bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2022‒06‒05
nineteen papers selected by
Fawaz Alzaïd
Sorbonne Université

  1. Nat Commun. 2022 May 30. 13(1): 2997
      Posttranscriptional adenosine-to-inosine modifications amplify the functionality of RNA molecules in the brain, yet the cellular and genetic regulation of RNA editing is poorly described. We quantify base-specific RNA editing across three major cell populations from the human prefrontal cortex: glutamatergic neurons, medial ganglionic eminence-derived GABAergic neurons, and oligodendrocytes. We identify more selective editing and hyper-editing in neurons relative to oligodendrocytes. RNA editing patterns are highly cell type-specific, with 189,229 cell type-associated sites. The cellular specificity for thousands of sites is confirmed by single nucleus RNA-sequencing. Importantly, cell type-associated sites are enriched in GTEx RNA-sequencing data, edited ~twentyfold higher than all other sites, and variation in RNA editing is largely explained by neuronal proportions in bulk brain tissue. Finally, we uncover 661,791 cis-editing quantitative trait loci across thirteen brain regions, including hundreds with cell type-associated features. These data reveal an expansive repertoire of highly regulated RNA editing sites across human brain cell types and provide a resolved atlas linking cell types to editing variation and genetic regulatory effects.
  2. Nat Commun. 2022 May 31. 13(1): 3027
      The cardiac vascular and perivascular niche are of major importance in homeostasis and during disease, but we lack a complete understanding of its cellular heterogeneity and alteration in response to injury as a major driver of heart failure. Using combined genetic fate tracing with confocal imaging and single-cell RNA sequencing of this niche in homeostasis and during heart failure, we unravel cell type specific transcriptomic changes in fibroblast, endothelial, pericyte and vascular smooth muscle cell subtypes. We characterize a specific fibroblast subpopulation that exists during homeostasis, acquires Thbs4 expression and expands after injury driving cardiac fibrosis, and identify the transcription factor TEAD1 as a regulator of fibroblast activation. Endothelial cells display a proliferative response after injury, which is not sustained in later remodeling, together with transcriptional changes related to hypoxia, angiogenesis, and migration. Collectively, our data provides an extensive resource of transcriptomic changes in the vascular niche in hypertrophic cardiac remodeling.
  3. Nat Commun. 2022 May 31. 13(1): 3022
      PARP inhibitors (PARPi) have drastically changed the treatment landscape of advanced ovarian tumors with BRCA mutations. However, the impact of this class of inhibitors in patients with advanced BRCA-mutant breast cancer is relatively modest. Using a syngeneic genetically-engineered mouse model of breast tumor driven by Brca1 deficiency, we show that tumor-associated macrophages (TAMs) blunt PARPi efficacy both in vivo and in vitro. Mechanistically, BRCA1-deficient breast tumor cells induce pro-tumor polarization of TAMs, which in turn suppress PARPi-elicited DNA damage in tumor cells, leading to reduced production of dsDNA fragments and synthetic lethality, hence impairing STING-dependent anti-tumor immunity. STING agonists reprogram M2-like pro-tumor macrophages into an M1-like anti-tumor state in a macrophage STING-dependent manner. Systemic administration of a STING agonist breaches multiple layers of tumor cell-mediated suppression of immune cells, and synergizes with PARPi to suppress tumor growth. The therapeutic benefits of this combination require host STING and are mediated by a type I IFN response and CD8+ T cells, but do not rely on tumor cell-intrinsic STING. Our data illustrate the importance of targeting innate immune suppression to facilitate PARPi-mediated engagement of anti-tumor immunity in breast cancer.
  4. Nat Commun. 2022 May 31. 13(1): 3016
      Double-strand breaks (DSBs) are one of the most toxic forms of DNA damage and represent a major source of genomic instability. Members of the bromodomain and extra-terminal (BET) protein family are characterized as epigenetic readers that regulate gene expression. However, evidence suggests that BET proteins also play a more direct role in DNA repair. Here, we establish a cell-free system using Xenopus egg extracts to elucidate the gene expression-independent functions of BET proteins in DSB repair. We identify the BET protein BRD4 as a critical regulator of homologous recombination and describe its role in stimulating DNA processing through interactions with the SWI/SNF chromatin remodeling complex and resection machinery. These results establish BRD4 as a multifunctional regulator of chromatin binding that links transcriptional activity and homology-directed repair.
