ABSTRACT
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.
Subject(s)
Bile Acids and Salts/metabolism , Chikungunya Fever/pathology , Gastrointestinal Microbiome , Interferon Type I/metabolism , Animals , Anti-Bacterial Agents/pharmacology , Chikungunya Fever/immunology , Chikungunya Fever/veterinary , Chikungunya virus/genetics , Chikungunya virus/isolation & purification , Clostridiales/physiology , Dendritic Cells/cytology , Dendritic Cells/immunology , Dendritic Cells/metabolism , Fecal Microbiota Transplantation , Gastrointestinal Microbiome/drug effects , Male , Membrane Glycoproteins/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Monocytes/cytology , Monocytes/immunology , Monocytes/metabolism , Myeloid Differentiation Factor 88/deficiency , Myeloid Differentiation Factor 88/genetics , Myeloid Differentiation Factor 88/metabolism , RNA, Viral/blood , STAT1 Transcription Factor/deficiency , Signal Transduction , Toll-Like Receptor 7/metabolismABSTRACT
Caloric restriction is known to improve inflammatory and autoimmune diseases. However, the mechanisms by which reduced caloric intake modulates inflammation are poorly understood. Here we show that short-term fasting reduced monocyte metabolic and inflammatory activity and drastically reduced the number of circulating monocytes. Regulation of peripheral monocyte numbers was dependent on dietary glucose and protein levels. Specifically, we found that activation of the low-energy sensor 5'-AMP-activated protein kinase (AMPK) in hepatocytes and suppression of systemic CCL2 production by peroxisome proliferator-activator receptor alpha (PPARα) reduced monocyte mobilization from the bone marrow. Importantly, we show that fasting improves chronic inflammatory diseases without compromising monocyte emergency mobilization during acute infectious inflammation and tissue repair. These results reveal that caloric intake and liver energy sensors dictate the blood and tissue immune tone and link dietary habits to inflammatory disease outcome.
Subject(s)
Caloric Restriction , Monocytes/metabolism , AMP-Activated Protein Kinases/metabolism , Adult , Animals , Antigens, Ly/metabolism , Bone Marrow Cells/cytology , Bone Marrow Cells/metabolism , Chemokine CCL2/deficiency , Chemokine CCL2/genetics , Chemokine CCL2/metabolism , Female , Hepatocytes/cytology , Hepatocytes/metabolism , Humans , Inflammation/metabolism , Inflammation/pathology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Monocytes/cytology , PPAR alpha/deficiency , PPAR alpha/genetics , PPAR alpha/metabolismABSTRACT
Immune cells residing in white adipose tissue have been highlighted as important factors contributing to the pathogenesis of metabolic diseases, but the molecular regulators that drive adipose tissue immune cell remodeling during obesity remain largely unknown. Using index and transcriptional single-cell sorting, we comprehensively map all adipose tissue immune populations in both mice and humans during obesity. We describe a novel and conserved Trem2+ lipid-associated macrophage (LAM) subset and identify markers, spatial localization, origin, and functional pathways associated with these cells. Genetic ablation of Trem2 in mice globally inhibits the downstream molecular LAM program, leading to adipocyte hypertrophy as well as systemic hypercholesterolemia, body fat accumulation, and glucose intolerance. These findings identify Trem2 signaling as a major pathway by which macrophages respond to loss of tissue-level lipid homeostasis, highlighting Trem2 as a key sensor of metabolic pathologies across multiple tissues and a potential therapeutic target in metabolic diseases.
