bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2022‒02‒06
thirty-two papers selected by
Fawaz Alzaïd
Sorbonne Université

  1. Nat Immunol. 2022 Feb;23(2): 251-261
      Tumor necrosis factor (TNF) drives chronic inflammation and cell death in the intestine, and blocking TNF is a therapeutic approach in inflammatory bowel disease (IBD). Despite this knowledge, the pathways that protect the intestine from TNF are incompletely understood. Here we demonstrate that group 3 innate lymphoid cells (ILC3s) protect the intestinal epithelium from TNF-induced cell death. This occurs independent of interleukin-22 (IL-22), and we identify that ILC3s are a dominant source of heparin-binding epidermal growth factor-like growth factor (HB-EGF). ILC3s produce HB-EGF in response to prostaglandin E2 (PGE2) and engagement of the EP2 receptor. Mice lacking ILC3-derived HB-EGF exhibit increased susceptibility to TNF-mediated epithelial cell death and experimental intestinal inflammation. Finally, human ILC3s produce HB-EGF and are reduced from the inflamed intestine. These results define an essential role for ILC3-derived HB-EGF in protecting the intestine from TNF and indicate that disruption of this pathway contributes to IBD.
  2. Cell. 2022 Feb 03. pii: S0092-8674(22)00003-4. [Epub ahead of print]185(3): 563-575.e11
      Metastatic progression is the main cause of death in cancer patients, whereas the underlying genomic mechanisms driving metastasis remain largely unknown. Here, we assembled MSK-MET, a pan-cancer cohort of over 25,000 patients with metastatic diseases. By analyzing genomic and clinical data from this cohort, we identified associations between genomic alterations and patterns of metastatic dissemination across 50 tumor types. We found that chromosomal instability is strongly correlated with metastatic burden in some tumor types, including prostate adenocarcinoma, lung adenocarcinoma, and HR+/HER2+ breast ductal carcinoma, but not in others, including colorectal cancer and high-grade serous ovarian cancer, where copy-number alteration patterns may be established early in tumor development. We also identified somatic alterations associated with metastatic burden and specific target organs. Our data offer a valuable resource for the investigation of the biological basis for metastatic spread and highlight the complex role of chromosomal instability in cancer progression.
    Keywords:  DNA sequencing; cancer; clinical sequencing; genomics; metastasis; molecular profiling; mutations; next-generation sequencing; organotropism; pan-cancer
  3. Mediators Inflamm. 2022 ;2022 9968847
      Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibody production and chronic inflammation. The etiology and pathogenesis of SLE are complicated in which dysfunction of CD4+ T cells is largely engaged. In this study, we investigated the manners of CD4+ T cells in antibody production in a lupus-like mouse model through peritoneal injection of pristane reagent. With the increase in total IgG/IgM and autoantibody production after 6 months, CD4+ T cells exhibited activated phenotypes with the elevated CD44, ICOS, OX40, and PD-1 expression. Pristane injection induced the increase in IgM levels in both wild-type and T cell-deficient TCRα -/- mice whereas IgG, IgG1, and IgG2a production was impaired. When adoptively transferring CD4+ T cells into T cell-deficient mice or coculturing CD4+ T cells and B cells in vitro, it was found that CD4+ T cells derived from pristane-treated mice could help the production of total IgG as well as IgG1/IgG2a in a more efficient manner both in vivo and in vitro. While MHC was dispensable for IgG production, ICAM-1 likely functioned as an attenuating factor for IgG production. Our study thus reveals that CD4+ T cells in pristane-treated mice play important roles in IgG production, which implies the critical roles in the induction of pathological autoantibodies in MHC-independent and ICAM-1-dependent manners.
  4. J Clin Invest. 2022 Feb 03. pii: e144334. [Epub ahead of print]
      Genetic variants at the SORT1 locus in humans causing increased SORT1 expression in liver are significantly associated with reduced plasma levels of LDL cholesterol and apolipoprotein B (apoB). However, the role of hepatic sortilin remains controversial, as genetic deletion of sortilin in mice has yielded variable and conflicting effects on apoB secretion. Sort1 knockout mice on a chow diet and several Sort1-deficient hepatocyte lines displayed no difference in apoB secretion. When these models were challenged with high fat or ER stress, the loss of Sort1 expression resulted in a significant increase in apoB-100 secretion. Sort1 overexpression studies yielded reciprocal results. Importantly, diabetic carriers of SORT1 variant have larger decreases in plasma apoB, TG, and VLDL and LDL particle number as compared to non-diabetics with the same variants. We conclude that under basal non-stressed conditions, loss of sortilin has little effect on hepatocyte apoB secretion, but that in the setting of lipid-loading or ER stress, sortilin deficiency leads to increased apoB secretion. These results are consistent with the directionality of effect in human genetics studies and suggest that under stress conditions, hepatic sortilin directs apoB toward lysosomal degradation rather than secretion, potentially serving as a quality control step in the apoB secretion pathway in hepatocytes.
