bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2022‒01‒30
28 papers selected by
Fawaz Alzaïd
Sorbonne Université

  1. JAMA. 2022 01 25. 327(4): 350-359
      Importance: Population-based assessment of disease risk associated with gene variants informs clinical decisions and risk stratification approaches.Objective: To evaluate the population-based disease risk of clinical variants in known disease predisposition genes.
    Design, Setting, and Participants: This cohort study included 72 434 individuals with 37 780 clinical variants who were enrolled in the BioMe Biobank from 2007 onwards with follow-up until December 2020 and the UK Biobank from 2006 to 2010 with follow-up until June 2020. Participants had linked exome and electronic health record data, were older than 20 years, and were of diverse ancestral backgrounds.
    Exposures: Variants previously reported as pathogenic or predicted to cause a loss of protein function by bioinformatic algorithms (pathogenic/loss-of-function variants).
    Main Outcomes and Measures: The primary outcome was the disease risk associated with clinical variants. The risk difference (RD) between the prevalence of disease in individuals with a variant allele (penetrance) vs in individuals with a normal allele was measured.
    Results: Among 72 434 study participants, 43 395 were from the UK Biobank (mean [SD] age, 57 [8.0] years; 24 065 [55%] women; 2948 [7%] non-European) and 29 039 were from the BioMe Biobank (mean [SD] age, 56 [16] years; 17 355 [60%] women; 19 663 [68%] non-European). Of 5360 pathogenic/loss-of-function variants, 4795 (89%) were associated with an RD less than or equal to 0.05. Mean penetrance was 6.9% (95% CI, 6.0%-7.8%) for pathogenic variants and 0.85% (95% CI, 0.76%-0.95%) for benign variants reported in ClinVar (difference, 6.0 [95% CI, 5.6-6.4] percentage points), with a median of 0% for both groups due to large numbers of nonpenetrant variants. Penetrance of pathogenic/loss-of-function variants for late-onset diseases was modified by age: mean penetrance was 10.3% (95% CI, 9.0%-11.6%) in individuals 70 years or older and 8.5% (95% CI, 7.9%-9.1%) in individuals 20 years or older (difference, 1.8 [95% CI, 0.40-3.3] percentage points). Penetrance of pathogenic/loss-of-function variants was heterogeneous even in known disease predisposition genes, including BRCA1 (mean [range], 38% [0%-100%]), BRCA2 (mean [range], 38% [0%-100%]), and PALB2 (mean [range], 26% [0%-100%]).
    Conclusions and Relevance: In 2 large biobank cohorts, the estimated penetrance of pathogenic/loss-of-function variants was variable but generally low. Further research of population-based penetrance is needed to refine variant interpretation and clinical evaluation of individuals with these variant alleles.
  2. Front Immunol. 2021 ;12 789788
      Innate lymphoid cells (ILC) are a heterogeneous group of immune cells characterized by lymphoid morphology and cytokine profile similar to T cells but which do not express clonally distributed diverse antigen receptors. These particular cells express transcription factors and cytokines reflecting their similarities to T helper (Th)1, Th2, and Th17 cells and are therefore referred to as ILC1, ILC2, and ILC3. Other members of the ILC subsets include lymphoid tissue inducer (LTi) and regulatory ILC (ILCreg). Natural killer (NK) cells share a common progenitor with ILC and also exhibit a lymphoid phenotype without antigen specificity. ILC are found in low numbers in peripheral blood but are much more abundant at barrier sites such as the skin, liver, airways, lymph nodes, and the gastrointestinal tract. They play an important role in innate immunity due to their capacity to respond rapidly to pathogens through the production of cytokines. Recent evidence has shown that ILC also play a key role in autoimmunity, as alterations in their number or function have been identified in systemic lupus erythematosus, systemic sclerosis, and rheumatoid arthritis. Here, we review recent advances in the understanding of the role of ILC in the pathogenesis of autoimmune diseases, with particular emphasis on their role as a potential diagnostic biomarker and as therapeutic targets.
