Publications by authors named "Marco Colonna"

367 Publications

TREM2 is a receptor for non-glycosylated mycolic acids of mycobacteria that limits anti-mycobacterial macrophage activation.

Nat Commun 2021 04 16;12(1):2299. Epub 2021 Apr 16.

Department of Immunology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.

Mycobacterial cell-wall glycolipids elicit an anti-mycobacterial immune response via FcRγ-associated C-type lectin receptors, including Mincle, and caspase-recruitment domain family member 9 (CARD9). Additionally, mycobacteria harbor immuno-evasive cell-wall lipids associated with virulence and latency; however, a mechanism of action is unclear. Here, we show that the DAP12-associated triggering receptor expressed on myeloid cells 2 (TREM2) recognizes mycobacterial cell-wall mycolic acid (MA)-containing lipids and suggest a mechanism by which mycobacteria control host immunity via TREM2. Macrophages respond to glycosylated MA-containing lipids in a Mincle/FcRγ/CARD9-dependent manner to produce inflammatory cytokines and recruit inducible nitric oxide synthase (iNOS)-positive mycobactericidal macrophages. Conversely, macrophages respond to non-glycosylated MAs in a TREM2/DAP12-dependent but CARD9-independent manner to recruit iNOS-negative mycobacterium-permissive macrophages. Furthermore, TREM2 deletion enhances Mincle-induced macrophage activation in vitro and inflammation in vivo and accelerates the elimination of mycobacterial infection, suggesting that TREM2-DAP12 signaling counteracts Mincle-FcRγ-CARD9-mediated anti-mycobacterial immunity. Mycobacteria, therefore, harness TREM2 for immune evasion.
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http://dx.doi.org/10.1038/s41467-021-22620-3DOI Listing
April 2021

Single-cell analyses of Crohn's disease tissues reveal intestinal intraepithelial T cells heterogeneity and altered subset distributions.

Nat Commun 2021 03 26;12(1):1921. Epub 2021 Mar 26.

Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, USA.

Crohn's disease (CD) is a chronic transmural inflammation of intestinal segments caused by dysregulated interaction between microbiome and gut immune system. Here, we profile, via multiple single-cell technologies, T cells purified from the intestinal epithelium and lamina propria (LP) from terminal ileum resections of adult severe CD cases. We find that intraepithelial lymphocytes (IEL) contain several unique T cell subsets, including NKp30γδT cells expressing RORγt and producing IL-26 upon NKp30 engagement. Further analyses comparing tissues from non-inflamed and inflamed regions of patients with CD versus healthy controls show increased activated T17 but decreased CD8T, γδT, T and Treg cells in inflamed tissues. Similar analyses of LP find increased CD8, as well as reduced CD4T cells with an elevated T17 over Treg/T ratio. Our analyses of CD tissues thus suggest a potential link, pending additional validations, between transmural inflammation, reduced IEL γδT cells and altered spatial distribution of IEL and LP T cell subsets.
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http://dx.doi.org/10.1038/s41467-021-22164-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997960PMC
March 2021

Microglia control small vessel calcification via TREM2.

Sci Adv 2021 Feb 26;7(9). Epub 2021 Feb 26.

Department of Neurosurgery, Clinical Neurocentre, Zurich University Hospital, Zurich University, Zürich, Switzerland.

Microglia participate in central nervous system (CNS) development and homeostasis and are often implicated in modulating disease processes. However, less is known about the role of microglia in the biology of the neurovascular unit (NVU). In particular, data are scant on whether microglia are involved in CNS vascular pathology. In this study, we use a mouse model of primary familial brain calcification, , to investigate the role of microglia in calcification of the NVU. We report that microglia enclosing vessel calcifications, coined calcification-associated microglia, display a distinct activation phenotype. Pharmacological ablation of microglia with the CSF1R inhibitor PLX5622 leads to aggravated vessel calcification. Mechanistically, we show that microglia require functional TREM2 for controlling vascular calcification. Our results demonstrate that microglial activity in the setting of pathological vascular calcification is beneficial. In addition, we identify a previously unrecognized function of microglia in halting the expansion of vascular calcification.
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http://dx.doi.org/10.1126/sciadv.abc4898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7909879PMC
February 2021

Dysregulation of the Leukocyte Signaling Landscape during Acute COVID-19.

Res Sq 2021 Feb 16. Epub 2021 Feb 16.