    Keywords:  Genetics; Lipoproteins; Vascular Biology
  5. Nat Cancer. 2022 Jan;3(1): 90-107
      Cancer cells disseminate and seed in distant organs, where they can remain dormant for many years before forming clinically detectable metastases. Here we studied how disseminated tumor cells sense and remodel the extracellular matrix (ECM) to sustain dormancy. ECM proteomics revealed that dormant cancer cells assemble a type III collagen-enriched ECM niche. Tumor-derived type III collagen is required to sustain tumor dormancy, as its disruption restores tumor cell proliferation through DDR1-mediated STAT1 signaling. Second-harmonic generation two-photon microscopy further revealed that the dormancy-to-reactivation transition is accompanied by changes in type III collagen architecture and abundance. Analysis of clinical samples revealed that type III collagen levels were increased in tumors from patients with lymph node-negative head and neck squamous cell carcinoma compared to patients who were positive for lymph node colonization. Our data support the idea that the manipulation of these mechanisms could serve as a barrier to metastasis through disseminated tumor cell dormancy induction.
  6. Proc Natl Acad Sci U S A. 2022 Feb 08. pii: e2114912119. [Epub ahead of print]119(6):
      Cells acquire essential nutrients from the environment and utilize adaptive mechanisms to survive when nutrients are scarce. How nutrients are trafficked and compartmentalized within cells and whether they are stored in response to stress remain poorly understood. Here, we investigate amino acid trafficking and uncover evidence for the lysosomal transit of numerous essential amino acids. We find that starvation induces the lysosomal retention of leucine in a manner requiring RAG-GTPases and the lysosomal protein complex Ragulator, but that this process occurs independently of mechanistic target of rapamycin complex 1 activity. We further find that stored leucine is utilized in protein synthesis and that inhibition of protein synthesis releases lysosomal stores. These findings identify a regulated starvation response that involves the lysosomal storage of leucine.
    Keywords:  leucine; lysosome; mTOR
  7. Science. 2022 Feb 04. 375(6580): eabj4008
      Regulation of cytokine production in stimulated T cells can be disrupted in autoimmunity, immunodeficiencies, and cancer. Systematic discovery of stimulation-dependent cytokine regulators requires both loss-of-function and gain-of-function studies, which have been challenging in primary human cells. We now report genome-wide CRISPR activation (CRISPRa) and interference (CRISPRi) screens in primary human T cells to identify gene networks controlling interleukin-2 (IL-2) and interferon-γ (IFN-γ) production. Arrayed CRISPRa confirmed key hits and enabled multiplexed secretome characterization, revealing reshaped cytokine responses. Coupling CRISPRa screening with single-cell RNA sequencing enabled deep molecular characterization of screen hits, revealing how perturbations tuned T cell activation and promoted cell states characterized by distinct cytokine expression profiles. These screens reveal genes that reprogram critical immune cell functions, which could inform the design of immunotherapies.
  8. J Clin Invest. 2022 Feb 01. pii: e156624. [Epub ahead of print]132(3):
      Sortilin is a glycoprotein mainly known for its role as a trafficking molecule directing proteins to specific secretory or endocytic compartments of the cell. Its actual contribution to essential hypertension has remained hitherto elusive. Combining top-notch in vivo, ex vivo, and in vitro approaches to clinical investigations, Di Pietro et al. explored the signaling pathway evoked by sortilin in endothelial cells and report on such exploration in this issue of the JCI. The researchers identified circulating sortilin as a biomarker associated with high blood pressure. Mechanistically, they demonstrate that sortilin altered sphingolipid/ceramide homeostasis, initiating a signaling cascade that, from sphingosine-1-phosphate (S1P), leads to the augmented production of reactive oxygen species. Herein, we discuss the main implications of these findings, and we anticipate some of the potential avenues of investigation prompted by this discovery, which could eventually lead to treatments for cardiometabolic disorders.
  9. Front Immunol. 2021 ;12 818758
      In response to T-cell-dependent antigens, mature B cells in the secondary lymphoid organs are stimulated to form germinal centers (GCs), which are histological structures deputed to antibody affinity maturation, a process associated with immunoglobulin gene editing by somatic hypermutation (SHM) and class switch recombination (CSR). GC B cells are heterogeneous and transition across multiple stages before being eliminated by apoptosis or committing to post-GC differentiation as memory B cells or plasma cells. In order to explore the dynamics of SHM and CSR during the GC reaction, we identified GC subpopulations by single-cell (sc) transcriptomics and analyzed the load of immunoglobulin variable (V) region mutations as well as the isotype class distribution in each subpopulation. The results showed that the large majority of GC B cells display a quantitatively similar mutational load in the V regions and analogous IGH isotype class distribution, except for the precursors of memory B cells (PreM) and plasma cells (PBL). PreM showed a bimodal pattern with about half of the cells displaying high V region germline identity and enrichment for unswitched IGH, while the rest of the cells carried a mutational load similar to the bulk of GC B cells and showed a switched isotype. PBL displayed a bias toward expression of IGHG and higher V region germline identity compared to the bulk of GC B cells. Genes implicated in SHM and CSR were significantly induced in specific GC subpopulations, consistent with the occurrence of SHM in dark zone cells and suggesting that CSR can occur within the GC.