    Keywords:  ANCA-associated vasculitis; NK cell; autoimmune diseases; autoimmunity; innate lymphoid cell (ILC); rheumatoid arthritis; systemic lupus erythematosus; systemic sclerosis
  3. J Hepatol. 2022 Jan 20. pii: S0168-8278(22)00006-X. [Epub ahead of print]
    Keywords:  NASH; fungi; microbiome; microbiota
  4. FASEB J. 2022 Feb;36(2): e22146
      Mitochondria are maternally inherited organelles that play critical tissue-specific roles, including hormone synthesis and energy production, that influence human development, health, and aging. However, whether mitochondria from women and men exhibit consistent biological differences remains unclear, representing a major gap in knowledge. This meta-analysis systematically examined four domains and six subdomains of mitochondrial biology (total 39 measures), including mitochondrial content, respiratory capacity, reactive oxygen species (ROS) production, morphometry, and mitochondrial DNA copy number. Standardized effect sizes (Hedge's g) of sex differences were computed for each measure using data in 2258 participants (51.5% women) from 50 studies. Only two measures demonstrated aggregate binary sex differences: higher mitochondrial content in women's WAT and isolated leukocyte subpopulations (g = 0.20, χ2 p = .01), and higher ROS production in men's skeletal muscle (g = 0.49, χ2 p < .0001). Sex differences showed weak to no correlation with age or BMI. Studies with small sample sizes tended to overestimate effect sizes (r = -.17, p < .001), and sex differences varied by tissue examined. Our findings point to a wide variability of findings in the literature concerning possible binary sex differences in mitochondrial biology. Studies specifically designed to capture sex- and gender-related differences in mitochondrial biology are needed, including detailed considerations of physical activity and sex hormones.
    Keywords:  mitochondrion; mtDNAcn; respirometry; sex differences; sexual dimorphism
  5. Nat Immunol. 2022 Jan 27.
      Intravital confocal microscopy and two-photon microscopy are powerful tools to explore the dynamic behavior of immune cells in mouse lymph nodes (LNs), with penetration depth of ~100 and ~300 μm, respectively. Here, we used intravital three-photon microscopy to visualize the popliteal LN through its entire depth (600-900 μm). We determined the laser average power and pulse energy that caused measurable perturbation in lymphocyte migration. Long-wavelength three-photon imaging within permissible parameters was able to image the entire LN vasculature in vivo and measure CD8+ T cells and CD4+ T cell motility in the T cell zone over the entire depth of the LN. We observed that the motility of naive CD4+ T cells in the T cell zone during lipopolysaccharide-induced inflammation was dependent on depth. As such, intravital three-photon microscopy had the potential to examine immune cell behavior in the deeper regions of the LN in vivo.
  6. FASEB J. 2022 Feb;36(2): e22169
      The role of mitochondria in enamel, the most mineralized tissue in the body, is poorly defined. Enamel is formed by ameloblast cells in two main sequential stages known as secretory and maturation. Defining the physiological features of each stage is essential to understand mineralization. Here, we analyzed functional features of mitochondria in rat primary secretory and maturation-stage ameloblasts focusing on their role in Ca2+ signaling. Quantification of the Ca2+ stored in the mitochondria by trifluoromethoxy carbonylcyanide phenylhydrazone stimulation was comparable in both stages. The release of endoplasmic reticulum Ca2+ pools by adenosine triphosphate in rhod2AM-loaded cells showed similar mitochondrial Ca2+ (m Ca2+ ) uptake. However, m Ca2+ extrusion via Na+ -Li+ -Ca2+ exchanger was more prominent in maturation. To address if m Ca2+ uptake via the mitochondrial Ca2+ uniporter (MCU) played a role in cytosolic Ca2+ (c Ca2+ ) buffering, we stimulated Ca2+ influx via the store-operated Ca2+ entry (SOCE) and blocked MCU with the inhibitor Ru265. This inhibitor was first tested using the enamel cell line LS8 cells. Ru265 prevented c Ca2+ clearance in permeabilized LS8 cells like ruthenium red, and it did not affect ΔΨm in intact cells. In primary ameloblasts, SOCE stimulation elicited a significantly higher m Ca2+ uptake in maturation ameloblasts. The uptake of Ca2+ into the mitochondria was dramatically decreased in the presence of Ru265. Combined, these results suggest an increased mitochondrial Ca2+ handling in maturation but only upon stimulation of Ca2+ influx via SOCE. These functional studies provide insights not only on the role of mitochondria in ameloblast Ca2+ physiology, but also advance the concept that SOCE and m Ca2+ uptake are complementary processes in biological mineralization.