The global COVID-19 pandemic has claimed the lives of more than 450,000 US citizens. Dysregulation of the immune system underlies the pathogenesis of COVID-19, with inflammation mediated local tissue injury to the lung in the setting of suppressed systemic immune function. To define the molecular mechanisms of immune dysfunction in COVID-19 we utilized a systems immunology approach centered on the circulating leukocyte phosphoproteome measured by mass cytometry. COVID-19 is associated with wholesale activation of a broad set of signaling pathways across myeloid and lymphoid cell populations. STAT3 phosphorylation predominated in both monocytes and T cells and was tightly correlated with circulating IL-6 levels. High levels of STAT3 phosphorylation was associated with decreased markers of myeloid cell maturation/activation and decreased ex-vivo T cell IFN-gamma production, demonstrating that during COVID-19 dysregulated cellular activation is associated with suppression of immune effector cell function. Collectively, these data reconcile the systemic inflammatory response and functional immunosuppression induced by COVID-19 and suggest STAT3 signaling may be the central pathophysiologic mechanism driving immune dysfunction in COVID-19.
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http://dx.doi.org/10.21203/rs.3.rs-244150/v1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7899466PMC
February 2021

TREM2 sustains macrophage-hepatocyte metabolic coordination in nonalcoholic fatty liver disease and sepsis.

J Clin Invest 2021 Feb;131(4)

Department of Anesthesiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.

Sepsis is a leading cause of death in critical illness, and its pathophysiology varies depending on preexisting medical conditions. Here we identified nonalcoholic fatty liver disease (NAFLD) as an independent risk factor for sepsis in a large clinical cohort and showed a link between mortality in NAFLD-associated sepsis and hepatic mitochondrial and energetic metabolism dysfunction. Using in vivo and in vitro models of liver lipid overload, we discovered a metabolic coordination between hepatocyte mitochondria and liver macrophages that express triggering receptor expressed on myeloid cells-2 (TREM2). Trem2-deficient macrophages released exosomes that impaired hepatocytic mitochondrial structure and energy supply because of their high content of miR-106b-5p, which blocks Mitofusin 2 (Mfn2). In a mouse model of NAFLD-associated sepsis, TREM2 deficiency accelerated the initial progression of NAFLD and subsequent susceptibility to sepsis. Conversely, overexpression of TREM2 in liver macrophages improved hepatic energy supply and sepsis outcome. This study demonstrates that NAFLD is a risk factor for sepsis, providing a basis for precision treatment, and identifies hepatocyte-macrophage metabolic coordination and TREM2 as potential targets for future clinical trials.
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http://dx.doi.org/10.1172/JCI135197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880419PMC
February 2021

P2Y receptor antagonism resolves sialadenitis and improves salivary flow in a Sjögren's syndrome mouse model.

Arch Oral Biol 2021 Apr 3;124:105067. Epub 2021 Feb 3.

Department of Biochemistry and Christopher S. Bond Life Sciences Center, University of Missouri, 1201 Rollins St., Columbia, MO, 65211-7310, USA.

Objective: Sjögren's syndrome (SS) is a chronic autoimmune exocrinopathy characterized by lymphocytic infiltration of the salivary and lacrimal glands and decreased saliva and tear production. Previous studies indicate that the G protein-coupled P2Y nucleotide receptor (P2YR) is upregulated in numerous models of salivary gland inflammation (i.e., sialadenitis), where it has been implicated as a key mediator of chronic inflammation. Here, we evaluate both systemic and localized P2YR antagonism as a means to resolve sialadenitis in the NOD.H-2,IFNγ,CD28 (NOD.H-2 DKO) mouse model of SS.

Design: Female 4.5 month old NOD.H-2 DKO mice received daily intraperitoneal injections for 10 days of the selective P2YR antagonist, AR-C118925, or vehicle-only control. Single-dose localized intraglandular antagonist delivery into the Wharton's duct was also evaluated. Carbachol-induced saliva was measured and then submandibular glands (SMGs) were isolated and either fixed and paraffin-embedded for H&E staining, homogenized for RNA isolation or dissociated for flow cytometry analysis.

Results: Intraperitoneal injection, but not localized intraglandular administration, of AR-C118925 significantly enhanced carbachol-induced salivation and reduced lymphocytic foci and immune cell markers in SMGs of 5 month old NOD.H-2 DKO mice, compared to vehicle-injected control mice. We found that B cells represent the primary immune cell population in inflamed SMGs of NOD.H-2 DKO mice that express elevated levels of P2YR compared to C57BL/6 control mice. We further demonstrate a role for P2YRs in mediating B cell migration and the release of IgM.

Conclusion: Our findings suggest that the P2YR represents a novel therapeutic target for the treatment of Sjögren's syndrome.
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http://dx.doi.org/10.1016/j.archoralbio.2021.105067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7958986PMC
April 2021

Killing the Invaders: NK Cell Impact in Tumors and Anti-Tumor Therapy.

