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1.
Cell ; 185(4): 614-629.e21, 2022 02 17.
Article in English | MEDLINE | ID: mdl-35148840

ABSTRACT

Activation of the innate immune system via pattern recognition receptors (PRRs) is key to generate lasting adaptive immunity. PRRs detect unique chemical patterns associated with invading microorganisms, but whether and how the physical properties of PRR ligands influence the development of the immune response remains unknown. Through the study of fungal mannans, we show that the physical form of PRR ligands dictates the immune response. Soluble mannans are immunosilent in the periphery but elicit a potent pro-inflammatory response in the draining lymph node (dLN). By modulating the physical form of mannans, we developed a formulation that targets both the periphery and the dLN. When combined with viral glycoprotein antigens, this mannan formulation broadens epitope recognition, elicits potent antigen-specific neutralizing antibodies, and confers protection against viral infections of the lung. Thus, the physical properties of microbial ligands determine the outcome of the immune response and can be harnessed for vaccine development.


Subject(s)
Adjuvants, Immunologic/pharmacology , Antigens, Viral/immunology , Candida albicans/chemistry , Mannans/immunology , Aluminum Hydroxide/chemistry , Animals , Antibodies, Neutralizing/immunology , Antibody Specificity/immunology , B-Lymphocytes/immunology , COVID-19/immunology , COVID-19/prevention & control , COVID-19/virology , Chlorocebus aethiops , Epitopes/immunology , Immunity, Innate , Immunization , Inflammation/pathology , Interferons/metabolism , Lectins, C-Type/metabolism , Ligands , Lung/immunology , Lung/pathology , Lung/virology , Lymph Nodes/immunology , Lymph Nodes/metabolism , Macrophages/metabolism , Mice, Inbred C57BL , Paranasal Sinuses/metabolism , Protein Subunits/metabolism , Sialic Acid Binding Ig-like Lectin 1/metabolism , Solubility , Spike Glycoprotein, Coronavirus/metabolism , T-Lymphocytes/immunology , Transcription Factor RelB/metabolism , Vero Cells , beta-Glucans/metabolism
2.
Nat Immunol ; 20(5): 559-570, 2019 05.
Article in English | MEDLINE | ID: mdl-30996332

ABSTRACT

The C-type lectin receptor-Syk (spleen tyrosine kinase) adaptor CARD9 facilitates protective antifungal immunity within the central nervous system (CNS), as human deficiency in CARD9 causes susceptibility to fungus-specific, CNS-targeted infection. CARD9 promotes the recruitment of neutrophils to the fungus-infected CNS, which mediates fungal clearance. In the present study we investigated host and pathogen factors that promote protective neutrophil recruitment during invasion of the CNS by Candida albicans. The cytokine IL-1ß served an essential function in CNS antifungal immunity by driving production of the chemokine CXCL1, which recruited neutrophils expressing the chemokine receptor CXCR2. Neutrophil-recruiting production of IL-1ß and CXCL1 was induced in microglia by the fungus-secreted toxin Candidalysin, in a manner dependent on the kinase p38 and the transcription factor c-Fos. Notably, microglia relied on CARD9 for production of IL-1ß, via both transcriptional regulation of Il1b and inflammasome activation, and of CXCL1 in the fungus-infected CNS. Microglia-specific Card9 deletion impaired the production of IL-1ß and CXCL1 and neutrophil recruitment, and increased fungal proliferation in the CNS. Thus, an intricate network of host-pathogen interactions promotes antifungal immunity in the CNS; this is impaired in human deficiency in CARD9, which leads to fungal disease of the CNS.


Subject(s)
CARD Signaling Adaptor Proteins/immunology , Candidiasis/immunology , Chemokine CXCL1/immunology , Interleukin-1beta/immunology , Microglia/immunology , Neutrophils/immunology , Animals , Brain/immunology , Brain/metabolism , Brain/microbiology , CARD Signaling Adaptor Proteins/genetics , CARD Signaling Adaptor Proteins/metabolism , Candida albicans/immunology , Candida albicans/physiology , Candidiasis/genetics , Candidiasis/microbiology , Chemokine CXCL1/genetics , Chemokine CXCL1/metabolism , Cytokines/genetics , Cytokines/immunology , Cytokines/metabolism , Host-Pathogen Interactions/immunology , Inflammasomes/genetics , Inflammasomes/immunology , Inflammasomes/metabolism , Interleukin-1beta/genetics , Interleukin-1beta/metabolism , Mice, Knockout , Mice, Transgenic , Microglia/metabolism , Microglia/microbiology , Neutrophil Infiltration/genetics , Neutrophil Infiltration/immunology , Neutrophils/metabolism , Neutrophils/microbiology
3.
Nat Immunol ; 19(7): 755-765, 2018 07.
Article in English | MEDLINE | ID: mdl-29915298