  5. Cell Host Microbe. 2022 May 24. pii: S1931-3128(22)00264-5. [Epub ahead of print]
      The impacts of individual commensal microbes on immunity and disease can differ dramatically depending on the surrounding microbial context; however, the specific bacterial combinations that dictate divergent immunological outcomes remain largely undefined. Here, we characterize an immunostimulatory Allobaculum species from an inflammatory bowel disease patient that exacerbates colitis in gnotobiotic mice. Allobaculum inversely associates with the taxonomically divergent immunostimulatory species Akkermansia muciniphila in human-microbiota-associated mice and human cohorts. Co-colonization with A. muciniphila ameliorates Allobaculum-induced intestinal epithelial cell activation and colitis in mice, whereas Allobaculum blunts the A.muciniphila-specific systemic antibody response and reprograms the immunological milieu in mesenteric lymph nodes by blocking A.muciniphila-induced dendritic cell activation and T cell expansion. These studies thus identify a pairwise reciprocal interaction between human gut bacteria that dictates divergent immunological outcomes. Furthermore, they establish a generalizable framework to define the contextual cues contributing to the "incomplete penetrance" of microbial impacts on human disease.
    Keywords:  IgA; IgA-Seq; gut microbiota; human gut bacteria; human microbiota-associated gnotobiotic mice; immunoglobulin A; immunostimulatory commensals; inflammatory bowel disease; mucosal immunity; reciprocal epistasis
  6. Nat Commun. 2022 Jun 01. 13(1): 3060
      A vital question in neuroscience is how neurons align their postsynaptic structures with presynaptic release sites. Although synaptic adhesion proteins are known to contribute in this process, the role of neurotransmitters remains unclear. Here we inquire whether de novo biosynthesis and vesicular release of a noncanonical transmitter can facilitate the assembly of its corresponding postsynapses. We demonstrate that, in both stem cell-derived human neurons as well as in vivo mouse neurons of purely glutamatergic identity, ectopic expression of GABA-synthesis enzymes and vesicular transporters is sufficient to both produce GABA from ambient glutamate and transmit it from presynaptic terminals. This enables efficient accumulation and consistent activation of postsynaptic GABAA receptors, and generates fully functional GABAergic synapses that operate in parallel but independently of their glutamatergic counterparts. These findings suggest that presynaptic release of a neurotransmitter itself can signal the organization of relevant postsynaptic apparatus, which could be directly modified to reprogram the synapse identity of neurons.
  7. Nat Commun. 2022 Jun 01. 13(1): 3053
      In addition to central functions in cell adhesion signalling, integrin-associated proteins have wider roles at sites distal to adhesion receptors. In experimentally defined adhesomes, we noticed that there is clear enrichment of proteins that localise to the nucleus, and conversely, we now report that nuclear proteomes contain a class of adhesome components that localise to the nucleus. We here define a nucleo-adhesome, providing experimental evidence for a remarkable scale of nuclear localisation of adhesion proteins, establishing a framework for interrogating nuclear adhesion protein functions. Adding to nuclear FAK's known roles in regulating transcription, we now show that nuclear FAK regulates expression of many adhesion-related proteins that localise to the nucleus and that nuclear FAK binds to the adhesome component and nuclear protein Hic-5. FAK and Hic-5 work together in the nucleus, co-regulating a subset of genes transcriptionally. We demonstrate the principle that there are subcomplexes of nuclear adhesion proteins that cooperate to control transcription.
  8. J Clin Invest. 2022 Jun 01. pii: e160474. [Epub ahead of print]132(11):
      HIV infection results in defective CD8+ T cell functions that are incompletely resolved by antiretroviral therapy (ART) except in natural controllers, who have functional CD8+ T cells associated with viral control. In this issue of the JCI, Perdomo-Celis et al. demonstrated that targeting the Wnt/transcription factor T cell factor 1 (Wnt/TCF-1) pathway in dysfunctional CD8+ T cells led to gains in stemness phenotype, metabolic quiescence, survival potential, response to homeostatic γ-chain cytokines, and antiviral capacities, similar to profiles of functional CD8+ T cells in natural controllers. Although reprogramming might not sufficiently reverse the imprinted dysfunction of CD8+ T cells in HIV infection, these findings outline the Wnt/TCF-1 pathway as a potential target to reprogram dysfunctional CD8+ T cells in efforts to achieve HIV remission.