Cancers (Basel) 2021 Feb 3;13(4). Epub 2021 Feb 3.

Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.

Natural Killer cells belong to group 1 innate lymphoid cells, which also includes ILC1s. NK/ILC1s are highly heterogeneous cell types showing distinct phenotypes across tissues and conditions. NK cells have long been described as innate lymphocytes able to directly and rapidly kill tumor cells without antigen-restriction. Different mechanisms were shown to modulate NK cell activation and tumor resistance, mainly based on cytokine stimulation and receptor-ligand interactions, and several strategies have been developed to target NK cells in tumor immunotherapy to promote NK cell function and overcome tumor evasion. The characterization of ILC1 distinct phenotype and function and the specific role in tumors still needs further investigation and will be essential to better understand the impact of innate lymphoid cells in tumors. Here, we review key aspects of NK cell biology that are relevant in tumor immune surveillance, emphasizing the most recent findings in the field. We describe the novel therapeutical strategies that have been developed in tumor immunotherapy targeting NK cells, and we summarize some recent findings related to NK cell/ILC1 transition in tumor models.
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http://dx.doi.org/10.3390/cancers13040595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7913353PMC
February 2021

Prior activation state shapes the microglia response to antihuman TREM2 in a mouse model of Alzheimer's disease.

Proc Natl Acad Sci U S A 2021 Jan;118(3)

Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO 63110;

Triggering receptor expressed on myeloid cells 2 (TREM2) sustains microglia response to brain injury stimuli including apoptotic cells, myelin damage, and amyloid β (Aβ). Alzheimer's disease (AD) risk is associated with the variant, which impairs ligand binding and consequently microglia responses to Aβ pathology. Here, we show that TREM2 engagement by the mAb hT2AB as surrogate ligand activates microglia in 5XFAD transgenic mice that accumulate Aβ and express either the common TREM2 variant () or scRNA-seq of microglia from -5XFAD mice treated once with control hIgG1 exposed four distinct trajectories of microglia activation leading to disease-associated (DAM), interferon-responsive (IFN-R), cycling (Cyc-M), and MHC-II expressing (MHC-II) microglia types. All of these were underrepresented in -5XFAD mice, suggesting that TREM2 ligand engagement is required for microglia activation trajectories. Moreover, Cyc-M and IFN-R microglia were more abundant in female than male -5XFAD mice, likely due to greater Aβ load in female 5XFAD mice. A single systemic injection of hT2AB replenished Cyc-M, IFN-R, and MHC-II pools in -5XFAD mice. In -5XFAD mice, however, hT2AB brought the representation of male Cyc-M and IFN-R microglia closer to that of females, in which these trajectories had already reached maximum capacity. Moreover, hT2AB induced shifts in gene expression patterns in all microglial pools without affecting representation. Repeated treatment with a murinized hT2AB version over 10 d increased chemokines brain content in -5XFAD mice, consistent with microglia expansion. Thus, the impact of hT2AB on microglia is shaped by the extent of TREM2 endogenous ligand engagement and basal microglia activation.
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http://dx.doi.org/10.1073/pnas.2017742118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826333PMC
January 2021

Altered ratio of dendritic cell subsets in skin-draining lymph nodes promotes Th2-driven contact hypersensitivity.

Proc Natl Acad Sci U S A 2021 Jan;118(3)

Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110;

Plasmacytoid dendritic cells (pDCs) specialize in the production of type I IFN (IFN-I). pDCs can be depleted in vivo by injecting diphtheria toxin (DT) in a mouse in which pDCs express a diphtheria toxin receptor (DTR) transgene driven by the human CLEC4C promoter. This promoter is enriched for binding sites for TCF4, a transcription factor that promotes pDC differentiation and expression of pDC markers, including CLEC4C. Here, we found that injection of DT in CLEC4C-DTR mice markedly augmented Th2-dependent skin inflammation in a model of contact hypersensitivity (CHS) induced by the hapten fluorescein isothiocyanate. Unexpectedly, this biased Th2 response was independent of reduced IFN-I accompanying pDC depletion. In fact, DT treatment altered the representation of conventional dendritic cells (cDCs) in the skin-draining lymph nodes during the sensitization phase of CHS; there were fewer Th1-priming CD326 CD103 cDC1 and more Th2-priming CD11b cDC2. Single-cell RNA-sequencing of CLEC4C-DTR cDCs revealed that CD326 DCs, like pDCs, expressed DTR and were depleted together with pDCs by DT treatment. Since CD326 DCs did not express , DTR expression might be driven by yet-undefined transcription factors activating the CLEC4C promoter. These results demonstrate that altered DC representation in the skin-draining lymph nodes during sensitization to allergens can cause Th2-driven CHS.
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http://dx.doi.org/10.1073/pnas.2021364118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826349PMC
January 2021

Comprehensive Profiling of an Aging Immune System Reveals Clonal GZMK CD8 T Cells as Conserved Hallmark of Inflammaging.