ABSTRACT

The cytokines IL-17A and IL-17F have 50% amino-acid identity and bind the same receptor; however, their functional differences have remained obscure. Here we found that Il17f-/- mice resisted chemically induced colitis, but Il17a-/- mice did not, and that Il17f-/- CD45RBhiCD4+ T cells induced milder colitis in lymphocyte-deficient Rag2-/- mice, accompanied by an increase in intestinal regulatory T cells (Treg cells). Clostridium cluster XIVa in colonic microbiota capable of inducing Treg cells was increased in both Il17f-/- mice and mice given transfer Il17f-/- T cells, due to decreased expression of a group of antimicrobial proteins. There was substantial production of IL-17F, but not of IL-17A, not only by naive T cells but also by various colon-resident cells under physiological conditions. Furthermore, antibody to IL-17F suppressed the development of colitis, but antibody to IL-17A did not. These observations suggest that IL-17F is an effective target for the treatment of colitis.


Subject(s)
Colitis/immunology , Gastrointestinal Microbiome , Interleukin-17/antagonists & inhibitors , T-Lymphocytes, Regulatory/immunology , Animals , Cells, Cultured , Clostridium/growth & development , Clostridium/isolation & purification , Colitis/drug therapy , Interleukin-17/genetics , Interleukin-17/physiology , Intestines/immunology , Mice , Mice, Inbred C57BL , Mice, Knockout , Phospholipases A2/biosynthesis , Phospholipases A2/genetics , Prevotella/isolation & purification , Ribonuclease, Pancreatic/biosynthesis , Ribonuclease, Pancreatic/genetics , beta-Defensins/biosynthesis
4.
Nat Immunol ; 17(5): 583-92, 2016 May.
Article in English | MEDLINE | ID: mdl-26998763

ABSTRACT

Interleukin 1ß (IL-1ß) is critical for the in vivo survival, expansion and effector function of IL-17-producing helper T (T(H)17) cells during autoimmune responses, including experimental autoimmune encephalomyelitis (EAE). However, the spatiotemporal role and cellular source of IL-1ß during EAE pathogenesis are poorly defined. In the present study, we uncovered a T cell-intrinsic inflammasome that drives IL-1ß production during T(H)17-mediated EAE pathogenesis. Activation of T cell antigen receptors induced expression of pro-IL-1ß, whereas ATP stimulation triggered T cell production of IL-1ß via ASC-NLRP3-dependent caspase-8 activation. IL-1R was detected on T(H)17 cells but not on type 1 helper T (T(H)1) cells, and ATP-treated T(H)17 cells showed enhanced survival compared with ATP-treated T(H)1 cells, suggesting autocrine action of T(H)17-derived IL-1ß. Together these data reveal a critical role for IL-1ß produced by a T(H)17 cell-intrinsic ASC-NLRP3-caspase-8 inflammasome during inflammation of the central nervous system.


Subject(s)
Apoptosis Regulatory Proteins/immunology , Encephalomyelitis, Autoimmune, Experimental/immunology , T-Lymphocytes/immunology , Th17 Cells/immunology , Adenosine Triphosphate/pharmacology , Animals , Apoptosis Regulatory Proteins/genetics , Apoptosis Regulatory Proteins/metabolism , CARD Signaling Adaptor Proteins , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , Carrier Proteins/genetics , Carrier Proteins/immunology , Carrier Proteins/metabolism , Caspase 8/genetics , Caspase 8/immunology , Caspase 8/metabolism , Cell Survival/genetics , Cell Survival/immunology , Cells, Cultured , Encephalomyelitis, Autoimmune, Experimental/genetics , Encephalomyelitis, Autoimmune, Experimental/metabolism , Flow Cytometry , Gene Expression/immunology , Immunoblotting , Inflammasomes/genetics , Inflammasomes/immunology , Inflammasomes/metabolism , Interleukin-17/genetics , Interleukin-17/immunology , Interleukin-17/metabolism , Interleukin-1beta/genetics , Interleukin-1beta/immunology , Interleukin-1beta/metabolism , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , NLR Family, Pyrin Domain-Containing 3 Protein , Reverse Transcriptase Polymerase Chain Reaction , Signal Transduction/genetics , Signal Transduction/immunology , T-Lymphocytes/drug effects , T-Lymphocytes/metabolism , Th17 Cells/drug effects , Th17 Cells/metabolism
5.
Cell ; 148(3): 447-57, 2012 Feb 03.
Article in English | MEDLINE | ID: mdl-22304915

ABSTRACT

Although it is believed that neural activation can affect immune responses, very little is known about the neuroimmune interactions involved, especially the regulators of immune traffic across the blood-brain barrier which occurs in neuroimmune diseases such as multiple sclerosis (MS). Using a mouse model of MS, experimental autoimmune encephalomyelitis, we show that autoreactive T cells access the central nervous system via the fifth lumbar spinal cord. This location is defined by IL-6 amplifier-dependent upregulation of the chemokine CCL20 in associated dorsal blood vessels, which in turn depends on gravity-induced activation of sensory neurons by the soleus muscle in the leg. Impairing soleus muscle contraction by tail suspension is sufficient to reduce localized chemokine expression and block entry of pathogenic T cells at the fifth lumbar cord, suggesting that regional neuroimmune interactions may offer therapeutic targets for a variety of neurological diseases.