    Keywords:  MCU; enamel; maturation; mitochondria; secretory
  7. Nat Commun. 2022 Jan 26. 13(1): 528
      Neutrophils perform critical functions in the innate response to infection, including through the production of neutrophil extracellular traps (NETs) - web-like DNA structures which are extruded from neutrophils upon activation. Elevated levels of NETs have been linked to autoimmunity but this association is poorly understood. By contrast, IL-17 producing Th17 cells are a key player in various autoimmune diseases but are also crucial for immunity against fungal and bacterial infections. Here we show that NETs, through their protein component histones, directly activate T cells and specifically enhance Th17 cell differentiation. This modulatory role of neutrophils, NETs and their histones is mediated downstream of TLR2 in T cells, resulting in phosphorylation of STAT3. The innate stimulation of a specific adaptive immune cell subset provides an additional mechanism demonstrating a direct link between neutrophils, NETs and T cell autoimmunity.
  8. Nat Commun. 2022 Jan 26. 13(1): 512
      Mechanical overload of the vascular wall is a pathological hallmark of life-threatening abdominal aortic aneurysms (AAA). However, how this mechanical stress resonates at the unicellular level of vascular smooth muscle cells (VSMC) is undefined. Here we show defective mechano-phenotype signatures of VSMC in AAA measured with ultrasound tweezers-based micromechanical system and single-cell RNA sequencing technique. Theoretical modelling predicts that cytoskeleton alterations fuel cell membrane tension of VSMC, thereby modulating their mechanoallostatic responses which are validated by live micromechanical measurements. Mechanistically, VSMC gradually adopt a mechanically solid-like state by upregulating cytoskeleton crosslinker, α-actinin2, in the presence of AAA-promoting signal, Netrin-1, thereby directly powering the activity of mechanosensory ion channel Piezo1. Inhibition of Piezo1 prevents mice from developing AAA by alleviating pathological vascular remodeling. Our findings demonstrate that deviations of mechanosensation behaviors of VSMC is detrimental for AAA and identifies Piezo1 as a novel culprit of mechanically fatigued aorta in AAA.
  9. Nat Commun. 2022 Jan 27. 13(1): 542
      Excitons play a dominant role in the optoelectronic properties of atomically thin van der Waals (vdW) semiconductors. These excitons are amenable to on-demand engineering with diverse control knobs, including dielectric screening, interlayer hybridization, and moiré potentials. However, external stimuli frequently yield heterogeneous excitonic responses at the nano- and meso-scales, making their spatial characterization with conventional diffraction-limited optics a formidable task. Here, we use a scattering-type scanning near-field optical microscope (s-SNOM) to acquire exciton spectra in atomically thin transition metal dichalcogenide microcrystals with previously unattainable 20 nm resolution. Our nano-optical data revealed material- and stacking-dependent exciton spectra of MoSe2, WSe2, and their heterostructures. Furthermore, we extracted the complex dielectric function of these prototypical vdW semiconductors. s-SNOM hyperspectral images uncovered how the dielectric screening modifies excitons at length scales as short as few nanometers. This work paves the way towards understanding and manipulation of excitons in atomically thin layers at the nanoscale.