    Keywords:  B cell receptor; gene expression; germinal center; memory B cells; plasma cells; single-cell analysis
  10. Nat Commun. 2022 Feb 03. 13(1): 646
      Efficacy of monoclonal antibodies against calcitonin gene-related peptide (CGRP) or its receptor (calcitonin receptor-like receptor/receptor activity modifying protein-1, CLR/RAMP1) implicates peripherally-released CGRP in migraine pain. However, the site and mechanism of CGRP-evoked peripheral pain remain unclear. By cell-selective RAMP1 gene deletion, we reveal that CGRP released from mouse cutaneous trigeminal fibers targets CLR/RAMP1 on surrounding Schwann cells to evoke periorbital mechanical allodynia. CLR/RAMP1 activation in human and mouse Schwann cells generates long-lasting signals from endosomes that evoke cAMP-dependent formation of NO. NO, by gating Schwann cell transient receptor potential ankyrin 1 (TRPA1), releases ROS, which in a feed-forward manner sustain allodynia via nociceptor TRPA1. When encapsulated into nanoparticles that release cargo in acidified endosomes, a CLR/RAMP1 antagonist provides superior inhibition of CGRP signaling and allodynia in mice. Our data suggest that the CGRP-mediated neuronal/Schwann cell pathway mediates allodynia associated with neurogenic inflammation, contributing to the algesic action of CGRP in mice.
  11. Mol Metab. 2022 Feb 01. pii: S2212-8778(22)00021-7. [Epub ahead of print] 101452
      OBJECTIVE: One-carbon metabolism is routinely dysregulated in nonalcoholic fatty liver disease. This includes decreased glycine N-methyltransferase (GNMT), a critical regulator of s-adenosylmethionine (SAM). Deletion of GNMT in mice increases SAM and promotes liver steatosis. Lower liver oxidative metabolism as indicated by a decline in gluconeogenesis, citric acid cycle flux, and oxidative phosphorylation contributes to liver steatosis in GNMT-null mice, however, the extent to which this phenotype is mediated by higher SAM remains unclear. Here, we determined the SAM-dependent impairment in liver oxidative metabolism by loss of GNMT.METHODS: GNMT knockout (KO) mice were fed a methionine-restricted diet to prevent increased SAM. 2H/13C metabolic flux analysis was performed in conscious, unrestrained mice to quantify liver nutrient fluxes. Metabolomics and high-resolution respirometry was used to quantify liver nutrient pool sizes and mitochondrial oxidative phosphorylation, respectively. Folic acid-supplemented and serine/glycine-deficient diets were used independently to further define the metabolic implications of perturbed one-carbon donor availability.
    RESULTS: Dietary methionine restriction prevented a 75-fold increase in SAM and 53% rise in triacylglycerides in livers of KO mice. Dietary methionine restriction increased gluconeogenesis independent of genotype and restored cytochrome c oxidase respiratory function in KO mice. Citric acid cycle fluxes remained lower in KO mice irrespective of diet. Restricting dietary methionine abrogated markers of increased lipogenesis and folate cycle dysfunction in KO mice.
    CONCLUSION: The impaired liver oxidative metabolism following loss of GNMT is both dependent and independent of greater SAM availability. Lower in vivo citric acid cycle flux is independent of increased SAM. In contrast, gluconeogenesis and oxidative phosphorylation are negatively regulated by excess SAM. Lipid accumulation in livers of mice lacking GNMT is also linked to the higher SAM.
    Keywords:  citric acid cycle; gluconeogenesis; lipogenesis; nonalcoholic fatty liver disease; one-carbon metabolism; oxidative phosphorylation
  12. Immunol Rev. 2022 Jan 31.
      Age-associated B cells (ABCs) have emerged as critical components of immune responses. Their inappropriate expansion and differentiation have increasingly been linked to the pathogenesis of autoimmune disorders, aging-associated diseases, and infections. ABCs exhibit a distinctive phenotype and, in addition to classical B cell markers, often express the transcription factor T-bet and myeloid markers like CD11c; hence, these cells are also commonly known as CD11c+ T-bet+ B cells. Formation of ABCs is promoted by distinctive combinations of innate and adaptive signals. In addition to producing antibodies, these cells display antigen-presenting and proinflammatory capabilities. It is becoming increasingly appreciated that the ABC compartment exhibits a high degree of heterogeneity, plasticity, and sex-specific regulation and that ABCs can differentiate into effector progeny via several routes particularly in autoimmune settings. In this review, we will discuss the initial insights that have been obtained on the molecular machinery that controls ABCs and we will highlight some of the unique aspects of this control system that may enable ABCs to fulfill their distinctive role in immune responses. Given the expanding array of autoimmune disorders and pathophysiological settings in which ABCs are being implicated, a deeper understanding of this machinery could have important and broad therapeutic implications for the successful, albeit daunting, task of targeting these cells.