Subject(s)
Macrophages/metabolism , Membrane Glycoproteins/metabolism , Receptors, Immunologic/metabolism , Adipose Tissue, White/metabolism , Adipose Tissue, White/pathology , Animals , Diet, High-Fat , Glucose Intolerance , Humans , Intra-Abdominal Fat/metabolism , Intra-Abdominal Fat/pathology , Lipid Metabolism/genetics , Lipids/analysis , Macrophages/cytology , Membrane Glycoproteins/deficiency , Membrane Glycoproteins/genetics , Mice , Mice, Inbred C57BL , Mice, Knockout , Monocytes/cytology , Monocytes/metabolism , Obesity/metabolism , Obesity/pathology , Receptors, Immunologic/deficiency , Receptors, Immunologic/genetics , Signal Transduction , Single-Cell AnalysisABSTRACT
Most tissue-resident macrophage (RTM) populations are seeded by waves of embryonic hematopoiesis and are self-maintained independently of a bone marrow contribution during adulthood. A proportion of RTMs, however, is constantly replaced by blood monocytes, and their functions compared to embryonic RTMs remain unclear. The kinetics and extent of the contribution of circulating monocytes to RTM replacement during homeostasis, inflammation, and disease are highly debated. Here, we identified Ms4a3 as a specific gene expressed by granulocyte-monocyte progenitors (GMPs) and subsequently generated Ms4a3TdT reporter, Ms4a3Cre, and Ms4a3CreERT2 fate-mapping models. These models traced efficiently monocytes and granulocytes, but no lymphocytes or tissue dendritic cells. Using these models, we precisely quantified the contribution of monocytes to the RTM pool during homeostasis and inflammation. The unambiguous identification of monocyte-derived cells will permit future studies of their function under any condition.
Subject(s)
Cell Cycle Proteins/genetics , Gene Expression , Granulocyte-Macrophage Progenitor Cells/metabolism , Granulocytes/metabolism , Macrophages/metabolism , Membrane Proteins/genetics , Monocytes/metabolism , Animals , Granulocyte-Macrophage Progenitor Cells/cytology , Granulocytes/cytology , Hematopoiesis/physiology , Homeostasis/physiology , Inflammation/metabolism , Macrophages/cytology , Mice , Monocytes/cytologyABSTRACT
Classical monocytes (CMs) are ephemeral myeloid immune cells that circulate in the blood. Emerging evidence suggests that CMs can have distinct ontogeny and originate from either granulocyte-monocyte- or monocyte-dendritic-cell progenitors (GMPs or MDPs). Here, we report surface markers that allowed segregation of murine GMP- and MDP-derived CMs, i.e., GMP-Mo and MDP-Mo, as well as their functional characterization, including fate definition following adoptive cell transfer. GMP-Mo and MDP-Mo yielded an equal increase in homeostatic CM progeny, such as blood-resident non-classical monocytes and gut macrophages; however, these cells differentially seeded various other selected tissues, including the dura mater and lung. Specifically, GMP-Mo and MDP-Mo differentiated into distinct interstitial lung macrophages, linking CM dichotomy to previously reported pulmonary macrophage heterogeneity. Collectively, we provide evidence for the existence of two functionally distinct CM subsets in the mouse that differentially contribute to peripheral tissue macrophage populations in homeostasis and following challenge.
Subject(s)
Cell Differentiation , Macrophages , Monocytes , Animals , Monocytes/immunology , Monocytes/cytology , Mice , Cell Differentiation/immunology , Macrophages/immunology , Macrophages/metabolism , Lung/cytology , Lung/immunology , Homeostasis , Mice, Inbred C57BL , Dendritic Cells/immunology , Cell Lineage , Adoptive TransferABSTRACT
Post-translational modifications of histone proteins and exchanges of histone variants of chromatin are central to the regulation of nearly all DNA-templated biological processes. However, the degree and variability of chromatin modifications in specific human immune cells remain largely unknown. Here, we employ a highly multiplexed mass cytometry analysis to profile the global levels of a broad array of chromatin modifications in primary human immune cells at the single-cell level. Our data reveal markedly different cell-type- and hematopoietic-lineage-specific chromatin modification patterns. Differential analysis between younger and older adults shows that aging is associated with increased heterogeneity between individuals and elevated cell-to-cell variability in chromatin modifications. Analysis of a twin cohort unveils heritability of chromatin modifications and demonstrates that aging-related chromatin alterations are predominantly driven by non-heritable influences. Together, we present a powerful platform for chromatin and immunology research. Our discoveries highlight the profound impacts of aging on chromatin modifications.