  10. Front Immunol. 2021 ;12 752888
      Effector and regulatory functions of various leukocytes in allergic diseases have been well reported. Although the role of conventional natural killer (NK) cells has been established, information on its regulatory phenotype and function are very limited. Therefore, the objective of this study was to investigate the phenotype and inhibitory functions of transforming growth factor (TGF)-β-producing regulatory NK (NKreg) subset in mice with MC903-induced atopic dermatitis (AD). Interestingly, the population of TGF-β-producing NK cells in peripheral blood monocytes (PBMCs) was decreased in AD patients than in healthy subjects. The number of TGF-β+ NK subsets was decreased in the spleen or cervical lymph node (cLN), but increased in ear tissues of mice with AD induced by MC903 than those of normal mice. We further observed that TGF-β+ NK subsets were largely included in CD1dhiPD-L1hiCD27+ NK cell subset. We also found that numbers of ILC2s and TH2 cells were significantly decreased by adoptive transfer of CD1dhiPD-L1hiCD27+ NK subsets. Notably, the ratio of splenic Treg per TH2 was increased by the adoptive transfer of CD1dhiPD-L1hiCD27+ NK cells in mice. Taken together, our findings demonstrate that the TGF-β-producing CD1dhiPD-L1hiCD27+ NK subset has a previously unrecognized role in suppressing TH2 immunity and ILC2 activation in AD mice, suggesting that the function of TGF-β-producing NK subset is closely associated with the severity of AD in humans.
    Keywords:  T helper 2 (TH2) cells; atopic dermatitis (AD); group 2 innate lymphoid cells (ILC2s); regulatory natural killer cells (NKreg); transforming growth factor (TGF)-β
  11. Nat Commun. 2022 Jan 27. 13(1): 549
      Adjuvants hold great potential in enhancing vaccine efficacy, making the understanding and improving of adjuvants critical goals in vaccinology. The TLR7/8 agonist, 3M-052, induces long-lived humoral immunity in non-human primates and is currently being evaluated in human clinical trials. However, the innate mechanisms of 3M-052 have not been fully characterized. Here, we perform flow cytometry, single cell RNA-seq and ATAC-seq to profile the kinetics, transcriptomics and epigenomics of innate immune cells in murine draining lymph nodes following 3M-052-Alum/Ovalbumin immunization. We find that 3M-052-Alum/OVA induces a robust antiviral and interferon gene program, similar to the yellow fever vaccine, which is known to confer long-lasting protection. Activation of myeloid cells in dLNs persists through day 28 and single cell analysis reveals putative TF-gene regulatory programs in distinct myeloid cells and heterogeneity of monocytes. This study provides a comprehensive characterization of the transcriptomics and epigenomics of innate populations in the dLNs after vaccination.
  12. Cell Death Differ. 2022 Jan 24.
      Ferroptosis is an iron-dependent form of non-apoptotic cell death characterized by excessive lipid peroxidation and associated with a plethora of pathological conditions in the liver. Emerging evidence supports the notion that dysregulated metabolic pathways and impaired iron homeostasis play a role in the progression of liver disease via ferroptosis. Although the molecular mechanisms by which ferroptosis causes disease are poorly understood, several ferroptosis-associated genes and pathways have been implicated in liver disease. Here, we review the physiological role of the liver in processing nutrients, our current understanding of iron metabolism, the characteristics of ferroptosis, and the mechanisms that regulate ferroptosis. In addition, we summarize the role of ferroptosis in the pathogenesis of liver disease, including liver injury, non-alcoholic steatohepatitis, liver fibrosis, liver cirrhosis, and hepatocellular carcinoma. Finally, we discuss the therapeutic potential of targeting ferroptosis for managing liver disease.
  13. Sci Rep. 2022 Jan 24. 12(1): 1207
      Metabolic associated fatty liver disease (MAFLD), commonly known as non-alcoholic fatty liver disease, represents a continuum of events characterized by excessive hepatic fat accumulation which can progress to nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and in some severe cases hepatocellular carcinoma. MAFLD might be considered as a multisystem disease that affects not only the liver but involves wider implications, relating to several organs and systems, the brain included. The present study aims to investigate changes associated with MAFLD-induced alteration of thalamic metabolism in vivo. DIAMOND (Diet-induced animal model of non-alcoholic fatty liver disease) mice were fed a chow diet and tap water (NC NW) or fat Western Diet (WD SW) for up to 28 weeks. At the baseline and weeks 4, 8, 20, 28 the thalamic neurochemical profile and total cerebral brain volume were evaluated longitudinally in both diet groups using 1H-MRS. To confirm the disease progression, at each time point, a subgroup of animals was sacrificed, the livers excised and placed in formalin. Liver histology was assessed and reviewed by an expert liver pathologist. MAFLD development significantly increases the thalamic levels of total N-acetylaspartate, total creatine, total choline, and taurine. Furthermore, in the WD SW group a reduction in total cerebral brain volume has been observed (p < 0.05 vs NC NW). Our results suggest that thalamic energy metabolism is affected by MAFLD progression. This metabolic imbalance, that is quantifiable by 1H-MRS in vivo, might cause structural damage to brain cells and dysfunctions of neurotransmitter release.
