of FoxP3 when healthy peripheral blood mononuclear cells (PBMCs) are treated with pCons (10 μg/ml, for 24-48 hours). In addition, we found that pCons reduced apoptosis in CD4+ and CD8+ T cells and B220+ B cells of BWF1 lupus mice. These data suggest that pCons stimulates cellular, immunological, and molecular changes in regulatory T cells which in turn protect against SLE autoimmunity.
    Keywords:  anti-DNA Ab; immune regulation; immune tolerance; pCons; regulatory T cells; systemic lupus erythematosus
  23. J Immunol. 2021 Dec 10. pii: ji2100514. [Epub ahead of print]
      T cells must shift their metabolism to respond to infections and tumors and to undergo memory formation. The ATP-binding cassette transporter ABCB10 localizes to the mitochondrial inner membrane, where it is thought to export a substrate important in heme biosynthesis and metabolism, but its role in T cell development and activation is unknown. In this article, we use a combination of methods to study the effect of ABCB10 loss in primary and malignantly transformed T cells. Although Abcb10 is dispensable for development of both CD4+ and CD8+ T cells, it is required for expression of specific cytokines in CD4+, but not CD8+, T cells activated in vitro. These defects in cytokine expression are magnified on repeated stimulation. In vivo, CD8+ cells lacking ABCB10 expand more in response to viral infection than their control counterparts, while CD4+ cells show reductions in both number and percentage. CD4+ cells lacking ABCB10 show impairment in Ag-specific memory formation and recall responses that become more severe with time. In malignant human CD4+ Jurkat T cells, we find that CRISPR-mediated ABCB10 disruption recapitulates the same cytokine expression defects upon activation as observed in primary mouse T cells. Mechanistically, ABCB10 deletion in Jurkat T cells disrupts the ability to switch to aerobic glycolysis upon activation. Cumulatively, these results show that ABCB10 is selectively required for specific cytokine responses and memory formation in CD4+ T cells, suggesting that targeting this molecule could be used to mitigate aberrant T cell activation.
  24. Sci Rep. 2021 Dec 08. 11(1): 23604
      Osteopontin (OPN) is a proinflammatory marker produced by systemic immune and central nervous system (CNS) resident cells. We examined, if the level of OPN in the cerebrospinal fluid (CSF) and blood is associated with late-time regional brain volumes and white matter (WM) lesion load in MS. Concentrations of OPN in blood and CSF were related to MRI findings 10.1 ± 2.0 years later in 46 patients with MS. OPN concentration was measured by ELISA, while regional brain volumes and lesion load was assessed by magnetic resonance imaging (MRI) using 3D MPRAGE sequence and automated MR volumetry. OPN measured in the CSF was associated with several regional brain volumes and WM lesion load measured 10.1 ± 2.0 years later. CSF OPN concentration correlated with long-term enlargement of lateral- and inferior lateral ventricles and the elevation of gross CSF volume, in conjunction with the reduction of several cortical/subcortical gray matter and WM volumes. Serum OPN showed no long-term association with regional brain volumes. OPN measured from the CSF but not from the serum was associated with lower regional brain volumes measured a decade later, indicating the primary role of inflammation within the CNS in developing long-term brain related alterations.
  25. FASEB J. 2022 Jan;36(1): e21995
      While the eye is considered an immune privileged site, its privilege is abrogated when immune cells are recruited from the surrounding vasculature in response to trauma, infection, aging, and autoimmune diseases like uveitis. Here, we investigate whether in uveitis immune cells become associated with the lens capsule and compromise its privilege in studies of C57BL/6J mice with experimental autoimmune uveitis. These studies show that at D14, the peak of uveitis in these mice, T cells, macrophages, and Ly6G/Ly6C+ immune cells associate with the lens basement membrane capsule, burrow into the capsule matrix, and remain integrated with the capsule as immune resolution is occurring at D26. 3D surface rendering image analytics of confocal z-stacks and scanning electron microscopy imaging of the lens surface show the degradation of the lens capsule as these lens-associated immune cells integrate with and invade the lens capsule, with a subset infiltrating both epithelial and fiber cell regions of lens tissue, abrogating its immune privilege. Those immune cells that remain on the surface often become entwined with a fibrillar net-like structure. Immune cell invasion of the lens capsule in uveitis has not been described previously and may play a role in induction of lens and other eye pathologies associated with autoimmunity.
    Keywords:  basement membrane; immune cell attachment; immune cell infiltration; immune cell migration; immune privilege; inflammation; lens; matrix; uveitic
  26. Mol Metab. 2021 Dec 07. pii: S2212-8778(21)00271-4. [Epub ahead of print] 101413
      OBJECTIVES: Loss of functional β-cell mass is a key factor contributing to poor glycaemic control in advanced type 2 diabetes. We previously reported that inhibition of the neuropeptide Y1 receptor improves islet transplantation outcome in type 1 diabetes. The aim of this study was to identify the pathophysiological role of the neuropeptide Y system in human type 2 diabetes, and further evaluate the therapeutic potential of using the neuropeptide Y1 receptor antagonist, BIBO3304 to improve β-cell function and survival in type 2 diabetes.METHODS: The gene expression of the NPY system in human islets from non-diabetic and subjects with type 2 diabetes was determined and correlated with stimulation index. The glucose lowering and β-cell protective effects of BIBO3304, a selective orally bioavailable neuropeptide Y1 receptor antagonist, in high-fat-diet/multiple low-dose streptozotocin- and genetic obese (db/db) type 2 diabetic mouse models were assessed.