Subject(s)
Aging , Chromatin/chemistry , Epigenesis, Genetic , Adolescent , Adult , Aged , Cell Lineage , Cell Separation , Diseases in Twins , Female , Flow Cytometry , Histones/metabolism , Humans , Immune System , Immunophenotyping , Leukocytes, Mononuclear/cytology , Male , Middle Aged , Monocytes/cytology , Principal Component Analysis , Protein Processing, Post-Translational , Registries , Young AdultABSTRACT
Innate immune memory is an emerging area of research. However, innate immune memory at major mucosal sites remains poorly understood. Here, we show that respiratory viral infection induces long-lasting memory alveolar macrophages (AMs). Memory AMs are programed to express high MHC II, a defense-ready gene signature, and increased glycolytic metabolism, and produce, upon re-stimulation, neutrophil chemokines. Using a multitude of approaches, we reveal that the priming, but not maintenance, of memory AMs requires the help from effector CD8 T cells. T cells jump-start this process via IFN-γ production. We further find that formation and maintenance of memory AMs are independent of monocytes or bone marrow progenitors. Finally, we demonstrate that memory AMs are poised for robust trained immunity against bacterial infection in the lung via rapid induction of chemokines and neutrophilia. Our study thus establishes a new paradigm of immunological memory formation whereby adaptive T-lymphocytes render innate memory of mucosal-associated macrophages.
Subject(s)
CD8-Positive T-Lymphocytes/immunology , Immunity, Innate , Lung/immunology , Macrophages, Alveolar/immunology , T-Lymphocytes, Helper-Inducer/immunology , Animals , CD8-Positive T-Lymphocytes/cytology , Immunologic Memory , Lung/cytology , Macrophages, Alveolar/cytology , Mice , Mice, Inbred BALB C , Mice, Transgenic , Monocytes/cytology , Monocytes/immunology , Respiratory Mucosa/cytology , Respiratory Mucosa/immunology , T-Lymphocytes, Helper-Inducer/cytologyABSTRACT
The lung is inhabited by resident alveolar and interstitial macrophages as well as monocytic cells that survey lung tissues. Each cell type plays distinct functional roles under homeostatic and inflammatory conditions, but mechanisms establishing their molecular identities and functional potential remain poorly understood. In the present study, systematic evaluation of transcriptomes and open chromatin of alveolar macrophages (AMs), interstitial macrophages (IMs) and lung monocytes from two mouse strains enabled inference of common and cell-specific transcriptional regulators. We provide evidence that these factors drive selection of regulatory landscapes that specify distinct phenotypes of AMs and IMs and entrain qualitatively different responses to toll-like receptor 4 signaling in vivo. These studies reveal a striking divergence in a fundamental innate immune response pathway in AMs and establish a framework for further understanding macrophage diversity in the lung.
Subject(s)
Immunity, Innate/immunology , Lung/immunology , Macrophages/immunology , Monocytes/immunology , Animals , Epigenesis, Genetic/immunology , Macrophages/cytology , Mice , Monocytes/cytology , Transcriptome/immunologyABSTRACT
Detection of cytosolic DNA constitutes a central event in the context of numerous infectious and sterile inflammatory conditions. Recent studies have uncovered a bipartite mode of cytosolic DNA recognition, in which the cGAS-STING axis triggers antiviral immunity, whereas AIM2 triggers inflammasome activation. Here, we show that AIM2 is dispensable for DNA-mediated inflammasome activation in human myeloid cells. Instead, detection of cytosolic DNA by the cGAS-STING axis induces a cell death program initiating potassium efflux upstream of NLRP3. Forward genetics identified regulators of lysosomal trafficking to modulate this cell death program, and subsequent studies revealed that activated STING traffics to the lysosome, where it triggers membrane permeabilization and thus lysosomal cell death (LCD). Importantly, the cGAS-STING-NLRP3 pathway constitutes the default inflammasome response during viral and bacterial infections in human myeloid cells. We conclude that targeting the cGAS-STING-LCD-NLRP3 pathway will ameliorate pathology in inflammatory conditions that are associated with cytosolic DNA sensing.