Subject(s)
Blood-Brain Barrier , CD4-Positive T-Lymphocytes/cytology , Encephalomyelitis, Autoimmune, Experimental/immunology , Animals , Cell Movement , Chemokine CCL20/immunology , Encephalomyelitis, Autoimmune, Experimental/pathology , Gravitation , Interleukin-6/immunology , Mice , Mice, Inbred C57BL , Multiple Sclerosis/immunology , Muscle, Skeletal/innervation , Neuroimmunomodulation , Spinal Cord/blood supply
6.
Nature ; 595(7866): 266-271, 2021 07.
Article in English | MEDLINE | ID: mdl-34163066

ABSTRACT

Obesity is a worldwide epidemic that predisposes individuals to many age-associated diseases, but its exact effects on organ dysfunction are largely unknown1. Hair follicles-mini-epithelial organs that grow hair-are miniaturized by ageing to cause hair loss through the depletion of hair follicle stem cells (HFSCs)2. Here we report that obesity-induced stress, such as that induced by a high-fat diet (HFD), targets HFSCs to accelerate hair thinning. Chronological gene expression analysis revealed that HFD feeding for four consecutive days in young mice directed activated HFSCs towards epidermal keratinization by generating excess reactive oxygen species, but did not reduce the pool of HFSCs. Integrative analysis using stem cell fate tracing, epigenetics and reverse genetics showed that further feeding with an HFD subsequently induced lipid droplets and NF-κB activation within HFSCs via autocrine and/or paracrine IL-1R signalling. These integrated factors converge on the marked inhibition of Sonic hedgehog (SHH) signal transduction in HFSCs, thereby further depleting lipid-laden HFSCs through their aberrant differentiation and inducing hair follicle miniaturization and eventual hair loss. Conversely, transgenic or pharmacological activation of SHH rescued HFD-induced hair loss. These data collectively demonstrate that stem cell inflammatory signals induced by obesity robustly represses organ regeneration signals to accelerate the miniaturization of mini-organs, and suggests the importance of daily prevention of organ dysfunction.


Subject(s)
Alopecia/pathology , Alopecia/physiopathology , Hair Follicle/pathology , Obesity/physiopathology , Stem Cells/pathology , Animals , Autocrine Communication , Cell Count , Cell Differentiation , Cell Lineage , Cellular Senescence , Diet, High-Fat/adverse effects , Disease Models, Animal , Hedgehog Proteins/metabolism , Inflammation , Male , Mice , Mice, Inbred C57BL , Obesity/pathology , Oxidative Stress , Paracrine Communication , Receptors, Interleukin-1/metabolism
7.
Nat Immunol ; 15(11): 1064-9, 2014 Nov.
Article in English | MEDLINE | ID: mdl-25240383

ABSTRACT

It remains largely unclear how antigen-presenting cells (APCs) encounter effector or memory T cells efficiently in the periphery. Here we used a mouse contact hypersensitivity (CHS) model to show that upon epicutaneous antigen challenge, dendritic cells (DCs) formed clusters with effector T cells in dermal perivascular areas to promote in situ proliferation and activation of skin T cells in a manner dependent on antigen and the integrin LFA-1. We found that DCs accumulated in perivascular areas and that DC clustering was abrogated by depletion of macrophages. Treatment with interleukin 1α (IL-1α) induced production of the chemokine CXCL2 by dermal macrophages, and DC clustering was suppressed by blockade of either the receptor for IL-1 (IL-1R) or the receptor for CXCL2 (CXCR2). Our findings suggest that the dermal leukocyte cluster is an essential structure for elicitating acquired cutaneous immunity.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Dendritic Cells/immunology , Dermatitis, Contact/immunology , Skin/immunology , Animals , CD11c Antigen/genetics , Cell Proliferation , Chemokine CXCL2/biosynthesis , Female , Immunologic Memory/immunology , Interleukin-1alpha/pharmacology , Lymphocyte Activation/immunology , Lymphocyte Function-Associated Antigen-1/immunology , Macrophages/cytology , Macrophages/immunology , Mice , Mice, Inbred C57BL , Mice, Knockout , Models, Animal , Neutrophils/immunology , Receptors, Interleukin-1/antagonists & inhibitors , Receptors, Interleukin-8B/antagonists & inhibitors , Skin/pathology
8.
Immunity ; 47(1): 148-158.e5, 2017 07 18.
Article in English | MEDLINE | ID: mdl-28709803