    Keywords:  CD11c+T-bet+; Def6; IRF; IRF5; IRF8; SWAP-70; SWEF; T-bet; age-associated B cells
  13. Front Immunol. 2021 ;12 779119
      Disintegrin and metalloproteinase domain-containing protein 17 (ADAM17) is a ubiquitously expressed membrane-bound enzyme that mediates shedding of a wide variety of important regulators in inflammation including cytokines and adhesion molecules. Hepatic expression of numerous cytokines and adhesion molecules are increased in cholestatic liver diseases including primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), however, the pathophysiological role of ADAM17 in regulating these conditions remains unknown. Therefore, we evaluated the role of ADAM17 in a mouse model of cholestatic liver injury due to bile duct ligation (BDL). We found that BDL enhanced hepatic ADAM17 protein expression, paralleled by increased ADAM17 bioactivity. Moreover, inhibition of ADAM17 bioactivity with the specific inhibitor DPC 333 significantly improved both biochemical and histological evidence of liver damage in BDL mice. Patients with cholestatic liver disease commonly experience adverse behavioral symptoms, termed sickness behaviors. Similarly, BDL in mice induces reproducible sickness behavior development, driven by the upregulated expression of cytokines and adhesion molecules that are in turn regulated by ADAM17 activity. Indeed, inhibition of ADAM17 activity significantly ameliorated BDL-associated sickness behavior development. In translational studies, we evaluated changes in ADAM17 protein expression in liver biopsies obtained from patients with PBC and PSC, compared to normal control livers. PSC and PBC patients demonstrated increased hepatic ADAM17 expression in hepatocytes, cholangiocytes and in association with liver-infiltrating immune cells compared to normal controls. In summary, cholestatic liver injury in mice and humans is associated with increased hepatic ADAM17 expression. Furthermore, inhibition of ADAM17 activity improves both cholestatic liver injury and associated sickness behavior development, suggesting that ADAM17 inhibition may represent a novel therapeutic approach for treating patients with PBC/PSC.
    Keywords:  ADAM17 (a disintegrin and metalloprotease 17); TACE (TNF-α converting enzyme); autoimmune liver disease; cholestasis; inflammation; sickness behavior; therapeutic
  14. Alzheimers Dement. 2021 Dec;17 Suppl 3 e056541
      BACKGROUND: APOE4 isoform and female sex are genetic risk factors for Alzheimer's disease (AD) with women APOE4 carriers being at greater and accelerated risk for developing AD than men. Inflammation contributes to the AD disease progression. Apolipoprotein E (ApoE), and endocrine aging in women are known to impact antigen presentation, microglial function, T cell activation and the systemic inflammatory profile. We hypothesize that the interaction of female sex and APOE4 isoform exacerbates inflammation and thereby be evident in microglial reactivity, loss of function and peripheral immune cell activation contributing to the at-risk AD profile.METHOD: 18-month-old Humanized (h)APOE3/3, APOE3/4 and APOE4/4 male and female mice from the Jackson labs were used. Single cell suspension generated from blood, spleen and brain were analyzed using flow cytometry. In the brain, microglial phagocytosis, cellular reactive oxygen species (ROS) production, MHC-II expression and lipid droplet accumulation was measured. T cell infiltration in the brain was also established. Additionally, metabolic flux assays on microglial cells. In the periphery, CD4 and CD8 T cell populations and T cell activation were quantified.
    RESULT: In the brain, microglia from hAPOE4/4 females had the highest expression of MHC-II and significantly lower phagocytic activity in comparison to hAPOE4/4 males and hAPOE3/3 females. Coincident with increased microglial reactivity, significantly higher T cells were detected in hAPOE4/4 female brain in comparison to hAPOE3/3 males. Interestingly, neutral lipid droplet accumulation was significantly higher in hAPOE3/3 females in comparison to hAPOE3/4 females consistent with a profile of increased phagocytic activity. Peripheral immune profile from the blood and spleen indicated patterns consistent with the brain-immune analyses. APOE4 genotype had a significant impact on the proportion of activated CD4 and CD8 T cells. Female hAPOE4/4 had significantly higher CD4+CD69+ and CD8+CD69+ T cells in comparison to hAPOE3/3 and hAPOE3/4 females in blood. In spleen, females across all the genotype had greater proportions of activated T cells, of which female hAPOE4/4 had the highest proportions of activated CD4 and CD8 T cells.