Immunity 2021 Jan 2;54(1):99-115.e12. Epub 2020 Dec 2.

Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address:

Systematic understanding of immune aging on a whole-body scale is currently lacking. We characterized age-associated alterations in immune cells across multiple mouse organs using single-cell RNA and antigen receptor sequencing and flow cytometry-based validation. We defined organ-specific and common immune alterations and identified a subpopulation of age-associated granzyme K (GZMK)-expressing CD8 T (Taa) cells that are distinct from T effector memory (Tem) cells. Taa cells were highly clonal, had specific epigenetic and transcriptional signatures, developed in response to an aged host environment, and expressed markers of exhaustion and tissue homing. Activated Taa cells were the primary source of GZMK, which enhanced inflammatory functions of non-immune cells. In humans, proportions of the circulating GZMKCD8 T cell population that shares transcriptional and epigenetic signatures with mouse Taa cells increased during healthy aging. These results identify GZMK Taa cells as a potential target to address age-associated dysfunctions of the immune system.
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http://dx.doi.org/10.1016/j.immuni.2020.11.005DOI Listing
January 2021

Negative feedback control of neuronal activity by microglia.

Nature 2020 10 30;586(7829):417-423. Epub 2020 Sep 30.

Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Microglia, the brain's resident macrophages, help to regulate brain function by removing dying neurons, pruning non-functional synapses, and producing ligands that support neuronal survival. Here we show that microglia are also critical modulators of neuronal activity and associated behavioural responses in mice. Microglia respond to neuronal activation by suppressing neuronal activity, and ablation of microglia amplifies and synchronizes the activity of neurons, leading to seizures. Suppression of neuronal activation by microglia occurs in a highly region-specific fashion and depends on the ability of microglia to sense and catabolize extracellular ATP, which is released upon neuronal activation by neurons and astrocytes. ATP triggers the recruitment of microglial protrusions and is converted by the microglial ATP/ADP hydrolysing ectoenzyme CD39 into AMP; AMP is then converted into adenosine by CD73, which is expressed on microglia as well as other brain cells. Microglial sensing of ATP, the ensuing microglia-dependent production of adenosine, and the adenosine-mediated suppression of neuronal responses via the adenosine receptor AR are essential for the regulation of neuronal activity and animal behaviour. Our findings suggest that this microglia-driven negative feedback mechanism operates similarly to inhibitory neurons and is essential for protecting the brain from excessive activation in health and disease.
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http://dx.doi.org/10.1038/s41586-020-2777-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577179PMC
October 2020

TREM2 Modulation Remodels the Tumor Myeloid Landscape Enhancing Anti-PD-1 Immunotherapy.

Cell 2020 08 11;182(4):886-900.e17. Epub 2020 Aug 11.

Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address:

Checkpoint immunotherapy unleashes T cell control of tumors, but is undermined by immunosuppressive myeloid cells. TREM2 is a myeloid receptor that transmits intracellular signals that sustain microglial responses during Alzheimer's disease. TREM2 is also expressed by tumor-infiltrating macrophages. Here, we found that Trem2 mice are more resistant to growth of various cancers than wild-type mice and are more responsive to anti-PD-1 immunotherapy. Furthermore, treatment with anti-TREM2 mAb curbed tumor growth and fostered regression when combined with anti-PD-1. scRNA-seq revealed that both TREM2 deletion and anti-TREM2 are associated with scant MRC1 and CXCR1 macrophages in the tumor infiltrate, paralleled by expansion of myeloid subsets expressing immunostimulatory molecules that promote improved T cell responses. TREM2 was expressed in tumor macrophages in over 200 human cancer cases and inversely correlated with prolonged survival for two types of cancer. Thus, TREM2 might be targeted to modify tumor myeloid infiltrates and augment checkpoint immunotherapy.
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http://dx.doi.org/10.1016/j.cell.2020.07.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7485282PMC
August 2020

Interferon responses in viral pneumonias.

Science 2020 08;369(6504):626-627

Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.

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http://dx.doi.org/10.1126/science.abd2208DOI Listing
August 2020

Keeping time in group 3 innate lymphoid cells.

Nat Rev Immunol 2020 12 5;20(12):720-726. Epub 2020 Aug 5.

Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.