ABSTRACT

Mucosal sites such as the intestine, oral cavity, nasopharynx, and vagina all have associated commensal flora. The surface of the eye is also a mucosal site, but proof of a living, resident ocular microbiome remains elusive. Here, we used a mouse model of ocular surface disease to reveal that commensals were present in the ocular mucosa and had functional immunological consequences. We isolated one such candidate commensal, Corynebacterium mastitidis, and showed that this organism elicited a commensal-specific interleukin-17 response from γδ T cells in the ocular mucosa that was central to local immunity. The commensal-specific response drove neutrophil recruitment and the release of antimicrobials into the tears and protected the eye from pathogenic Candida albicans or Pseudomonas aeruginosa infection. Our findings provide direct evidence that a resident commensal microbiome exists on the ocular surface and identify the cellular mechanisms underlying its effects on ocular immune homeostasis and host defense.


Subject(s)
Candida albicans/immunology , Candidiasis/immunology , Cornea/immunology , Corynebacterium Infections/immunology , Corynebacterium/immunology , Eye Infections/immunology , Immunity, Mucosal , Interleukin-17/metabolism , Microbiota/immunology , Neutrophils/immunology , Pseudomonas Infections/immunology , Pseudomonas aeruginosa/immunology , T-Lymphocytes/immunology , Tears/immunology , Animals , Candidiasis/microbiology , Cornea/microbiology , Corynebacterium Infections/microbiology , Disease Models, Animal , Eye Infections/microbiology , Host-Pathogen Interactions , Humans , Interleukin-17/genetics , Mice , Mice, Inbred C57BL , Mice, Knockout , Neutrophil Infiltration , Neutrophils/microbiology , Pseudomonas Infections/microbiology , Receptors, Antigen, T-Cell, gamma-delta/genetics , Receptors, Antigen, T-Cell, gamma-delta/metabolism
9.
Development ; 149(19)2022 10 01.
Article in English | MEDLINE | ID: mdl-36245218

ABSTRACT

Periodontal tissue supports teeth in the alveolar bone socket via fibrous attachment of the periodontal ligament (PDL). The PDL contains periodontal fibroblasts and stem/progenitor cells, collectively known as PDL cells (PDLCs), on top of osteoblasts and cementoblasts on the surface of alveolar bone and cementum, respectively. However, the characteristics and lineage hierarchy of each cell type remain poorly defined. This study identified periodontal ligament associated protein-1 (Plap-1) as a PDL-specific extracellular matrix protein. We generated knock-in mice expressing CreERT2 and GFP specifically in Plap-1-positive PDLCs. Genetic lineage tracing confirmed the long-standing hypothesis that PDLCs differentiate into osteoblasts and cementoblasts. A PDL single-cell atlas defined cementoblasts and osteoblasts as Plap-1-Ibsp+Sparcl1+ and Plap-1-Ibsp+Col11a2+, respectively. Other populations, such as Nes+ mural cells, S100B+ Schwann cells, and other non-stromal cells, were also identified. RNA velocity analysis suggested that a Plap-1highLy6a+ cell population was the source of PDLCs. Lineage tracing of Plap-1+ PDLCs during periodontal injury showed periodontal tissue regeneration by PDLCs. Our study defines diverse cell populations in PDL and clarifies the role of PDLCs in periodontal tissue homeostasis and repair.


Subject(s)
Periodontal Ligament , Transcriptome , Animals , Calcium-Binding Proteins/metabolism , Cell Differentiation/genetics , Extracellular Matrix Proteins/metabolism , Mice , Osteoblasts , RNA/metabolism
10.
PLoS Pathog ; 19(11): e1011747, 2023 Nov.
Article in English | MEDLINE | ID: mdl-37910490

ABSTRACT

Buruli ulcer is an emerging chronic infectious skin disease caused by Mycobacterium ulcerans. Mycolactone, an exotoxin produced by the bacterium, is the only identified virulence factor so far, but the functions of this toxin and the mechanisms of disease progression remain unclear. By interfering Sec61 translocon, mycolactone inhibits the Sec61-dependent co-translational translocation of newly synthesized proteins, such as induced cytokines and immune cell receptors, into the endoplasmic reticulum. However, in regard to IL-1ß, which is secreted by a Sec61-independent mechanism, mycolactone has been shown to induce IL-1ß secretion via activation of inflammasomes. In this study, we clarified that cytokine induction, including that of IL-1ß, in infected macrophages was suppressed by mycolactone produced by M. ulcerans subsp. shinshuense, despite the activation of caspase-1 through the inflammasome activation triggered in a manner independent of mycolactone. Intriguingly, mycolactone suppressed the expression of proIL-1ß as well as TNF-α at the transcriptional level, suggesting that mycolactone of M. ulcerans subsp. shinshuense may exert additional inhibitory effect on proIL-1ß expression. Remarkably, constitutively produced IL-18 was cleaved and mature IL-18 was actually released from macrophages infected with the causative mycobacterium. IL-18-deficient mice infected subcutaneously with M. ulcerans exhibited exacerbated skin inflammation during the course of disease progression. On the other hand, IL-1ß controls bacterial multiplication in skin tissues. These results provide information regarding the mechanisms and functions of the induced cytokines in the pathology of Buruli ulcer.