    CONCLUSION: The interaction of APOE4 genotype and sex affects the immune profile in the brain and periphery which is consistent with accelerated generation of at-risk for AD immune profile.
  15. Nat Commun. 2022 Feb 03. 13(1): 675
      Alzheimer's Disease (AD) is a neurodegenerative disorder that is still not fully understood. Sex modifies AD vulnerability, but the reasons for this are largely unknown. We utilize two independent electronic medical record (EMR) systems across 44,288 patients to perform deep clinical phenotyping and network analysis to gain insight into clinical characteristics and sex-specific clinical associations in AD. Embeddings and network representation of patient diagnoses demonstrate greater comorbidity interactions in AD in comparison to matched controls. Enrichment analysis identifies multiple known and new diagnostic, medication, and lab result associations across the whole cohort and in a sex-stratified analysis. With this data-driven method of phenotyping, we can represent AD complexity and generate hypotheses of clinical factors that can be followed-up for further diagnostic and predictive analyses, mechanistic understanding, or drug repurposing and therapeutic approaches.
  16. Nat Cancer. 2020 Aug;1(8): 774-783
      The molecular characterization of tumors now informs clinical cancer care for many patients. This advent of molecular oncology has been driven by the expanding number of therapeutic biomarkers that can predict sensitivity to both approved agents and investigational agents. Beyond its role in driving clinical-trial enrollments and guiding therapy in individual patients, large-scale clinical genomics in oncology also represents a rapidly expanding research resource for translational scientific discovery. Here we review the progress, opportunities, and challenges of scientific and translational discovery from prospective clinical genomic screening programs now routinely conducted for patients with cancer.
  17. Alzheimers Dement. 2021 Dec;17 Suppl 3 e052738
      BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive impairments linked to pathological deposition of misfolded self-protein amyloid beta (Aβ) which in kind facilitates tau aggregation and neurodegeneration. Neuroinflammation is accepted as key disease driver caused by innate microglia activation. Recently, adaptive immune alterations have been uncovered beginning early and extending throughout the disease. How these occurs and whether they can be harnessed to affect disease progress is unclear. We propose that self-antigens would induct autoreactive effector T cells (Teff) serving to drive pro-inflammatory and neurodestructive immunity. Here, we investigated the role of effector immunity could affect cellular level disease pathobiology in an AD animal model.METHOD: Aβ-specific Th1 and Th17 Teff were induced by Aβ-immunization of donors, CD4+ T cells isolated, expanded by selective culture in the presence of Aβ, and cloned as monoclonal Teff lines. Aβ-specific Th1 and Th17 Teff were adoptively transferred into the APP/PS1 double transgenic mice. Three weeks after transfer, radial arm water maze (RAWM), biochemical, immunohistochemical and transcriptomic tests assessed memory functions, pathologies, and mechanism.
    RESULT: Development of stable monoclonal Aβ-Th1 and Aβ-Th17 cells was verified by specific cytokine signatures, nuclear transcription factors and haplotype matched major histocompatibility-II (MHCII)-Aβ tetramer staining. Accelerated memory impairments were observed in APP/PS1 mice that received Aβ-specific Teffs. Both Aβ-Th1 and Aβ-Th17 cells significantly induced pro-inflammatory cytokines TNF-α, IFN-γ and IL-17 and transcription factors Tbet and RORγ compared to controls in the periphery. Aβ load significantly increased while synaptic plasticity decreased in the brain of AD mice received Aβ-Th1 cells. Aβ-Teff driven systemic inflammatory responses were attributed to the decreased numbers and functions of regulatory T cells (Treg) in both the CNS and periphery. Additionally, transferred Aβ-Teff increased microglia reactivity and neuroinflammatory activities in the affected brain regions.
    CONCLUSION: Autoreactive Aβ-Teff transform a pro-inflammatory microenvironment accelerating AD pathology. This is sped by limiting Treg activities. Control of this neurodestructive environment represents a potential therapeutic strategy and can be sped by augmenting peripheral Treg numbers and function. Similar therapeutic ends have been shown to be efficacious in both pre-clinical and clinical trials in related neurodegenerative disorders.