Each day, the gastrointestinal tract encounters an influx of microbial and nutrient-derived signals and its physiological activities often adhere to a circadian rhythm. As such, group 3 innate lymphoid cells (ILC3s) that reside in the intestinal mucosa must function within a highly dynamic environment. In this Progress article, we highlight a series of recent reports that have characterized the circadian clock in ILC3s. We discuss how these studies have illustrated the roles of environmental cues and clock genes in regulating ILC3 biology and consider the implications for intestinal immunity.
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http://dx.doi.org/10.1038/s41577-020-0397-zDOI Listing
December 2020

The Intestinal Microbiome Restricts Alphavirus Infection and Dissemination through a Bile Acid-Type I IFN Signaling Axis.

Cell 2020 08 14;182(4):901-918.e18. Epub 2020 Jul 14.

Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA; Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address:

Chikungunya virus (CHIKV), an emerging alphavirus, has infected millions of people. However, the factors modulating disease outcome remain poorly understood. Here, we show in germ-free mice or in oral antibiotic-treated conventionally housed mice with depleted intestinal microbiomes that greater CHIKV infection and spread occurs within 1 day of virus inoculation. Alteration of the microbiome alters TLR7-MyD88 signaling in plasmacytoid dendritic cells (pDCs) and blunts systemic production of type I interferon (IFN). Consequently, circulating monocytes express fewer IFN-stimulated genes and become permissive for CHIKV infection. Reconstitution with a single bacterial species, Clostridium scindens, or its derived metabolite, the secondary bile acid deoxycholic acid, can restore pDC- and MyD88-dependent type I IFN responses to restrict systemic CHIKV infection and transmission back to vector mosquitoes. Thus, symbiotic intestinal bacteria modulate antiviral immunity and levels of circulating alphaviruses within hours of infection through a bile acid-pDC-IFN signaling axis, which affects viremia, dissemination, and potentially transmission.
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http://dx.doi.org/10.1016/j.cell.2020.06.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483520PMC
August 2020

Group 2 Innate Lymphoid Cells Must Partner with the Myeloid-Macrophage Lineage for Long-Term Postviral Lung Disease.

J Immunol 2020 08 8;205(4):1084-1101. Epub 2020 Jul 8.

Division of Pulmonary and Critical Care Medicine, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110;

Group 2 innate lymphoid cells (ILC2s) are implicated in host defense and inflammatory disease, but these potential functional roles need more precise definition, particularly using advanced technologies to better target ILC2s and engaging experimental models that better manifest both acute infection and chronic, even lifelong, disease. In this study, we use a mouse model that applies an improved genetic definition of ILC2s via -conditional gene targeting and takes advantage of a distinct progression from acute illness to chronic disease, based on a persistent type 2 immune response to respiratory infection with a natural pathogen (Sendai virus). We first show that ILC2s are activated but are not required to handle acute illness after respiratory viral infection. In contrast, we find that this type of infection also activates ILC2s chronically for IL-13 production and consequent asthma-like disease traits that peak and last long after active viral infection is cleared. However, to manifest this type of disease, the -dependent myeloid-macrophage lineage is also active at two levels: first, at a downstream level, this lineage provides lung tissue macrophages (interstitial macrophages and tissue monocytes) that represent a major site of gene expression in the diseased lung; and second, at an upstream level, this same lineage is required for gene induction that is necessary to activate ILC2s for participation in disease at all, including IL-13 production. Together, these findings provide a revised scheme for understanding and controlling the innate immune response leading to long-term postviral lung diseases with features of asthma and related progressive conditions.
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http://dx.doi.org/10.4049/jimmunol.2000181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415724PMC
August 2020

Group 2 Innate Lymphoid Cells Induce Antibody Production in Gastric Tissue.

Trends Immunol 2020 08 28;41(8):643-645. Epub 2020 Jun 28.

Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address:

A recent article published in Immunity by Naoko Satoh-Takayama et al. examines interactions between group 2 innate lymphocytes and gastric microbes that enhance IgA production.
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http://dx.doi.org/10.1016/j.it.2020.06.001DOI Listing
August 2020

Anti-human TREM2 induces microglia proliferation and reduces pathology in an Alzheimer's disease model.

J Exp Med 2020 09;217(9)

Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO.

TREM2 is a receptor for lipids expressed in microglia. The R47H variant of human TREM2 impairs ligand binding and increases Alzheimer's disease (AD) risk. In mouse models of amyloid β (Aβ) accumulation, defective TREM2 function affects microglial response to Aβ plaques, exacerbating tissue damage, whereas TREM2 overexpression attenuates pathology. Thus, AD may benefit from TREM2 activation. Here, we examined the impact of an anti-human TREM2 agonistic mAb, AL002c, in a mouse AD model expressing either the common variant (CV) or the R47H variant of TREM2. Single-cell RNA-seq of microglia after acute systemic administration of AL002c showed induction of proliferation in both CV- and R47H-transgenic mice. Prolonged administration of AL002c reduced filamentous plaques and neurite dystrophy, impacted behavior, and tempered microglial inflammatory response. We further showed that a variant of AL002c is safe and well tolerated in a first-in-human phase I clinical trial and engages TREM2 based on cerebrospinal fluid biomarkers. We conclude that AL002 is a promising candidate for AD therapy.
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http://dx.doi.org/10.1084/jem.20200785DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7478730PMC
September 2020

STING Gain-of-Function Disrupts Lymph Node Organogenesis and Innate Lymphoid Cell Development in Mice.