  14. Nat Commun. 2022 Jan 25. 13(1): 494
      Chronic obstructive pulmonary disease (COPD) is a leading cause of death worldwide, however our understanding of cell specific mechanisms underlying COPD pathobiology remains incomplete. Here, we analyze single-cell RNA sequencing profiles of explanted lung tissue from subjects with advanced COPD or control lungs, and we validate findings using single-cell RNA sequencing of lungs from mice exposed to 10 months of cigarette smoke, RNA sequencing of isolated human alveolar epithelial cells, functional in vitro models, and in situ hybridization and immunostaining of human lung tissue samples. We identify a subpopulation of alveolar epithelial type II cells with transcriptional evidence for aberrant cellular metabolism and reduced cellular stress tolerance in COPD. Using transcriptomic network analyses, we predict capillary endothelial cells are inflamed in COPD, particularly through increased CXCL-motif chemokine signaling. Finally, we detect a high-metallothionein expressing macrophage subpopulation enriched in advanced COPD. Collectively, these findings highlight cell-specific mechanisms involved in the pathobiology of advanced COPD.
  15. Diabetes. 2022 Jan 26. pii: db210674. [Epub ahead of print]
      Genome-wide association studies identified single nucleotide polymorphisms on chromosome 7 upstream of KLF14 to be associated with metabolic syndrome traits and increased risk for Type 2 Diabetes (T2D). The associations were more significant in women than in men. The risk allele carriers expressed lower levels of the transcription factor KLF14 in adipose tissues than non-risk allele carriers. To investigate how adipocyte KLF14 regulates metabolic traits in a sex-dependent manner, we characterized high-fat diet fed male and female mice with adipocyte-specific KLF14 deletion or overexpression. KLF14 deletion resulted in increased fat mass in female mice and decreased fat mass in male mice. Female KLF14-deficient mice had overall smaller adipocytes in subcutaneous fat depots but larger adipocytes in parametrial depots, indicating a shift in lipid storage from subcutaneous to visceral fat depots. They had reduced metabolic rates and increased respiratory exchange ratios consistent with increased utilization of carbohydrates as an energy source. Fasting and isoproterenol-induced adipocyte lipolysis was defective in female KLF14-deficient mice and concomitantly adipocyte triglycerides lipase mRNA levels were downregulated. Female KLF14-deficient mice cleared blood triglyceride and NEFA less efficiently than wild type. Finally, adipocyte-specific overexpression of KLF14 resulted in lower total body fat in female but not male mice. Taken together, consistent with human studies, adipocyte KLF14 deficiency in female but not in male mice causes increased adiposity and redistribution of lipid storage from subcutaneous to visceral adipose tissues. Increasing KLF14 abundance in adipocytes of females with obesity and T2D may provide a novel treatment option to alleviate metabolic abnormalities.
  16. Nat Rev Genet. 2022 Jan 26.
      Cell fusions have a long history of supporting biomedical research. These experimental models, historically referred to as 'somatic cell hybrids', involve combining the plasma membranes of two cells and merging their nuclei within a single cytoplasm. Cell fusion studies involving human and chimpanzee pluripotent stem cells, rather than somatic cells, highlight the need for responsible communication and a revised nomenclature. Applying the terms 'hybrid' and 'parental' to the fused and source cell lines, respectively, evokes reproductive relationships that do not exist between humans and other species. These misnomers become more salient in the context of fused pluripotent stem cells derived from different but closely related species. Here, we propose a precise, versatile and generalizable framework to describe these fused cell lines. We recommend the term 'composite cell line', to distinguish cell lines that are experimentally created through fusions from both reproductive hybrids and natural cell fusion events without obscuring the model in overly technical terms. For scientific audiences, we further recommend technical nomenclature that describes the contributing species, ploidy and cell type.