Subject(s)
Buruli Ulcer , Mycobacterium ulcerans , Animals , Mice , Buruli Ulcer/microbiology , Inflammasomes/metabolism , Interleukin-18/metabolism , Mycobacterium ulcerans/metabolism , Macrolides/metabolism , Cytokines/metabolism , Disease Progression , Inflammation
11.
Nat Immunol ; 14(10): 1045-53, 2013 Oct.
Article in English | MEDLINE | ID: mdl-23995233

ABSTRACT

Chronic inflammation is a fundamental aspect of metabolic disorders such as obesity, diabetes and cardiovascular disease. Cholesterol crystals are metabolic signals that trigger sterile inflammation in atherosclerosis, presumably by activating inflammasomes for IL-1ß production. We found here that atherogenesis was mediated by IL-1α and we identified fatty acids as potent inducers of IL-1α-driven vascular inflammation. Fatty acids selectively stimulated the release of IL-1α but not of IL-1ß by uncoupling mitochondrial respiration. Fatty acid-induced mitochondrial uncoupling abrogated IL-1ß secretion, which deviated the cholesterol crystal-elicited response toward selective production of IL-1α. Our findings delineate a previously unknown pathway for vascular immunopathology that links the cellular response to metabolic stress with innate inflammation, and suggest that IL-1α, not IL-1ß, should be targeted in patients with cardiovascular disease.


Subject(s)
Atherosclerosis/metabolism , Fatty Acids/metabolism , Inflammasomes/metabolism , Interleukin-1alpha/metabolism , Mitochondria/metabolism , Vasculitis/metabolism , Animals , Atherosclerosis/genetics , Atherosclerosis/pathology , Calcium Signaling , Dietary Fats/metabolism , Fatty Acids/pharmacology , Female , Humans , Interleukin-1beta/genetics , Interleukin-1beta/metabolism , Ion Channels/metabolism , Macrophages/drug effects , Macrophages/metabolism , Mice , Mice, Knockout , Mitochondria/drug effects , Mitochondrial Proteins/metabolism , Oleic Acid/pharmacology , Plaque, Atherosclerotic/metabolism , Plaque, Atherosclerotic/pathology , Uncoupling Protein 2 , Vasculitis/pathology
12.
Immunity ; 44(6): 1422-33, 2016 06 21.
Article in English | MEDLINE | ID: mdl-27317261

ABSTRACT

Obesity has been shown to increase the morbidity of infections, however, the underlying mechanisms remain largely unknown. Here we demonstrate that obesity caused adiponectin deficiency in the bone marrow (BM), which led to an inflamed BM characterized by increased tumor necrosis factor (TNF) production from bone marrow macrophages. Hematopoietic stem and progenitor cells (HSPCs) chronically exposed to excessive TNF in obese marrow aberrantly expressed cytokine signaling suppressor SOCS3, impairing JAK-STAT mediated signal transduction and cytokine-driven cell proliferation. Accordingly, both obese and adiponectin-deficient mice showed attenuated clearance of infected Listeria monocytogenes, indicating that obesity or loss of adiponectin is critical for exacerbation of infection. Adiponectin treatment restored the defective HSPC proliferation and bacterial clearance of obese and adiponectin-deficient mice, affirming the importance of adiponectin against infection. Taken together, our findings demonstrate that obesity impairs hematopoietic response against infections through a TNF-SOCS3-STAT3 axis, highlighting adiponectin as a legitimate target against obesity-related infections.


Subject(s)
Adiponectin/metabolism , Hematopoietic Stem Cells/physiology , Inflammation/immunology , Listeria monocytogenes/immunology , Listeriosis/immunology , Obesity/immunology , Adiponectin/genetics , Animals , Bacteriolysis , Bone Marrow/immunology , Cells, Cultured , Diet , Gene Expression Regulation , Hematopoiesis , Hematopoietic Stem Cell Mobilization , Mice , Mice, Inbred C57BL , Mice, Knockout , Signal Transduction , Suppressor of Cytokine Signaling 3 Protein/genetics , Suppressor of Cytokine Signaling 3 Protein/metabolism , Tumor Necrosis Factor-alpha/metabolism
13.
Immunity ; 45(6): 1299-1310, 2016 12 20.
Article in English | MEDLINE | ID: mdl-28002730