    RESULTS: In this study, we identified a more than 2-fold increase in neuropeptide Y1 receptor and its ligand, neuropeptide Y mRNA expression in primary human islets from subjects with type 2 diabetes, which was significantly associated with reduced insulin secretion. Consistently, pharmacological inhibition of Y1 receptors by BIBO3304 significantly protected β cells from dysfunction and death under multiple diabetogenic conditions in islets. In preclinical study, we demonstrated that inhibition of Y1 receptors by BIBO3304 led to reduced adiposity and enhanced insulin action in skeletal muscle. Importantly, Y1 receptor antagonist BIBO3304 treatment also improved β-cell function and preserved functional β-cell mass, thereby resulting in better glycaemic control in both high-fat-diet/multiple low-dose streptozotocin- and db/db type 2 diabetic mice.
    CONCLUSIONS: Our results uncovered a novel causal link of increased islet NPY-Y1 receptor gene expression to β-cell dysfunction and failure in human type 2 diabetes, contributing to the understanding of the pathophysiology of type 2 diabetes. Furthermore, our results demonstrate that inhibition of Y1 receptor by BIBO3304 represents a potential β-cell protective therapy for improving functional β-cell mass and glycaemic control in type 2 diabetes.
    Keywords:  NPY; Y1 receptor; insulin secretion; type 2 diabetes; β-cell
  27. Front Cell Dev Biol. 2021 ;9 716604
      Chronic intestinal inflammation and microbial dysbiosis are hallmarks of colorectal cancer (CRC) and inflammatory bowel diseases (IBD), such as Crohn's disease and ulcerative colitis. However, the mechanistic relationship between gut dysbiosis and disease has not yet been fully characterized. Although the "trigger" of intestinal inflammation remains unknown, a wealth of evidence supports the role of the gut microbiome as a mutualistic pseudo-organ that significantly influences intestinal homeostasis and is capable of regulating host immunity. In recent years, culture-independent methods for assessing microbial communities as a whole (termed meta-omics) have grown beyond taxonomic identification and genome characterization (metagenomics) into new fields of research that collectively expand our knowledge of microbiomes. Metatranscriptomics, metaproteomics, and metabolomics are meta-omics techniques that aim to describe and quantify the functional activity of the gut microbiome. Uncovering microbial metabolic contributions in the context of IBD and CRC using these approaches provides insight into how the metabolic microenvironment of the GI tract shapes microbial community structure and how the microbiome, in turn, influences the surrounding ecosystem. Immunological studies in germ-free and wild-type mice have described several host-microbiome interactions that may play a role in autoinflammation. Chronic colitis is a precursor to CRC, and changes in the gut microbiome may be an important link triggering the neoplastic process in chronic colitis. In this review, we describe several microbiome-mediated mechanisms of host immune signaling, such as short-chain fatty acid (SCFA) and bile acid metabolism, inflammasome activation, and cytokine regulation in the context of IBD and CRC, and discuss the supporting role for these mechanisms by meta-omics data.
    Keywords:  colorectal cancer; gut microbiome; inflammatory bowel diesases; metabolomics; metagenomics; metaproteomics
  28. Elife. 2021 Dec 08. pii: e69182. [Epub ahead of print]10
      The cellular barriers of the central nervous system proficiently protect the brain parenchyma from infectious insults. Yet, the single-celled parasite Toxoplasma gondii commonly causes latent cerebral infection in humans and other vertebrates. Here, we addressed the role of the cerebral vasculature in the passage of T. gondii to the brain parenchyma. Shortly after inoculation in mice, parasites mainly localized to cortical capillaries, in preference over post-capillary venules, cortical arterioles or meningeal and choroidal vessels. Early invasion to the parenchyma (days 1-5) occurred in absence of a measurable increase in blood-brain barrier (BBB) permeability, perivascular leukocyte cuffs or hemorrhage. However, sparse focalized permeability elevations were detected adjacently to replicative parasite foci. Further, T. gondii triggered inflammatory responses in cortical microvessels and endothelium. Pro- and anti-inflammatory treatments of mice with LPS and hydrocortisone, respectively, impacted BBB permeability and parasite loads in the brain parenchyma. Finally, pharmacological inhibition or Cre/loxP conditional knockout of endothelial focal adhesion kinase (FAK), a BBB intercellular junction regulator, facilitated parasite translocation to the brain parenchyma. The data reveal that the initial passage of T. gondii to the central nervous system occurs principally across cortical capillaries. The integrity of the microvascular BBB restricts parasite transit, which conversely is exacerbated by the inflammatory response.