Cell Rep 2020 06;31(11):107771

Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO 63110, USA; Department of Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA; Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, MO 63110, USA. Electronic address:

STING gain-of-function causes autoimmunity and immunodeficiency in mice and STING-associated vasculopathy with onset in infancy (SAVI) in humans. Here, we report that STING gain-of-function in mice prevents development of lymph nodes and Peyer's patches. We show that the absence of secondary lymphoid organs is associated with diminished numbers of innate lymphoid cells (ILCs), including lymphoid tissue inducer (LTi) cells. Although wild-type (WT) α4β7 progenitors differentiate efficiently into LTi cells, STING gain-of-function progenitors do not. Furthermore, STING gain-of-function impairs development of all types of ILCs. Patients with STING gain-of-function mutations have fewer ILCs, although they still have lymph nodes. In mice, expression of the STING mutant in RORγT-positive lineages prevents development of lymph nodes and reduces numbers of LTi cells. RORγT lineage-specific expression of STING gain-of-function also causes lung disease. Since RORγT is expressed exclusively in LTi cells during fetal development, our findings suggest that STING gain-of-function prevents lymph node organogenesis by reducing LTi cell numbers in mice.
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http://dx.doi.org/10.1016/j.celrep.2020.107771DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7372600PMC
June 2020

Impact of TREM2R47H variant on tau pathology-induced gliosis and neurodegeneration.

J Clin Invest 2020 09;130(9):4954-4968

Department of Neurology.

Alzheimer's disease (AD) is characterized by plaques containing amyloid-β (Aβ) and neurofibrillary tangles composed of aggregated, hyperphosphorylated tau. Beyond tau and Aβ, evidence suggests that microglia play an important role in AD pathogenesis. Rare variants in the microglia-expressed triggering receptor expressed on myeloid cells 2 (TREM2) gene increase AD risk 2- to 4-fold. It is likely that these TREM2 variants increase AD risk by decreasing the response of microglia to Aβ and its local toxicity. However, neocortical Aβ pathology occurs many years before neocortical tau pathology in AD. Thus, it will be important to understand the role of TREM2 in the context of tauopathy. We investigated the impact of the AD-associated TREM2 variant (R47H) on tau-mediated neuropathology in the PS19 mouse model of tauopathy. We assessed PS19 mice expressing human TREM2CV (common variant) or human TREM2R47H. PS19-TREM2R47H mice had significantly attenuated brain atrophy and synapse loss versus PS19-TREM2CV mice. Gene expression analyses and CD68 immunostaining revealed attenuated microglial reactivity in PS19-TREM2R47H versus PS19-TREM2CV mice. There was also a decrease in phagocytosis of postsynaptic elements by microglia expressing TREM2R47H in the PS19 mice and in human AD brains. These findings suggest that impaired TREM2 signaling reduces microglia-mediated neurodegeneration in the setting of tauopathy.
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http://dx.doi.org/10.1172/JCI138179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456230PMC
September 2020

Alternatives to amyloid for Alzheimer's disease therapies-a symposium report.

Ann N Y Acad Sci 2020 09 29;1475(1):3-14. Epub 2020 May 29.

Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.

For decades, Alzheimer's disease research has focused on amyloid as the primary pathogenic agent. This focus has driven the development of numerous amyloid-targeting therapies; however, with one possible exception, none of these therapies have been effective in preventing or delaying cognitive decline in patients, and there are no approved disease-modifying agents. It is becoming more apparent that alternative drug targets are needed to address this complex disease. An increased understanding of Alzheimer's disease pathology has highlighted the need to target the appropriate disease pathology at the appropriate time in the disease course. Preclinical and early clinical studies have focused on targets, including inflammation, tau, vascular health, and the microbiome. This report summarizes the presentations from a New York Academy of Sciences' one-day symposium entitled "Alzheimer's Disease Therapeutics: Alternatives to Amyloid," held on November 20, 2019.
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http://dx.doi.org/10.1111/nyas.14371DOI Listing
September 2020

Peripheral nerve resident macrophages share tissue-specific programming and features of activated microglia.