  9. Nat Genet. 2022 Jun 02.
    Regeneron Genetics Center
      Nonalcoholic fatty liver disease (NAFLD) is a growing cause of chronic liver disease. Using a proxy NAFLD definition of chronic elevation of alanine aminotransferase (cALT) levels without other liver diseases, we performed a multiancestry genome-wide association study (GWAS) in the Million Veteran Program (MVP) including 90,408 cALT cases and 128,187 controls. Seventy-seven loci exceeded genome-wide significance, including 25 without prior NAFLD or alanine aminotransferase associations, with one additional locus identified in European American-only and two in African American-only analyses (P < 5 × 10-8). External replication in histology-defined NAFLD cohorts (7,397 cases and 56,785 controls) or radiologic imaging cohorts (n = 44,289) replicated 17 single-nucleotide polymorphisms (SNPs) (P < 6.5 × 10-4), of which 9 were new (TRIB1, PPARG, MTTP, SERPINA1, FTO, IL1RN, COBLL1, APOH and IFI30). Pleiotropy analysis showed that 61 of 77 multiancestry and all 17 replicated SNPs were jointly associated with metabolic and/or inflammatory traits, revealing a complex model of genetic architecture. Our approach integrating cALT, histology and imaging reveals new insights into genetic liability to NAFLD.
  10. Sci Transl Med. 2022 Jun;14(647): eabi8593
      Microglia-mediated synaptic loss contributes to the development of cognitive impairments in Alzheimer's disease (AD). However, the basis for this immune-mediated attack on synapses remains to be elucidated. Treatment with the metabotropic glutamate receptor 5 (mGluR5) silent allosteric modulator (SAM), BMS-984923, prevents β-amyloid oligomer-induced aberrant synaptic signaling while preserving physiological glutamate response. Here, we show that oral BMS-984923 effectively occupies brain mGluR5 sites visualized by [18F]FPEB positron emission tomography (PET) at doses shown to be safe in rodents and nonhuman primates. In aged mouse models of AD (APPswe/PS1ΔE9 overexpressing transgenic and AppNL-G-F/hMapt double knock-in), SAM treatment fully restored synaptic density as measured by [18F]SynVesT-1 PET for SV2A and by histology, and the therapeutic benefit persisted after drug washout. Phospho-TAU accumulation in double knock-in mice was also reduced by SAM treatment. Single-nuclei transcriptomics demonstrated that SAM treatment in both models normalized expression patterns to a far greater extent in neurons than glia. Last, treatment prevented synaptic localization of the complement component C1Q and synaptic engulfment in AD mice. Thus, selective modulation of mGluR5 reversed neuronal gene expression changes to protect synapses from damage by microglial mediators in rodents.
  11. Nat Commun. 2022 Jun 02. 13(1): 3093
      The glycocalyx is a shell of heavily glycosylated proteins and lipids distributed on the cell surface of nearly all cell types. Recently, it has been found that bulky transmembrane glycoproteins such as MUC1 can modulate membrane shape by inducing membrane protrusions. In this work, we examine the reciprocal relationship of how membrane shape affects MUC1's spatial distribution on the cell membrane and its biological significance. By employing nanopatterned surfaces and membrane-sculpting proteins to manipulate membrane curvature, we show that MUC1 avoids positively-curved membranes (membrane invaginations) and accumulates on negatively-curved membranes (membrane protrusions). MUC1's curvature sensitivity is dependent on the length and the extent of glycosylation of its ectodomain, with large and highly glycosylated forms preferentially staying out of positive curvature. Interestingly, MUC1's avoidance of positive membrane curvature enables it to escape from endocytosis and being removed from the cell membrane. These findings also suggest that the truncation of MUC1's ectodomain, often observed in breast and ovarian cancers, may enhance its endocytosis and potentiate its intracellular accumulation and signaling.