ABSTRACT

Particulate pollution is thought to function as an adjuvant that can induce allergic responses. However, the exact cell types and immunological factors that initiate the lung-specific immune responses are unclear. We found that upon intratracheal instillation, particulates such as aluminum salts and silica killed alveolar macrophages (AMs), which then released interleukin-1α (IL-1α) and caused inducible bronchus-associated lymphoid tissue (iBALT) formation in the lung. IL-1α release continued for up to 2 weeks after particulate exposure, and type-2 allergic immune responses were induced by the inhalation of antigen during IL-1α release and iBALT formation, even long after particulate instillation. Recombinant IL-1α was sufficient to induce iBALTs, which coincided with subsequent immunoglobulin E responses, and IL-1-receptor-deficient mice failed to induce iBALT formation. Therefore, the AM-IL-1α-iBALT axis might be a therapeutic target for particulate-induced allergic inflammation.


Subject(s)
Bronchi/immunology , Interleukin-1alpha/immunology , Lymphoid Tissue/immunology , Macrophages, Alveolar/pathology , Particulate Matter/toxicity , Aluminum Compounds/toxicity , Animals , Female , Mice , Mice, Inbred C57BL , Silicon Dioxide/toxicity
14.
Proc Natl Acad Sci U S A ; 119(3)2022 01 18.
Article in English | MEDLINE | ID: mdl-35027453

ABSTRACT

Paneth cells are intestinal epithelial cells that release antimicrobial peptides, such as α-defensin as part of host defense. Together with mesenchymal cells, Paneth cells provide niche factors for epithelial stem cell homeostasis. Here, we report two subtypes of murine Paneth cells, differentiated by their production and utilization of fucosyltransferase 2 (Fut2), which regulates α(1,2)fucosylation to create cohabitation niches for commensal bacteria and prevent invasion of the intestine by pathogenic bacteria. The majority of Fut2- Paneth cells were localized in the duodenum, whereas the majority of Fut2+ Paneth cells were in the ileum. Fut2+ Paneth cells showed higher granularity and structural complexity than did Fut2- Paneth cells, suggesting that Fut2+ Paneth cells are involved in host defense. Signaling by the commensal bacteria, together with interleukin 22 (IL-22), induced the development of Fut2+ Paneth cells. IL-22 was found to affect the α-defensin secretion system via modulation of Fut2 expression, and IL-17a was found to increase the production of α-defensin in the intestinal tract. Thus, these intestinal cytokines regulate the development and function of Fut2+ Paneth cells as part of gut defense.


Subject(s)
Cytokines/metabolism , Fucosyltransferases/metabolism , Gastrointestinal Microbiome/physiology , Paneth Cells/metabolism , Animals , Fucosyltransferases/genetics , Ileum , Interleukin-17/metabolism , Interleukins/metabolism , Mice , Symbiosis , alpha-Defensins/metabolism , Interleukin-22 , Galactoside 2-alpha-L-fucosyltransferase
15.
Proc Natl Acad Sci U S A ; 119(48): e2211230119, 2022 11 29.
Article in English | MEDLINE | ID: mdl-36409919

ABSTRACT

Granulopoiesis in the bone marrow adjusts cellular output as demand for neutrophils changes. Reactive granulopoiesis is induced by profound neutropenia, but its mechanism remains to be clarified. We herein explored its mechanisms using mouse models of syngeneic hematopoietic stem cell transplantation (SCT) and 5-fluorouracil-induced neutropenia. After SCT, T cell production of IL-17A was up-regulated. Neutrophil recovery was significantly delayed in IL-17A-deficient or T cell-deficient RAG1-/- mice, and adoptive transfer of wild-type (WT) T cells facilitated neutrophil engraftment. Gut decontamination with oral antibiotics suppressed T cell production of IL-17A and impaired neutrophil recovery. Transplantation of fecal microbiota collected from neutropenic, not naive, mice promoted neutrophil recovery in these mice, suggesting that neutropenia-associated microbiota had a potential to stimulate reactive granulopoiesis. Our study uncovered a cross talk between gut microbiota and neutropenia after SCT and chemotherapy.