Nat Commun 2020 05 21;11(1):2552. Epub 2020 May 21.

Division of Immunobiology, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, 63110, USA.

Whereas microglia are recognized as fundamental players in central nervous system (CNS) development and function, much less is known about macrophages of the peripheral nervous system (PNS). Here, by comparing gene expression across neural and conventional tissue-resident macrophages, we identified transcripts that were shared among neural resident macrophages as well as selectively enriched in PNS macrophages. Remarkably, PNS macrophages constitutively expressed genes previously identified to be upregulated by activated microglia during aging, neurodegeneration, or loss of Sall1. Several microglial activation-associated and PNS macrophage-enriched genes were also expressed in spinal cord microglia at steady state. We further show that PNS macrophages rely on IL-34 for maintenance and arise from both embryonic and hematopoietic precursors, while their expression of activation-associated genes did not differ by ontogeny. Collectively, these data uncover shared and unique features between neural resident macrophages and emphasize the role of nerve environment for shaping PNS macrophage identity.
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http://dx.doi.org/10.1038/s41467-020-16355-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242366PMC
May 2020

Combined Prebiotic and Microbial Intervention Improves Oral Cholera Vaccination Responses in a Mouse Model of Childhood Undernutrition.

Cell Host Microbe 2020 06 28;27(6):899-908.e5. Epub 2020 Apr 28.

Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO 63110, USA; Center for Gut Microbiome and Nutrition Research, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address:

Undernourished children in low-income countries often exhibit poor responses to oral vaccination. Perturbed microbiota development is linked to undernutrition, but whether and how microbiota changes affect vaccine responsiveness remains unclear. Here, we show that gnotobiotic mice colonized with microbiota from undernourished Bangladeshi children and fed a Bangladeshi diet exhibited microbiota-dependent differences in mucosal IgA responses to oral vaccination with cholera toxin (CT). Supplementation with a nutraceutical consisting of spirulina, amaranth, flaxseed, and micronutrients augmented CT-IgA production. Mice initially colonized with a microbiota associated with poor CT responses exhibited improved immunogenicity upon invasion of bacterial taxa from cagemates colonized with a more "responsive" microbiota. Additionally, a consortium of five cultured bacterial invaders conferred augmented CT-IgA responses in mice fed the supplemented diet and colonized with the "hypo-responsive" community. These results provide preclinical proof-of-concept that diet and microbiota influence mucosal immune responses to CT vaccination and identify a candidate synbiotic formulation.
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http://dx.doi.org/10.1016/j.chom.2020.04.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7292785PMC
June 2020

Insulin-Like Growth Factors Are Key Regulators of T Helper 17 Regulatory T Cell Balance in Autoimmunity.

Immunity 2020 04;52(4):650-667.e10

Departments of Pathology, University of Alabama at Birmingham, Birmingham, AL 35203, USA; Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Alabama at Birmingham, Birmingham, AL 35203, USA; Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35203, USA. Electronic address:

Appropriate balance of T helper 17 (Th17) and regulatory T (Treg) cells maintains immune tolerance and host defense. Disruption of Th17-Treg cell balance is implicated in a number of immune-mediated diseases, many of which display dysregulation of the insulin-like growth factor (IGF) system. Here, we show that, among effector T cell subsets, Th17 and Treg cells selectively expressed multiple components of the IGF system. Signaling through IGF receptor (IGF1R) activated the protein kinase B-mammalian target of rapamycin (AKT-mTOR) pathway, increased aerobic glycolysis, favored Th17 cell differentiation over that of Treg cells, and promoted a heightened pro-inflammatory gene expression signature. Group 3 innate lymphoid cells (ILC3s), but not ILC1s or ILC2s, were similarly responsive to IGF signaling. Mice with deficiency of IGF1R targeted to T cells failed to fully develop disease in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis. Thus, the IGF system represents a previously unappreciated pathway by which type 3 immunity is modulated and immune-mediated pathogenesis controlled.
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http://dx.doi.org/10.1016/j.immuni.2020.03.013DOI Listing
April 2020

Leukemia Inhibitory Factor Inhibits Plasmacytoid Dendritic Cell Function and Development.

J Immunol 2020 04 13;204(8):2257-2268. Epub 2020 Mar 13.

Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110; and

Plasmacytoid dendritic cells (pDCs) produce abundant type I IFNs (IFN-I) in response to viral nucleic acids. Generation of pDCs from bone marrow dendritic cell (DC) progenitors and their maintenance is driven by the transcription factor E2-2 and inhibited by its repressor Id2. In this study, we find that mouse pDCs selectively express the receptor for LIF that signals through STAT3. Stimulation of pDCs with LIF inhibited IFN-I, TNF, and IL-6 responses to CpG and induced expression of the STAT3 targets SOCS3 and Bcl3, which inhibit IFN-I and NF-κB signaling. Moreover, although STAT3 has been also reported to induce E2-2, LIF paradoxically induced its repressor Id2. A late-stage bone marrow DC progenitor expressed low amounts of LIFR and developed into pDCs less efficiently after being exposed to LIF, consistent with the induction of Id2. Conversely, pDC development and serum IFN-I responses to lymphocytic choriomeningitis virus infection were augmented in newly generated mice lacking LIFR in either CD11c or hematopoietic cells. Thus, an LIF-driven STAT3 pathway induces SOCS3, Bcl3, and Id2, which render pDCs and late DC progenitors refractory to physiological stimuli controlling pDC functions and development. This pathway can be potentially exploited to prevent inappropriate secretion of IFN-I in autoimmune diseases or promote IFN-I secretion during viral infections.
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http://dx.doi.org/10.4049/jimmunol.1900604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7453765PMC
April 2020

Blood natural killer cell deficiency reveals an immunotherapy strategy for atopic dermatitis.

Sci Transl Med 2020 02;12(532)

Center for the Study of Itch and Sensory Disorders, Washington University School of Medicine, St. Louis, MO 63110, USA.

Atopic dermatitis (AD) is a widespread, chronic skin disease associated with aberrant allergic inflammation. Current treatments involve either broad or targeted immunosuppression strategies. However, enhancing the immune system to control disease remains untested. We demonstrate that patients with AD harbor a blood natural killer (NK) cell deficiency that both has diagnostic value and improves with therapy. Multidimensional protein and RNA profiling revealed subset-level changes associated with enhanced NK cell death. Murine NK cell deficiency was associated with enhanced type 2 inflammation in the skin, suggesting that NK cells play a critical immunoregulatory role in this context. On the basis of these findings, we used an NK cell-boosting interleukin-15 (IL-15) superagonist and observed marked improvement in AD-like disease in mice. These findings reveal a previously unrecognized application of IL-15 superagonism, currently in development for cancer immunotherapy, as an immunotherapeutic strategy for AD.
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http://dx.doi.org/10.1126/scitranslmed.aay1005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7433875PMC
February 2020

Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer's disease.

Nat Med 2020 01 13;26(1):131-142. Epub 2020 Jan 13.

Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.

Glia have been implicated in Alzheimer's disease (AD) pathogenesis. Variants of the microglia receptor triggering receptor expressed on myeloid cells 2 (TREM2) increase AD risk, and activation of disease-associated microglia (DAM) is dependent on TREM2 in mouse models of AD. We surveyed gene-expression changes associated with AD pathology and TREM2 in 5XFAD mice and in human AD by single-nucleus RNA sequencing. We confirmed the presence of Trem2-dependent DAM and identified a previously undiscovered Serpina3nC4b reactive oligodendrocyte population in mice. Interestingly, remarkably different glial phenotypes were evident in human AD. Microglia signature was reminiscent of IRF8-driven reactive microglia in peripheral-nerve injury. Oligodendrocyte signatures suggested impaired axonal myelination and metabolic adaptation to neuronal degeneration. Astrocyte profiles indicated weakened metabolic coordination with neurons. Notably, the reactive phenotype of microglia was less evident in TREM2-R47H and TREM2-R62H carriers than in non-carriers, demonstrating a TREM2 requirement in both mouse and human AD, despite the marked species-specific differences.
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http://dx.doi.org/10.1038/s41591-019-0695-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6980793PMC
January 2020

Brain Parenchymal and Extraparenchymal Macrophages in Development, Homeostasis, and Disease.

J Immunol 2020 01;204(2):294-305

Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, MO 63110

Microglia are parenchymal macrophages of the CNS; as professional phagocytes they are important for maintenance of the brain's physiology. These cells are generated through primitive hematopoiesis in the yolk sac and migrate into the brain rudiment after establishment of embryonic circulation. Thereafter, microglia develop in a stepwise fashion, reaching complete maturity after birth. In the CNS, microglia self-renew without input from blood monocytes. Recent RNA-sequencing studies have defined a molecular signature for microglia under homeostasis. However, during disease, microglia undergo remarkable phenotypic changes, which reflect the acquisition of specialized functions tailored to the pathological context. In addition to microglia, the brain-border regions host populations of extraparenchymal macrophages with disparate origins and phenotypes that have recently been delineated. In this review we outline recent findings that provide a deeper understanding of both parenchymal microglia and extraparenchymal brain macrophages in homeostasis and during disease.
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http://dx.doi.org/10.4049/jimmunol.1900821DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7034672PMC
January 2020