  18. Cell Mol Gastroenterol Hepatol. 2022 Jan 30. pii: S2352-345X(22)00018-2. [Epub ahead of print]
      BACKGROUND: /Aims: While basal cell hyperplasia is a histologic hallmark of eosinophilic esophagitis (EoE), little is known about the capabilities of epithelial renewal and differentiation in the EoE inflammatory milieu. In murine esophageal epithelium, there are self-renewing and slowly proliferating basal stem-like cells characterized by concurrent expression of CD73 (NT5E, 5'-nucleotidase ecto) and CD104 (ITGB4, integrin β4). Here we investigated CD73+CD104+ cells within the basal population of human esophageal epithelium and clarified the biological significance of these cells in the EoE epithelium.METHODS: We performed flow cytometry on esophageal biopsy samples from EoE and non-EoE patients to determine the quantity of CD73+CD104+ cells in the epithelium. Simulating the EoE milieu we stimulated primary patient-derived and immortalized cell line-derived esophageal organoids with IL-4 and IL-13 and analyzed by flow cytometry, IHC and qRT-PCR. We performed single-cell RNA-sequencing on primary organoids in the setting of IL-13 stimulation and evaluated CD73+CD104+ population. We performed fluorescent activated cell sorting to purify CD73+CD104+ and CD73- CD104+ populations and seeded these groups in organoid culture to evaluate organoid formation rate and organoid size. We used RNA interference (RNAi) to knock down CD73 in esophageal organoids to evaluate organoid formation rates and size. We evaluated the effects of signal transducer and activator of transcription 6 (STAT6) signaling inhibition by RNAi, a STAT6 inhibitor, AS1517499, as well as proton pump inhibitor, omeprazole.
    RESULTS: EoE patients demonstrated decreased epithelial CD73+CD104+ cell content. IL-4 and IL-13 stimulation depleted this population in 3D organoids with a recapitulation of basal cell hyperplasia as corroborated by single-cell RNA-sequencing of the organoids that suggested depletion of CD73+CD104+ cells. The CD73+CD104+ population had enhanced organoid formation compared to CD73- CD104+ population. Similarly, knock-down of CD73 resulted in decreased organoid formation rate. Genetic and pharmacological inhibition of STAT6 prevented Th2 cytokine-induced depletion of CD73+CD104+ cells. Lastly, omeprazole treatment prevented the effects of IL-4 and IL-13 on the CD73+CD104+ population.
    CONCLUSION: This study is the first to address the role of CD73+CD104+ cells in epithelial renewal and homeostasis in the context of EoE. The depletion of CD73+CD104+ self-renewal population by Th2 cytokines in EoE milieu may be perpetuating epithelial injury. Future therapies targeting epithelial restitution in EoE could decrease the need for immune modulation and steroid therapy.
    Keywords:  CD104; CD73; Eosinophilic esophagitis; epithelium; organoids
  19. Front Immunol. 2021 ;12 798155
      Atherosclerosis (ATS), the change in structure and function of arteries with associated lesion formation and altered blood flow, is the leading cause of cardiovascular disease, the number one killer worldwide. Beyond dyslipidemia, chronic inflammation, together with aberrant phenotype and function of cells of both the innate and adaptive immune system, are now recognized as relevant contributors to atherosclerosis onset and progression. While the role of macrophages and T cells in atherosclerosis has been addressed in several studies, Natural Killer cells (NKs) represent a poorly explored immune cell type, that deserves attention, due to NKs' emerging contribution to vascular homeostasis. Furthermore, the possibility to re-polarize the immune system has emerged as a relevant tool to design new therapies, with some succesfull exmples in the field of cancer immunotherapy. Thus, a deeper knowledge of NK cell pathophysiology in the context of atherosclerosis and atherosclerosis-associated risk factors could help developing new preventive and treatment strategies, and decipher the complex scenario/history from "the risk factors for atherosclerosis" Here, we review the current knowledge about NK cell phenotype and activities in atherosclerosis and selected atherosclerosis risk factors, namely type-2 diabetes and obesity, and discuss the related NK-cell oriented environmental signals.
    Keywords:  atherosclerosis; atherosclerosis-related risk factors; natural killer cells; obesity; type-2 diabetes
  20. J Clin Invest. 2022 Feb 01. pii: e146219. [Epub ahead of print]
      Multiple beneficial cardiovascular effects of HDL are dependent on sphingosine-1-phosphate (S1P). S1P associates with HDL by binding to apolipoprotein M (ApoM). Insulin resistance is a major driver of dyslipidemia and cardiovascular risk. However, the mechanisms linking alterations in insulin signaling with plasma lipoprotein metabolism are incompletely understood. The insulin-repressible FoxO transcription factors play a key role in mediating the effects of hepatic insulin action on glucose and lipoprotein metabolism. This work aims to determine whether hepatic insulin signaling regulates HDL-S1P, and the underlying molecular mechanisms.We report that insulin resistant, nondiabetic human subjects in two independent cohorts have decreased HDL-S1P levels, but no change in total plasma S1P. This also occurs in the mouse model of insulin resistance, db/db mice, which have low ApoM and a specific reduction of S1P in the HDL fraction, with no change in total plasma S1P. Using mice with hepatocyte deletion of the three insulin-repressible FoxO transcription factors (L-FoxO1,3,4), we found that hepatic FoxOs are required for ApoM expression and S1P association with HDL, without affecting total plasma S1P. In L-FoxO1,3,4 mice, total plasma S1P levels are similar to controls, but S1P is nearly absent from HDL, and is instead increased in the lipoprotein depleted plasma fraction. This phenotype is restored to normal by rescuing ApoM in L-FoxO1,3,4 mice. Our findings show that insulin resistance in humans and mice is associated with decreased HDL-associated S1P. Hepatic FoxO transcription factors are novel regulators of the ApoM-S1P pathway.