Subject(s)
Gastrointestinal Microbiome , Neutropenia , Mice , Animals , Interleukin-17 , T-Lymphocytes , Mice, Knockout
16.
Infect Immun ; 92(6): e0002424, 2024 Jun 11.
Article in English | MEDLINE | ID: mdl-38700335

ABSTRACT

Cryptococcus deneoformans is a yeast-type fungus that causes fatal meningoencephalitis in immunocompromised patients and evades phagocytic cell elimination through an escape mechanism. Memory T (Tm) cells play a central role in preventing the reactivation of this fungal pathogen. Among these cells, tissue-resident memory T (TRM) cells quickly respond to locally invaded pathogens. This study analyzes the kinetics of effector T (Teff) cells and Tm cells in the lungs after cryptococcal infection. Emphasis is placed on the kinetics and cytokine expression of TRM cells in the early phase of infection. CD4+ Tm cells exhibited a rapid increase by day 3, peaked at day 7, and then either maintained their levels or exhibited a slight decrease until day 56. In contrast, CD8+ Tm cells reached their peak on day 3 and thereafter decreased up to day 56 post-infection. These Tm cells were predominantly composed of CD69+ TRM cells and CD69+ CD103+ TRM cells. Disruption of the CARD9 gene resulted in reduced accumulation of these TRM cells and diminished interferon (IFN) -γ expression in TRM cells. TRM cells were derived from T cells with T cell receptors non-specific to ovalbumin in OT-II mice during cryptococcal infection. In addition, TRM cells exhibited varied behavior in different tissues. These results underscore the importance of T cells, which produce IFN-γ in the lungs during the early stage of infection, in providing early protection against cryptococcal infection through CARD9 signaling.


Subject(s)
Antigens, CD , Antigens, Differentiation, T-Lymphocyte , Cryptococcosis , Cryptococcus , Interferon-gamma , Lectins, C-Type , Lung , Animals , Cryptococcosis/immunology , Cryptococcosis/microbiology , Interferon-gamma/metabolism , Interferon-gamma/immunology , Mice , Antigens, Differentiation, T-Lymphocyte/metabolism , Cryptococcus/immunology , Antigens, CD/metabolism , Antigens, CD/genetics , Lectins, C-Type/metabolism , Lectins, C-Type/genetics , Lung/immunology , Lung/microbiology , Memory T Cells/immunology , Memory T Cells/metabolism , Mice, Inbred C57BL , Immunologic Memory , Immunity, Innate , CARD Signaling Adaptor Proteins/metabolism , CD4-Positive T-Lymphocytes/immunology
17.
Immunity ; 43(6): 1125-36, 2015 Dec 15.
Article in English | MEDLINE | ID: mdl-26682985

ABSTRACT

The interleukin-1 receptor I (IL-1RI) is critical for host resistance to Mycobacterium tuberculosis (Mtb), yet the mechanisms of IL-1RI-mediated pathogen control remain unclear. Here, we show that without IL-1RI, Mtb-infected newly recruited Ly6G(hi) myeloid cells failed to upregulate tumor necrosis factor receptor I (TNF-RI) and to produce reactive oxygen species, resulting in compromised pathogen control. Furthermore, simultaneous ablation of IL-1RI and TNF-RI signaling on either stroma or hematopoietic cells led to early lethality, indicating non-redundant and synergistic roles of IL-1 and TNF in mediating macrophage-stroma cross-talk that was critical for optimal control of Mtb infection. Finally, we show that even in the presence of functional Mtb-specific adaptive immunity, the lack of IL-1α and not IL-1ß led to an exuberant intracellular pathogen replication and progressive non-resolving inflammation. Our study reveals functional interdependence between IL-1 and TNF in enabling Mtb control mechanisms that are critical for host survival.


Subject(s)
Interleukin-1alpha/immunology , Tuberculosis/immunology , Tumor Necrosis Factor-alpha/immunology , Animals , Cell Separation , Disease Models, Animal , Flow Cytometry , Fluorescent Antibody Technique , Mice , Mice, Inbred C57BL , Mice, Knockout , Mycobacterium tuberculosis , Receptors, Interleukin-1 Type I/immunology
18.
Arch Toxicol ; 98(1): 181-205, 2024 Jan.
Article in English | MEDLINE | ID: mdl-37971544

ABSTRACT

Acrylamide is an environmental electrophile that has been produced in large amounts for many years. There is concern about the adverse health effects of acrylamide exposure due to its widespread industrial use and also presence in commonly consumed foods and others. IL-1ß is a key cytokine that protects the brain from inflammatory insults, but its role in acrylamide-induced neurotoxicity remains unknown. We reported recently that deletion of IL-1ß gene exacerbates ACR-induced neurotoxicity in mice. The aim of this study was to identify genes or signaling pathway(s) involved in enhancement of ACR-induced neurotoxicity by IL-1ß gene deletion or ACR-induced neurotoxicity to generate a hypothesis mechanism explaining ACR-induced neurotoxicity. C57BL/6 J wild-type and IL-1ß KO mice were exposed to ACR at 0, 12.5, 25 mg/kg by oral gavage for 7 days/week for 4 weeks, followed by extraction of mRNA from mice cerebral cortex for RNA sequence analysis. IL-1ß deletion altered the expression of genes involved in extracellular region, including upregulation of PFN1 gene related to amyotrophic lateral sclerosis and increased the expression of the opposite strand of IL-1ß. Acrylamide exposure enhanced mitochondria oxidative phosphorylation, synapse and ribosome pathways, and activated various pathways of different neurodegenerative diseases, such as Alzheimer disease, Parkinson disease, Huntington disease, and prion disease. Protein network analysis suggested the involvement of different proteins in related to learning and cognitive function, such as Egr1, Egr2, Fos, Nr4a1, and Btg2. Our results identified possible pathways involved in IL-1ß deletion-potentiated and ACR-induced neurotoxicity in mice.