Subject(s)
Cell Death , Inflammasomes/metabolism , Monocytes/cytology , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , DNA/metabolism , Humans , Membrane Proteins/metabolism , Monocytes/metabolism , Signal TransductionABSTRACT
Lower urinary tract infections are among the most common human bacterial infections, but extension to the kidneys is rare. This has been attributed to mechanical forces, such as urine flow, that prevent the ascent of bladder microbes. Here, we show that the regional hypersalinity, required for the kidney's urine-concentrating function, instructs epithelial cells to produce chemokines that localize monocyte-derived mononuclear phagocytes (MNPs) to the medulla. This hypersaline environment also increases the intrinsic bactericidal and neutrophil chemotactic activities of MNPs to generate a zone of defense. Because MNP positioning and function are dynamically regulated by the renal salt gradient, we find that patients with urinary concentrating defects are susceptible to kidney infection. Our work reveals a critical accessory role for the homeostatic function of a vital organ in optimizing tissue defense.
Subject(s)
Kidney/immunology , Phagocytes/immunology , Animals , Cell Line , Chemokine CCL2/metabolism , Chemokines/immunology , Diabetes Insipidus , Humans , Kidney/cytology , Kidney Medulla/immunology , Lipopolysaccharide Receptors/metabolism , Mice , Mice, Inbred C57BL , Monocytes/cytology , Salinity , Sodium/metabolism , Transcription Factors/genetics , Urinary Tract Infections/immunology , Urinary Tract Infections/microbiology , Urine/chemistry , Uropathogenic Escherichia coli/physiologyABSTRACT
Induction of the transcription factor Irf8 in the common dendritic cell progenitor (CDP) is required for classical type 1 dendritic cell (cDC1) fate specification, but the mechanisms controlling this induction are unclear. In the present study Irf8 enhancers were identified via chromatin profiling of dendritic cells and CRISPR/Cas9 genome editing was used to assess their roles in Irf8 regulation. An enhancer 32 kilobases (kb) downstream of the Irf8 transcriptional start site (+32-kb Irf8) that was active in mature cDC1s was required for the development of this lineage, but not for its specification. Instead, a +41-kb Irf8 enhancer, previously thought to be active only in plasmacytoid dendritic cells, was found to also be transiently accessible in cDC1 progenitors, and deleting this enhancer prevented the induction of Irf8 in CDPs and abolished cDC1 specification. Thus, cryptic activation of the +41-kb Irf8 enhancer in dendritic cell progenitors is responsible for cDC1 fate specification.
Subject(s)
Dendritic Cells/cytology , Enhancer Elements, Genetic/genetics , Interferon Regulatory Factors/metabolism , Macrophages/cytology , Monocytes/cytology , Animals , CRISPR-Cas Systems/genetics , Cell Differentiation , Cell Lineage , Dendritic Cells/immunology , Gene Expression Regulation , Interferon Regulatory Factors/genetics , Macrophages/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Monocytes/metabolism , Stem Cells/cytology , Tumor Cells, CulturedABSTRACT
Innate immune memory is the phenomenon whereby innate immune cells such as monocytes or macrophages undergo functional reprogramming after exposure to microbial components such as lipopolysaccharide (LPS). We apply an integrated epigenomic approach to characterize the molecular events involved in LPS-induced tolerance in a time-dependent manner. Mechanistically, LPS-treated monocytes fail to accumulate active histone marks at promoter and enhancers of genes in the lipid metabolism and phagocytic pathways. Transcriptional inactivity in response to a second LPS exposure in tolerized macrophages is accompanied by failure to deposit active histone marks at promoters of tolerized genes. In contrast, ß-glucan partially reverses the LPS-induced tolerance in vitro. Importantly, ex vivo ß-glucan treatment of monocytes from volunteers with experimental endotoxemia re-instates their capacity for cytokine production. Tolerance is reversed at the level of distal element histone modification and transcriptional reactivation of otherwise unresponsive genes. VIDEO ABSTRACT.