    Keywords:  Diabetes; Insulin signaling; Lipoproteins; Metabolism
  21. Immunol Rev. 2022 Feb 01.
      Pathologic T cell-B cell interactions underlie many autoimmune diseases. The T cells that help B cells in autoimmune diseases vary in phenotype and include T cells that lack typical features of T follicular helper cells, such as expression of CXCR5 and BCL6. A population of PD-1hi CXCR5- T peripheral helper (Tph) cells has now been recognized in multiple autoantibody-associated diseases. Tph cells display a distinctive set of features, merging the ability to provide B cell help with the capacity to migrate to inflamed peripheral tissues. Here, we review the scope of immune-related conditions in which Tph cells have been implicated and provide a perspective on their potential contributions to pathologic B cell activation in autoimmune diseases. We discuss Tph cells as a promising therapeutic strategy in autoimmunity and consider the utility of tracking Tph cells in blood as a biomarker to quantify aberrant T cell-B cell activation in patients with autoimmune diseases.
    Keywords:  Autoimmune disease; CXCL13; IL-21; T follicular helper; T peripheral helper
  22. Cell. 2022 Feb 03. pii: S0092-8674(21)01454-9. [Epub ahead of print]185(3): 419-446
      Adipose tissue, colloquially known as "fat," is an extraordinarily flexible and heterogeneous organ. While historically viewed as a passive site for energy storage, we now appreciate that adipose tissue regulates many aspects of whole-body physiology, including food intake, maintenance of energy levels, insulin sensitivity, body temperature, and immune responses. A crucial property of adipose tissue is its high degree of plasticity. Physiologic stimuli induce dramatic alterations in adipose-tissue metabolism, structure, and phenotype to meet the needs of the organism. Limitations to this plasticity cause diminished or aberrant responses to physiologic cues and drive the progression of cardiometabolic disease along with other pathological consequences of obesity.
    Keywords:  adipocyte; adipocyte progenitor; adipose tissue; beige fat; brown fat; diabetes; obesity; thermogenesis
  23. Alzheimers Dement. 2021 Dec;17 Suppl 3 e055688
      BACKGROUND: Cellular senescence and inflammation may contribute to the pathogenesis of Alzheimer's disease (AD). We sought to define their inter-relationship in cell culture and animal models of AD and determine if senolytic compounds could alleviate these conditions thereby improving cognition.METHOD: Male and female C57BL/6 mice received monthly oral treatment with fisetin (100 mg/kg BW), dasatinib+quercertin (D+Q; 5 mg/kg BW and 50 mg/kg BW, respectively), or vehicle control from 4 to 12 months of age followed by cognitive assessment with Morris water maze and novel object recognition. Hippocampal tissue from untreated 12 month old male AβPP/PS1 and C57BL/6 mice underwent RNA sequencing (RNAseq) to assess cellular senescence and inflammation. Primary neurons were treated with Aβ42 (10µM) and fisetin (15µM), dasatinib (1µM), quercetin (10µM), D+Q, or vehicle control. Cell viability, senescent cell burden, and cytokine profiles were assessed.
    RESULT: Long-term memory in mice treated with senolytic compounds was improved in males, but not in females. RNAseq results revealed elevated senescent and inflammatory markers in the hippocampus of AβPP/PS1 mice compared to C57BL/6 mice. Preliminary cell culture data indicate that primary neurons receiving senolytic treatment tended to have decreased senescence and inflammatory markers compared to controls.
    CONCLUSION: Preliminary results support elevated cellular senescence and inflammation in the hippocampus of an AD mouse and treatment with senolytic compounds may improve cognition in a sex-dependent manner. Senolytic treatments in primary neuronal cultures appeared to reduce Aβ42 -related cellular senescence. Together, our results support that elimination of senescent cells and the corresponding inflammatory profile may be effective at treating impaired memory in AD. Supported by the National Institutes of Health (R01 AG057767, R01 AG061937), Center for Alzheimer's Research and trEatment (CARE), and the Kenneth Stark Endowment.