Subject(s)
Acrylamide , Neurotoxicity Syndromes , Animals , Mice , Acrylamide/toxicity , Brain , Cerebral Cortex , Gene Expression Profiling , Mice, Inbred C57BL , Neurotoxicity Syndromes/genetics
19.
Proc Natl Acad Sci U S A ; 118(17)2021 04 27.
Article in English | MEDLINE | ID: mdl-33875594

ABSTRACT

Hepatitis B virus (HBV) vaccines are composed of surface antigen HBsAg that spontaneously assembles into subviral particles. Factors that impede its humoral immunity in 5% to 10% of vaccinees remain elusive. Here, we showed that the low-level interleukin-1 receptor antagonist (IL-1Ra) can predict antibody protection both in mice and humans. Mechanistically, murine IL-1Ra-inhibited T follicular helper (Tfh) cell expansion and subsequent germinal center (GC)-dependent humoral immunity, resulting in significantly weakened protection against the HBV challenge. Compared to soluble antigens, HBsAg particle antigen displayed a unique capture/uptake and innate immune activation, including IL-1Ra expression, preferably of medullary sinus macrophages. In humans, a unique polymorphism in the RelA/p65 binding site of IL-1Ra enhancer associated IL-1Ra levels with ethnicity-dependent vaccination outcome. Therefore, the differential IL-1Ra response to particle antigens probably creates a suppressive milieu for Tfh/GC development, and neutralization of IL-1Ra would resurrect antibody response in HBV vaccine nonresponders.


Subject(s)
Immunogenicity, Vaccine/immunology , Interleukin 1 Receptor Antagonist Protein/metabolism , T Follicular Helper Cells/metabolism , Animals , Antibodies/immunology , Antibodies, Viral/immunology , Antibody Formation/immunology , Antigens/immunology , B-Lymphocytes/immunology , Germinal Center/immunology , Hepatitis B Surface Antigens/immunology , Hepatitis B Vaccines/immunology , Hepatitis B virus/genetics , Hepatitis B virus/pathogenicity , Humans , Immunity, Humoral/immunology , Immunogenicity, Vaccine/physiology , Interleukin 1 Receptor Antagonist Protein/immunology , Macrophages/immunology , Macrophages/metabolism , Mice , Receptors, Interleukin-1/antagonists & inhibitors , Receptors, Interleukin-1/immunology , Receptors, Interleukin-1/metabolism , T Follicular Helper Cells/immunology , T-Lymphocytes, Helper-Inducer/immunology , Vaccination/methods
20.
Int Immunol ; 34(8): 409-420, 2022 07 26.
Article in English | MEDLINE | ID: mdl-35641096

ABSTRACT

IL-17 plays important roles in host defense against Candida albicans at barrier surfaces and during invasive infection. However, the role of IL-17 in host defense after colonization of the epidermis, a main site of C. albicans infection, remains poorly understood. Using a murine model of epicutaneous candidiasis without skin abrasion, we found that skin inflammation triggered by epidermal C. albicans colonization was self-limiting with fungal clearance completed by day 7 after inoculation in wild-type mice or animals deficient in IL-17A or IL-17F. In contrast, marked neutrophilic inflammation in the epidermis and impaired fungal clearance were observed in mice lacking both IL-17A and IL-17F. Clearance of C. albicans was independent of Dectin-1, Dectin-2, CARD9 (caspase-recruitment domain family, member 9), TLR2 (Toll-like receptor 2) and MyD88 in the epidermal colonization model. We found that group 3 innate lymphoid cells (ILC3s) and γδT cells were the major IL-17 producers in the epicutaneous candidiasis model. Analyses of Rag2-/- mice and Rag2-/-Il2rg-/- mice revealed that production of IL-17A and IL-17F by ILC3s was sufficient for C. albicans clearance. Finally, we found that depletion of neutrophils impaired C. albicans clearance in the epidermal colonization model. Taken together, these findings indicate a critical and redundant function of IL-17A and IL-17F produced by ILC3s in host defense against C. albicans in the epidermis. The results also suggest that epidermal C. albicans clearance is independent of innate immune receptors or that these receptors act redundantly in fungal recognition and clearance.


Subject(s)
Candida albicans , Candidiasis , Interleukin-17/immunology , Animals , CARD Signaling Adaptor Proteins , Epidermis/metabolism , Immunity, Innate , Inflammation , Lymphocytes , Mice , Mice, Inbred C57BL , Mice, Knockout
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