Subject(s)
Immune Tolerance , Lipopolysaccharides/immunology , Macrophages/immunology , Monocytes/immunology , Sepsis/immunology , Transcription, Genetic , beta-Glucans/immunology , Cell Differentiation , DNA Methylation , Epigenomics , Gene Regulatory Networks , Histone Code , Humans , Immunity, Innate , Immunologic Memory , Macrophages/cytology , Monocytes/cytology , Sepsis/geneticsABSTRACT
Small immune complexes cause type III hypersensitivity reactions that frequently result in tissue injury. The responsible mechanisms, however, remain unclear and differ depending on target organs. Here, we identify a kidney-specific anatomical and functional unit, formed by resident macrophages and peritubular capillary endothelial cells, which monitors the transport of proteins and particles ranging from 20 to 700 kDa or 10 to 200 nm into the kidney interstitium. Kidney-resident macrophages detect and scavenge circulating immune complexes "pumped" into the interstitium via trans-endothelial transport and trigger a FcγRIV-dependent inflammatory response and the recruitment of monocytes and neutrophils. In addition, FcγRIV and TLR pathways synergistically "super-activate" kidney macrophages when immune complexes contain a nucleic acid. These data identify a physiological function of tissue-resident kidney macrophages and a basic mechanism by which they initiate the inflammatory response to small immune complexes in the kidney.
Subject(s)
Immune Complex Diseases/immunology , Kidney/cytology , Kidney/immunology , Macrophages/immunology , Animals , Antigen-Antibody Complex , Endothelial Cells , Macrophages/cytology , Mice, Inbred C57BL , Microscopy, Immunoelectron , Monocytes/cytology , Monocytes/immunology , Neutrophils/cytology , Neutrophils/immunology , Receptors, IgG/immunologyABSTRACT
The extra-embryonic yolk sac contains the first definitive multipotent hematopoietic cells, denominated erythromyeloid progenitors. They originate in situ prior to the emergence of hematopoietic stem cells and give rise to erythroid, monocytes, granulocytes, mast cells and macrophages, the latter in a Myb transcription factor-independent manner. We uncovered here the heterogeneity of yolk sac erythromyeloid progenitors, at the single cell level, and discriminated multipotent from committed progenitors, prior to fetal liver colonization. We identified two temporally distinct megakaryocyte differentiation pathways. The first occurs in the yolk sac, bypasses intermediate bipotent megakaryocyte-erythroid progenitors and, similar to the differentiation of macrophages, is Myb-independent. By contrast, the second originates later, from Myb-dependent bipotent progenitors expressing Csf2rb and colonize the fetal liver, where they give rise to megakaryocytes and to large numbers of erythrocytes. Understanding megakaryocyte development is crucial as they play key functions during vascular development, in particular in separating blood and lymphatic networks.
Subject(s)
Cell Differentiation/physiology , Erythrocytes/cytology , Megakaryocytes/cytology , Myeloid Cells/cytology , Stem Cells/cytology , Yolk Sac/cytology , Animals , Cell Lineage/physiology , Cells, Cultured , Embryo, Mammalian/cytology , Female , Granulocytes/cytology , Hematopoiesis/physiology , Hematopoietic Stem Cells/cytology , Macrophages/cytology , Male , Mice , Mice, Inbred C57BL , Monocytes/cytology , Multipotent Stem Cells/cytology , PregnancyABSTRACT
Monocytic-lineage inflammatory Ly6c+CD103+ dendritic cells (DCs) promote antitumor immunity, but these DCs are infrequent in tumors, even upon chemotherapy. Here, we examined how targeting pathways that inhibit the differentiation of inflammatory myeloid cells affect antitumor immunity. Pharmacologic inhibition of Bruton's tyrosine kinase (BTK) and the tryptophan-degrading enzyme indoleamine 2,3-dioxygenase (IDO) or deletion of Btk or Ido1 allowed robust differentiation of inflammatory Ly6c+CD103+ DCs during chemotherapy, promoting antitumor T cell responses and inhibiting tumor growth. Immature Ly6c+c-kit+ precursor cells had epigenetic profiles similar to conventional DC precursors; deletion of Btk or Ido1 promoted differentiation of these cells. Mechanistically, a BTK-IDO axis inhibited a tryptophan-sensitive differentiation pathway driven by GATOR2 and mTORC1, and disruption of the GATOR2 in monocyte-lineage precursors prevented differentiation into inflammatory DCs in vivo. IDO-expressing DCs and monocytic cells were present across a range of human tumors. Thus, a BTK-IDO axis represses differentiation of inflammatory DCs during chemotherapy, with implications for targeted therapies.