  24. Cell Stem Cell. 2022 Feb 03. pii: S1934-5909(22)00004-2. [Epub ahead of print]29(2): 181-183
      Aberrant migration of GABAergic interneurons during cortical neurodevelopment is implicated in Timothy Syndrome, yet the underlying mechanisms remain elusive. In this issue of Cell Stem Cell, Birey et al. model developing brain circuitry using "assembloids" from patients, characterizing a bimodal mechanism of mechano-chemically driven interneuron migration inefficiencies.
  25. Diabetes Metab Res Rev. 2022 Feb 02. e3524
      AIMS: Sorbin and SH3-domain-containing-1 (SORBS1) play important roles in insulin signaling and cytoskeleton regulation. Variants of the SORBS1 gene have been inconsistently reported to be associated with type 2 diabetes or diabetic kidney disease (DKD).METHODS: Two independent case-control studies based on two randomized sampling cohorts (cohort 1, n = 3,345; cohort 2, n = 2,282) were used to confirm the association between rs2281939 of SORBS1 and impaired glucose regulation (IGR). An additional hospital-based cohort (cohort 3, n = 2,135) and cohort 1 was used to investigate the association between rs2281939 and DKD. The phenotype of rare variants of SORBS1 was explored in 453 patients with early onset type 2 diabetes (diagnosed before 40 years of age, EOD).
    RESULTS: The G allele was associated with type 2 diabetes (additive model: OR = 1.25, 95% CI [1.03-1.52], P = 0.022) in cohort 1, and IGR in cohort 2 (additive model: OR = 1.22, 95% CI [1.05-1.43], P = 0.01). We found that the G allele was also associated with HDL-c levels in women in both cohort 1 (P = 0.03) and 2 (P = 0.029) in the dominant model. The rare variant carriers also had lower HDL-c and LDL-c levels than non-carriers in patients with EOD. No association between rs2281939 or rare variants and DKD was observed.
    CONCLUSIONS: The variants in the SORBS1 gene were associated with IGR and HDL-c levels but not with DKD in the Chinese Han population. This article is protected by copyright. All rights reserved.
    Keywords:  SORBS1; high-density lipoprotein cholesterol; rs2281939; type 2 diabetes
  26. Nat Commun. 2022 Feb 03. 13(1): 676
      Ferroptosis is a nonapoptotic cell death process that requires cellular iron and the accumulation of lipid peroxides. In progressive rheumatoid arthritis (RA), synovial fibroblasts proliferate abnormally in the presence of reactive oxygen species (ROS) and elevated lipid oxidation. Here we show, using a collagen-induced arthritis (CIA) mouse model, that imidazole ketone erastin (IKE), a ferroptosis inducer, decreases fibroblast numbers in the synovium. Data from single-cell RNA sequencing further identify two groups of fibroblasts that have distinct susceptibility to IKE-induced ferroptosis, with the ferroptosis-resistant fibroblasts associated with an increased TNF-related transcriptome. Mechanistically, TNF signaling promotes cystine uptake and biosynthesis of glutathione (GSH) to protect fibroblasts from ferroptosis. Lastly, low dose IKE together with etanercept, a TNF antagonist, induce ferroptosis in fibroblasts and attenuate arthritis progression in the CIA model. Our results thus imply that the combination of TNF inhibitors and ferroptosis inducers may serve as a potential candidate for RA therapy.
  27. Adv Biol (Weinh). 2022 Feb 04. e2101078
      Many helminth life cycles, including hookworm, involve a mandatory lung phase, where myeloid and granulocyte subsets interact with the helminth and respond to infection-induced lung injury. To evaluate these innate subsets in Nippostrongylus brasiliensis infection, reporter mice for myeloid cells (CX3CR1GFP ) and granulocytes (PGRPdsRED ) are employed. Nippostrongylus infection induces lung infiltration of reporter cells, including CX3CR1+ myeloid cells and PGRP+ eosinophils. Strikingly, CX3CR1GFP/GFP mice, which are deficient in CX3CR1, are protected from Nippostrongylus infection with reduced weight loss, lung leukocyte infiltration, and worm burden compared to CX3CR1+/+ mice. This protective effect is specific for CX3CR1 as CCR2-deficient mice do not exhibit reduced worm burdens. Nippostrongylus co-culture with lung Ly6C+ monocytes or CD11c+ cells demonstrates that CX3CR1GFP/GFP monocytes secrete more pro-inflammatory cytokines and actively bind the parasites causing reduced motility. RNA sequencing of Ly6C+ or CD11c+ cells shows Nippostrongylus-induced gene expression changes, particularly in monocytes, associated with inflammation, chemotaxis, and extracellular matrix remodeling pathways. Analysis reveals cytotoxic and adhesion molecules as potential effectors against the parasite, such as Gzma and Gzmb, which are elevated in CX3CR1GFP/GFP monocytes. These studies validate a dual innate cell reporter for lung helminth infection and demonstrate that CX3CR1 impairs monocyte-helminth interaction.
    Keywords:  chemokine receptor; helminth; innate immunity; monocyte