  12. J Clin Invest. 2022 Jun 01. pii: e156243. [Epub ahead of print]132(11):
    HPAP Consortium
      BACKGROUNDMultiple islet autoantibodies (AAbs) predict the development of type 1 diabetes (T1D) and hyperglycemia within 10 years. By contrast, T1D develops in only approximately 15% of individuals who are positive for single AAbs (generally against glutamic acid decarboxylase [GADA]); hence, the single GADA+ state may represent an early stage of T1D.METHODSHere, we functionally, histologically, and molecularly phenotyped human islets from nondiabetic GADA+ and T1D donors.RESULTSSimilar to the few remaining β cells in the T1D islets, GADA+ donor islets demonstrated a preserved insulin secretory response. By contrast, α cell glucagon secretion was dysregulated in both GADA+ and T1D islets, with impaired glucose suppression of glucagon secretion. Single-cell RNA-Seq of GADA+ α cells revealed distinct abnormalities in glycolysis and oxidative phosphorylation pathways and a marked downregulation of cAMP-dependent protein kinase inhibitor β (PKIB), providing a molecular basis for the loss of glucose suppression and the increased effect of 3-isobutyl-1-methylxanthine (IBMX) observed in GADA+ donor islets.CONCLUSIONWe found that α cell dysfunction was present during the early stages of islet autoimmunity at a time when β cell mass was still normal, raising important questions about the role of early α cell dysfunction in the progression of T1D.FUNDINGThis work was supported by grants from the NIH (3UC4DK112217-01S1, U01DK123594-02, UC4DK112217, UC4DK112232, U01DK123716, and P30 DK019525) and the Vanderbilt Diabetes Research and Training Center (DK20593).
    Keywords:  Autoimmune diseases; Diabetes; Endocrinology; Islet cells
  13. Nat Commun. 2022 May 30. 13(1): 2995
      Hepatitis B virus has infected a third of the world's population, and 296 million people are living with chronic infection. Chronic infection leads to progressive liver disease, including hepatocellular carcinoma and liver failure, and there remains no reliable curative therapy. These gaps in our understanding are due, in large part, to a paucity of animal models of HBV infection. Here, we show that rhesus macaques regularly clear acute HBV infection, similar to adult humans, but can develop long-term infection if immunosuppressed. Similar to patients, we longitudinally detected HBV DNA, HBV surface antigen, and HBV e antigen in the serum of experimentally infected animals. In addition, we discovered hallmarks of HBV infection in the liver, including RNA transcription, HBV core and HBV surface antigen translation, and covalently closed circular DNA biogenesis. This pre-clinical animal model will serve to accelerate emerging HBV curative therapies into the clinic.
  14. J Clin Invest. 2022 Jun 02. pii: e160852. [Epub ahead of print]
      Purine nucleoside phosphorylase (PNP) enables the breakdown and recycling of guanine nucleosides. PNP insufficiency in humans is paradoxically associated with both immunodeficiency and autoimmunity, but the mechanistic basis for these outcomes is incompletely understood. Here we identify two immune lineage-dependent consequences of PNP inactivation dictated by distinct gene interactions. During T cell development, PNP inactivation is synthetically lethal with down-regulation of the dNTP triphosphohydrolase SAMHD1. This interaction requires deoxycytidine kinase activity and is antagonized by microenvironmental deoxycytidine. In B lymphocytes and macrophages, PNP regulates Toll like receptor 7 signaling by controlling the levels of its (deoxy)guanosine nucleoside ligands. Overriding this regulatory mechanism promotes germinal center formation in the absence of exogenous antigen and accelerates disease in a mouse model of autoimmunity. This work reveals that one purine metabolism gene protects against immunodeficiency and autoimmunity via independent mechanisms operating in distinct immune lineages and identifies PNP as a novel metabolic immune checkpoint.