  17. J Immunol Res. 2022 ;2022 6284124
      Iron plays an important role in macrophage polarization by altering metabolic and redox status. However, the impact of iron on the immune status of macrophages is still controversial. In this study, we report that ferric ammonium citrate (FAC) upregulates PD-L1 expression in macrophages. FAC not only altered the phenotype of macrophages but also led to enriching immune-modulatory T cell subsets. Since iron is known to be a constituent of coenzymes facilitating metabolic processes in mitochondria, we examined the metabolic status of FAC-overloaded macrophages by measuring the oxygen consumption rate (OCR) and the represented coenzyme, aconitase. In addition to enhancement of metabolic processes, FAC accelerated the Fenton reaction in macrophages, which also contributed to the facilitation of oxygen consumption. We reasoned that the enhancement of the OCR leads to the production of reactive oxygen species (ROS), which are directly linked to PD-L1 induction. Using ferrostatin, rotenone, and N-acetyl-L-cysteine, we confirmed that metabolic and redox regulation is responsible for FAC-mediated PD-L1 expression. Furthermore, we suggested that FAC-induced ROS production may explain FAC-mediated pro- and anti-inflammatory responses in macrophages. These findings may extend our understanding of regulating iron concentration during immune checkpoint therapy in cancer patients.
  18. Science. 2022 Jan 27. eabi7377
      Cerebrovascular diseases are a leading cause of death and neurologic disability. Further understanding of disease mechanisms and therapeutic strategies requires a deeper knowledge of cerebrovascular cells in humans. We profiled transcriptomes of 181,388 cells to define a cell atlas of the adult human cerebrovasculature, including endothelial cell molecular signatures with arteriovenous segmentation and expanded perivascular cell diversity. By leveraging this reference, we investigated cellular and molecular perturbations in brain arteriovenous malformations, a leading cause of stroke in young people, and identified pathologic endothelial transformations with abnormal vascular patterning and the ontology of vascularly derived inflammation. Here, we illustrate the interplay between vascular and immune cells that contributes to brain hemorrhage and catalog opportunities for targeting angiogenic and inflammatory programs in vascular malformations.
  19. Nat Med. 2022 Jan;28(1): 104-116
      Fused in sarcoma (FUS) is an RNA-binding protein that is genetically and pathologically associated with rare and aggressive forms of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). To explore the mechanisms by which mutant FUS causes neurodegeneration in ALS-FTD, we generated a series of FUS knock-in mouse lines that express the equivalent of ALS-associated mutant FUSP525L and FUSΔEX14 protein. In FUS mutant mice, we show progressive, age-dependent motor neuron loss as a consequence of a dose-dependent gain of toxic function, associated with the insolubility of FUS and related RNA-binding proteins. In this disease-relevant mouse model of ALS-FUS, we show that ION363, a non-allele-specific FUS antisense oligonucleotide, efficiently silences Fus and reduces postnatal levels of FUS protein in the brain and spinal cord, delaying motor neuron degeneration. In a patient with ALS with a FUSP525L mutation, we provide preliminary evidence that repeated intrathecal infusions of ION363 lower wild-type and mutant FUS levels in the central nervous system, resulting in a marked reduction in the burden of FUS aggregates that are a pathological hallmark of disease. In mouse genetic and human clinical studies, we provide evidence in support of FUS silencing as a therapeutic strategy in FUS-dependent ALS and FTD.