    Keywords:  immunology; infectious disease; inflammation; microbiology; mouse
  29. Sci Rep. 2021 Dec 08. 11(1): 23607
      Circulating CD4+CD8+ double-positive (DP) T cells are associated with a variety of disease states. However, unlike conventional T cells, the composition of this population is poorly understood. Here, we used single-cell RNA sequencing (scRNA-seq) to analyze the composition and characteristics of the DP T cell population circulating in the peripheral blood of cynomolgus monkeys. We found that circulating DP T cells not only contain a large number of naïve cells, but also comprise a heterogeneous population (CD4 CTL-, Eomes+ Tr1-, Th2-, Th17-, Tfh-, Treg-, CD8 CTL-, and innate-like cells) with multiple potential functions. Flow cytometry analysis revealed that a substantial number of the naïve DP T cells expressed CD8αβ, as well as CD8αα, along with high expression of CD31. Moreover, the CD4hiCD8lo and CD4hiCD8hi populations, which express high levels of the CD4 coreceptor, comprised subsets characterized by helper and regulatory functions, some of which also exhibited cytotoxic functions. By contrast, the CD4loCD8hi population with high CD8 coreceptor expression comprised a subset characterized by CD8 CTL- and innate-like properties. Taken together, the data show that scRNA-seq analysis identified a more diverse subset of the circulating DP cells than is currently known, despite this population being very small.
  30. Front Immunol. 2021 ;12 667834
      Transplantation (Tx) remains the optimal therapy for end-stage disease (ESD) of various solid organs. Although alloimmune events remain the leading cause of long-term allograft loss, many patients develop innate and adaptive immune responses leading to graft tolerance. The focus of this review is to provide an overview of selected aspects of the effects of inflammation on this delicate balance following solid organ transplantation. Initially, we discuss the inflammatory mediators detectable in an ESD patient. Then, the specific inflammatory mediators found post-Tx are elucidated. We examine the reciprocal relationship between donor-derived passenger leukocytes (PLs) and those of the recipient, with additional emphasis on extracellular vesicles, specifically exosomes, and we examine their role in determining the balance between tolerance and rejection. The concept of recipient antigen-presenting cell "cross-dressing" by donor exosomes is detailed. Immunological consequences of the changes undergone by cell surface antigens, including HLA molecules in donor and host immune cells activated by proinflammatory cytokines, are examined. Inflammation-mediated donor endothelial cell (EC) activation is discussed along with the effect of donor-recipient EC chimerism. Finally, as an example of a specific inflammatory mediator, a detailed analysis is provided on the dynamic role of Interleukin-6 (IL-6) and its receptor post-Tx, especially given the potential for therapeutic interdiction of this axis with monoclonal antibodies. We aim to provide a holistic as well as a reductionist perspective of the inflammation-impacted immune events that precede and follow Tx. The objective is to differentiate tolerogenic inflammation from that enhancing rejection, for potential therapeutic modifications. (Words 247).
    Keywords:  IL-6; allograft; endothelial cells; exosomes; inflammation; rejection; tolerance
  31. Proc Natl Acad Sci U S A. 2021 Dec 07. pii: e2106623118. [Epub ahead of print]118(49):
      Endothelial dysfunction is associated with vascular disease and results in disruption of endothelial barrier function and increased sensitivity to apoptosis. Currently, there are limited treatments for improving endothelial dysfunction. Activated protein C (aPC), a promising therapeutic, signals via protease-activated receptor-1 (PAR1) and mediates several cytoprotective responses, including endothelial barrier stabilization and anti-apoptotic responses. We showed that aPC-activated PAR1 signals preferentially via β-arrestin-2 (β-arr2) and dishevelled-2 (Dvl2) scaffolds rather than G proteins to promote Rac1 activation and barrier protection. However, the signaling pathways utilized by aPC/PAR1 to mediate anti-apoptotic activities are not known. aPC/PAR1 cytoprotective responses also require coreceptors; however, it is not clear how coreceptors impact different aPC/PAR1 signaling pathways to drive distinct cytoprotective responses. Here, we define a β-arr2-mediated sphingosine kinase-1 (SphK1)-sphingosine-1-phosphate receptor-1 (S1PR1)-Akt signaling axis that confers aPC/PAR1-mediated protection against cell death. Using human cultured endothelial cells, we found that endogenous PAR1 and S1PR1 coexist in caveolin-1 (Cav1)-rich microdomains and that S1PR1 coassociation with Cav1 is increased by aPC activation of PAR1. Our study further shows that aPC stimulates β-arr2-dependent SphK1 activation independent of Dvl2 and is required for transactivation of S1PR1-Akt signaling and protection against cell death. While aPC/PAR1-induced, extracellular signal-regulated kinase 1/2 (ERK1/2) activation is also dependent on β-arr2, neither SphK1 nor S1PR1 are integrated into the ERK1/2 pathway. Finally, aPC activation of PAR1-β-arr2-mediated protection against apoptosis is dependent on Cav1, the principal structural protein of endothelial caveolae. These studies reveal that different aPC/PAR1 cytoprotective responses are mediated by discrete, β-arr2-driven signaling pathways in caveolae.
    Keywords:  GPCR; biased signaling; cytoprotection; endothelial dysfunction