    Keywords:  Autoimmune diseases; Immunology; Immunotherapy; Metabolism; T cell development
  15. Nature. 2022 Jun 01.
      Antiretroviral therapy is highly effective in suppressing human immunodeficiency virus (HIV)1. However, eradication of the virus in individuals with HIV has not been possible to date2. Given that HIV suppression requires life-long antiretroviral therapy, predominantly on a daily basis, there is a need to develop clinically effective alternatives that use long-acting antiviral agents to inhibit viral replication3. Here we report the results of a two-component clinical trial involving the passive transfer of two HIV-specific broadly neutralizing monoclonal antibodies, 3BNC117 and 10-1074. The first component was a randomized, double-blind, placebo-controlled trial that enrolled participants who initiated antiretroviral therapy during the acute/early phase of HIV infection. The second component was an open-label single-arm trial that enrolled individuals with viraemic control who were naive to antiretroviral therapy. Up to 8 infusions of 3BNC117 and 10-1074, administered over a period of 24 weeks, were well tolerated without any serious adverse events related to the infusions. Compared with the placebo, the combination broadly neutralizing monoclonal antibodies maintained complete suppression of plasma viraemia (for up to 43 weeks) after analytical treatment interruption, provided that no antibody-resistant HIV was detected at the baseline in the study participants. Similarly, potent HIV suppression was seen in the antiretroviral-therapy-naive study participants with viraemia carrying sensitive virus at the baseline. Our data demonstrate that combination therapy with broadly neutralizing monoclonal antibodies can provide long-term virological suppression without antiretroviral therapy in individuals with HIV, and our experience offers guidance for future clinical trials involving next-generation antibodies with long half-lives.
  16. Nat Commun. 2022 Jun 01. 13(1): 3061
      Molecular variation between geographical populations and subtypes indicate potential genomic heterogeneity and novel genomic features within CCA. Here, we analyze exome-sequencing data of 87 perihilar cholangiocarcinoma (pCCA) and 261 intrahepatic cholangiocarcinoma (iCCA) cases from 3 Asian centers (including 43 pCCAs and 24 iCCAs from our center). iCCA tumours demonstrate a higher tumor mutation burden and copy number alteration burden (CNAB) than pCCA tumours, and high CNAB indicates a poorer pCCA prognosis. We identify 12 significantly mutated genes and 5 focal CNA regions, and demonstrate common mutations in post-transcriptional modification-related potential driver genes METTL14 and RBM10 in pCCA tumours. Finally we demonstrate the tumour-suppressive role of METTL14, a major RNA N6-adenosine methyltransferase (m6A), and illustrate that its loss-of-function mutation R298H may act through m6A modification on potential driver gene MACF1. Our results may be valuable for better understanding of how post-transcriptional modification can affect CCA development, and highlight both similarities and differences between pCCA and iCCA.
  17. Nature. 2022 06;606(7912): 9
    Keywords:  Medical research; Policy
  18. Nat Rev Immunol. 2022 Jun 01.
      Thymic stromal lymphopoietin (TSLP) is a pleiotropic cytokine that acts on multiple cell lineages, including dendritic cells, T cells, B cells, neutrophils, mast cells, eosinophils and innate lymphoid cells, affecting their maturation, survival and recruitment. It is best known for its role in promoting type 2 immune responses such as in allergic diseases and, in 2021, a monoclonal antibody targeting TSLP was approved for the treatment of severe asthma. However, it is now clear that TSLP has many other important roles in a variety of settings. Indeed, several genetic variants for TSLP are linked to disease severity, and chromosomal alterations in TSLP are common in certain cancers, indicating important roles of TSLP in disease. In this Review, we discuss recent advances in TSLP biology, highlighting how it regulates the tissue environment not only in allergic disease but also in infectious diseases, inflammatory diseases and cancer. Encouragingly, therapies targeting the TSLP pathway are being actively pursued for several diseases.
  19. Nat Genet. 2022 Jun 02.
      The substantial phenotypic heterogeneity in autism limits our understanding of its genetic etiology. To address this gap, here we investigated genetic differences between autistic individuals (nmax = 12,893) based on core and associated features of autism, co-occurring developmental disabilities and sex. We conducted a comprehensive factor analysis of core autism features in autistic individuals and identified six factors. Common genetic variants were associated with the core factors, but de novo variants were not. We found that higher autism polygenic scores (PGS) were associated with lower likelihood of co-occurring developmental disabilities in autistic individuals. Furthermore, in autistic individuals without co-occurring intellectual disability (ID), autism PGS are overinherited by autistic females compared to males. Finally, we observed higher SNP heritability for autistic males and for autistic individuals without ID. Deeper phenotypic characterization will be critical in determining how the complex underlying genetics shape cognition, behavior and co-occurring conditions in autism.