  20. Blood Adv. 2022 Jan 24. pii: bloodadvances.2021005103. [Epub ahead of print]
      Chronic graft-versus-host disease (cGVHD) remains a major obstacle impeding successful allogeneic hematopoietic cell transplantation (allo-HCT). MicroRNAs (miRs) play key roles in immune regulation during acute GVHD development. Preclinical studies to identify miRs that impact cGVHD pathogenesis are required to develop these as potential life-saving interventions. Using oligonucleotide array, we identified miR-31 that was significantly elevated in allogeneic T cells following HCT in mice. Using genetic and pharmacological approaches, we demonstrated a key role for miR-31 in mediating donor T-cell pathogenicity in cGVHD. Recipients of miR-31-deficient T cells displayed improved cutaneous and pulmonary cGVHD. Deficiency of miR-31 reduced T-cell expansion and Th17 differentiation, but increased generation and function of Tregs. MiR-31 facilitated Neuropilin-1 down-regulation, Foxp3 loss and IFNγ production in alloantigen-induced Tregs. Mechanistically, miR-31 was required for Hypoxia-inducible Factor 1α (HIF1α) upregulation in allogeneic T cells. Hence, miR-31-deficient CD4 T cells displayed impaired activation, survival, Th17 differentiation and glycolytic metabolism under hypoxia. Upregulation of Factor Inhibiting HIF1 (FIH1), a direct target of miR-31, in miR-31-deficient T cells was essential for attenuating T-cell pathogenicity. However, miR-31-deficienty CD8 T cells maintained intact glucose metabolism, cytolytic activity and graft-versus-leukemia response. Importantly, systemic administration of a specific inhibitor of miR-31 effectively reduced donor T-cell expansion, improved Treg generation, and attenuated cGVHD. Taken together, miR-31 is a key driver for T-cell pathogenicity in cGVHD but not for the anti-leukemia activity. Taken together, miR-31 is essential to drive cGVHD pathogenesis and represents a novel potential therapeutic target for controlling cGVHD.
  21. Front Immunol. 2021 ;12 816658
      NK cells play a crucial role in host protection during tumorigenesis. Throughout tumor development, however, NK cells become progressively dysfunctional through a combination of dynamic tissue-specific and systemic factors. While a number of immunosuppressive mechanisms present within the tumor microenvironment have been characterized, few studies have contextualized the spatiotemporal dynamics of these mechanisms during disease progression and across anatomical sites. Understanding how NK cell immunosuppression evolves in these contexts will be necessary to optimize NK cell therapy for solid and metastatic cancers. Here, we outline the spatiotemporal determinants of antitumor NK cell regulation, including heterogeneous tumor architecture, temporal disease states, diverse cellular communities, as well as the complex changes in NK cell states produced by the sum of these higher-order elements. Understanding of the signals encountered by NK cells across time and space may reveal new therapeutic targets to harness the full potential of NK cell therapy for cancer.
    Keywords:  NK cell; adoptive cell immunotherapy; immunotherapy; innate lymphoid cell (ILC); solid tumor; tumor microenvironment
  22. J Hepatol. 2022 Jan 21. pii: S0168-8278(22)00007-1. [Epub ahead of print]
      BACKGROUND AND AIMS: Myeloid cells are key regulators of cirrhosis, a major cause of mortality worldwide. Because stromal cells can modulate the functionality of myeloid cells in vitro, targeting stromal-myeloid interactions has become an attractive potential therapeutic strategy. We aimed to investigate how human liver stromal cells impact myeloid cell properties and to understand the utility of stromal-myeloid coculture systems to study these interactions in the context of cirrhosis.METHODS: Single cell RNA sequencing analyses of noncirrhotic (n=7) and cirrhotic (n=5) human liver tissue was correlated to the bulk RNA sequencing results of in vitro cocultured human CD14+ and primary liver stromal cells. Complimentary mechanistic experiments and flow cytometric analysis were performed on human liver stromal-myeloid coculture systems.
    RESULTS: We find that stromal-myeloid coculture reduces the frequency CD14+ cell subsets transcriptionally similar to liver macrophages, showing that stromal cells inhibit the maturation of monocytes into macrophages. Stromal cells also influenced in vitro macrophage differentiation by skewing away from cirrhosis-linked CD9+ scar-associated macrophage-like cells and towards CD163+ Kupffer Cell-like macrophages. We identify IL-6 production as a mechanism by which stromal cells limit CD9+ macrophage differentiation and find that local IL-6 levels are decreased in early-stage human liver disease compared to healthy liver tissue, suggesting a protective role for local IL-6 in healthy liver.