Subject(s)
Cell Differentiation/immunology , Dendritic Cells/immunology , Neoplasms/immunology , T-Lymphocytes/immunology , Agammaglobulinaemia Tyrosine Kinase/immunology , Agammaglobulinaemia Tyrosine Kinase/metabolism , Animals , Dendritic Cells/cytology , Dendritic Cells/metabolism , Female , Humans , Indoleamine-Pyrrole 2,3,-Dioxygenase/immunology , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism , Male , Mice , Monocytes/cytology , Monocytes/immunology , Monocytes/metabolism , Signal Transduction/immunology , T-Lymphocytes/metabolism , TOR Serine-Threonine Kinases/immunology , TOR Serine-Threonine Kinases/metabolismABSTRACT
The immune system has a critical role in orchestrating tissue healing. As a result, regenerative strategies that control immune components have proved effective1,2. This is particularly relevant when immune dysregulation that results from conditions such as diabetes or advanced age impairs tissue healing following injury2,3. Nociceptive sensory neurons have a crucial role as immunoregulators and exert both protective and harmful effects depending on the context4-12. However, how neuro-immune interactions affect tissue repair and regeneration following acute injury is unclear. Here we show that ablation of the NaV1.8 nociceptor impairs skin wound repair and muscle regeneration after acute tissue injury. Nociceptor endings grow into injured skin and muscle tissues and signal to immune cells through the neuropeptide calcitonin gene-related peptide (CGRP) during the healing process. CGRP acts via receptor activity-modifying protein 1 (RAMP1) on neutrophils, monocytes and macrophages to inhibit recruitment, accelerate death, enhance efferocytosis and polarize macrophages towards a pro-repair phenotype. The effects of CGRP on neutrophils and macrophages are mediated via thrombospondin-1 release and its subsequent autocrine and/or paracrine effects. In mice without nociceptors and diabetic mice with peripheral neuropathies, delivery of an engineered version of CGRP accelerated wound healing and promoted muscle regeneration. Harnessing neuro-immune interactions has potential to treat non-healing tissues in which dysregulated neuro-immune interactions impair tissue healing.
Subject(s)
Calcitonin Gene-Related Peptide , Macrophages , Neutrophils , Nociceptors , Wound Healing , Animals , Mice , Autocrine Communication , Calcitonin Gene-Related Peptide/metabolism , Calcitonin Gene-Related Peptide/pharmacology , Diabetes Mellitus, Experimental/complications , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Experimental/pathology , Efferocytosis , Macrophages/cytology , Macrophages/metabolism , Monocytes/cytology , Monocytes/metabolism , Muscle, Skeletal , NAV1.8 Voltage-Gated Sodium Channel/deficiency , NAV1.8 Voltage-Gated Sodium Channel/genetics , NAV1.8 Voltage-Gated Sodium Channel/metabolism , Neutrophils/cytology , Neutrophils/metabolism , Nociceptors/metabolism , Paracrine Communication , Peripheral Nervous System Diseases/complications , Receptor Activity-Modifying Protein 1/metabolism , Regeneration/drug effects , Skin , Thrombospondin 1/metabolism , Wound Healing/drug effects , Wound Healing/immunology , Humans , Male , FemaleABSTRACT
Granulocyte-monocyte progenitors (GMPs) have been previously defined for their potential to generate various myeloid progenies such as neutrophils and monocytes. Although studies have proposed lineage heterogeneity within GMPs, it is unclear if committed progenitors already exist among these progenitors and how they may behave differently during inflammation. By combining single-cell transcriptomic and proteomic analyses, we identified the early committed progenitor within the GMPs responsible for the strict production of neutrophils, which we designate as proNeu1. Our dissection of the GMP hierarchy led us to further identify a previously unknown intermediate proNeu2 population. Similar populations could be detected in human samples. proNeu1s, but not proNeu2s, selectively expanded during the early phase of sepsis at the expense of monocytes. Collectively, our findings help shape the neutrophil maturation trajectory roadmap and challenge the current definition of GMPs.