    CONCLUSIONS: Our work reveals an unanticipated role for liver stromal cells to impede the maturation and alter the differentiation of macrophages and prompts investigation into the role of local IL-6 production in the pathogenesis of liver disease. These studies provide a framework for investigating macrophage-stromal interactions during cirrhosis.
    LAY SUMMARY: The impact of human liver stromal cells on myeloid cell maturation and differentiation in liver disease is incompletely understood. In this study, we present a mechanistic analysis using a primary in vitro human liver stromal-myeloid coculture system that is translated to liver disease using scRNA-seq analysis of cirrhotic and noncirrhotic human liver tissue. Our work supports a role for stromal cell contact in restricting macrophage maturation and stromal-secreted IL-6 in limiting the differentiation of a cirrhotic macrophage subset.
    Keywords:  IL-6; Liver cirrhosis; human; macrophage differentiation; macrophage maturation; myeloid cells; single cell RNA-seq; stromal cells
  23. Front Immunol. 2021 ;12 811091
      Background: Populations of natural killer cells lacking CD56 expression [CD56neg natural killer (NK) cells] have been demonstrated to expand during human immunodeficiency virus (HIV)-1 infection. However, their phenotypic and functional characteristics have not been systematically analyzed, and their roles during disease progression remain poorly understood.Methods: In this study, 84 donors, namely 34 treatment-naïve HIV-1-infected patients (TNs), 29 HIV-1-infected patients with successful antiretroviral therapy (ARTs), and 21 healthy controls (HCs), were enrolled. The phenotypic and functional characteristics of CD56neg NK cells were analyzed using single-cell RNA-sequencing (scRNA-seq) and flow cytometry. A potential link between the characteristics of CD56neg NK cells and the clinical parameters associated with HIV-1 disease progression was examined.
    Results: The frequency of the CD56neg NK cell population was significantly increased in TNs, which could be partially rescued by ART. Flow cytometry analyses revealed that CD56neg NK cells were characterized by high expression of CD39, TIGIT, CD95, and Ki67 compared to CD56dim NK cells. In vitro assays revealed reduced IFN-γ and TNF-α secretion, as well as decreased expression of granzyme B and perforin in CD56neg NK cells. In line with the data obtained by flow cytometry, scRNA-seq analysis further demonstrated impaired cytotoxic activities of CD56neg NK cells. Notably, a negative correlation was observed between CD39, CD95, and Ki67 expression levels in CD56neg NK cells and CD4+ T cell counts.
    Conclusions: The results presented in this study indicate that the CD56neg NK cell population expanded in HIV-1-infected individuals is dysfunctional and closely correlates with HIV-1 disease progression.
    Keywords:  CD39; CD56neg NK cells; HIV-1; dysfunction; scRNA-seq
  24. J Immunol. 2022 Jan 24. pii: ji2100518. [Epub ahead of print]
      Antioxidant systems maintain cellular redox (oxidation-reduction) homeostasis. In contrast with other key redox pathways, such as the thioredoxin system, glutathione, and NF-E2-related factor 2 (Nrf2), little is known about the function of the redox-sensitive organelle "peroxisome" in immune cells. In this study, we show that the absence of peroxisomes in conditional Pex5-deficient mice strikingly results in impaired homeostatic maintenance of innate-like B cells, namely, B1 and marginal zone B cells, which translates into a defective Ab response to Streptococcus pneumoniae Surprisingly, however, follicular B2 cell development, homeostatic maintenance, germinal center reactions, Ab production, class switching, and B cell memory formation were unaffected in Pex5-deficient animals. Similarly, T cell development and responses to viral infections also remained unaltered in the absence of Pex5 Thus, this study highlights the differential requirement of peroxisomes in distinct lymphocyte subtypes and may provide a rationale for specifically targeting peroxisomal metabolism in innate-like B cells in certain forms of B cell malignancies involving B1 cells.