Subject(s)
Granulocyte Precursor Cells/cytology , Monocytes/cytology , Myelopoiesis/physiology , Neutrophils/cytology , Animals , Humans , Mice , Mice, Inbred C57BL , Mice, Knockout , Single-Cell AnalysisABSTRACT
Embryo-derived tissue-resident macrophages are the first representatives of the haematopoietic lineage to emerge in metazoans. In mammals, resident macrophages originate from early yolk sac progenitors and are specified into tissue-specific subsets during organogenesis-establishing stable spatial and functional relationships with specialized tissue cells-and persist in adults. Resident macrophages are an integral part of tissues together with specialized cells: for instance, microglia reside with neurons in brain, osteoclasts reside with osteoblasts in bone, and fat-associated macrophages reside with white adipocytes in adipose tissue. This ancillary cell type, which is developmentally and functionally distinct from haematopoietic stem cell and monocyte-derived macrophages, senses and integrates local and systemic information to provide specialized tissue cells with the growth factors, nutrient recycling and waste removal that are critical for tissue growth, homeostasis and repair. Resident macrophages contribute to organogenesis, promote tissue regeneration following damage and contribute to tissue metabolism and defence against infectious disease. A correlate is that genetic or environment-driven resident macrophage dysfunction is a cause of degenerative, metabolic and possibly inflammatory and tumoural diseases. In this Review, we aim to provide a conceptual outline of our current understanding of macrophage physiology and its importance in human diseases, which may inform and serve the design of future studies.
Subject(s)
Disease , Macrophages , Animals , Humans , Cell Differentiation , Cell Lineage , Hematopoietic Stem Cells/cytology , Macrophages/cytology , Macrophages/metabolism , Macrophages/pathology , Macrophages/physiology , Microglia/cytology , Monocytes/cytology , Organ SpecificityABSTRACT
Resident macrophages densely populate the normal arterial wall, yet their origins and the mechanisms that sustain them are poorly understood. Here we use gene-expression profiling to show that arterial macrophages constitute a distinct population among macrophages. Using multiple fate-mapping approaches, we show that arterial macrophages arise embryonically from CX3CR1(+) precursors and postnatally from bone marrow-derived monocytes that colonize the tissue immediately after birth. In adulthood, proliferation (rather than monocyte recruitment) sustains arterial macrophages in the steady state and after severe depletion following sepsis. After infection, arterial macrophages return rapidly to functional homeostasis. Finally, survival of resident arterial macrophages depends on a CX3CR1-CX3CL1 axis within the vascular niche.
Subject(s)
Cell Self Renewal , Embryonic Stem Cells/cytology , Embryonic Stem Cells/metabolism , Macrophages/cytology , Macrophages/metabolism , Monocytes/cytology , Monocytes/metabolism , Receptors, Chemokine/metabolism , Animals , CX3C Chemokine Receptor 1 , Cell Survival , Chemokine CX3CL1/metabolism , Cluster Analysis , Female , Gene Expression Profiling , Immunophenotyping , Macrophages/immunology , Macrophages/microbiology , Male , Mice , Mice, Transgenic , Phenotype , Protein Binding , Stem Cell Niche , TranscriptomeABSTRACT
In lymph nodes, subcapsular sinus macrophages (SSMs) form an immunological barrier that monitors lymph drained from peripheral tissues. Upon infection, SSMs activate B and natural killer T (NKT) cells while secreting inflammatory mediators. Here, we investigated the mechanisms regulating development and homeostasis of SSMs. Embryonic SSMs originated from yolk sac hematopoiesis and were replaced by a postnatal wave of bone marrow (BM)-derived monocytes that proliferated to establish the adult SSM network. The SSM network self-maintained by proliferation with minimal BM contribution. Upon pathogen-induced transient deletion, BM-derived cells contributed to restoring the SSM network. Lymphatic endothelial cells (LECs) were the main source of CSF-1 within the lymph node and conditional deletion of Csf1 in adult LECs decreased the network of SSMs and medullary sinus macrophages (MSMs). Thus, SSMs have a dual hematopoietic origin, and LECs are essential to the niche supporting these macrophages.