RESUMEN
Non-hematopoietic cells are essential contributors to hematopoiesis. However, heterogeneity and spatial organization of these cells in human bone marrow remain largely uncharacterized. We used single-cell RNA sequencing (scRNA-seq) to profile 29,325 non-hematopoietic cells and discovered nine transcriptionally distinct subtypes. We simultaneously profiled 53,417 hematopoietic cells and predicted their interactions with non-hematopoietic subsets. We employed co-detection by indexing (CODEX) to spatially profile over 1.2 million cells. We integrated scRNA-seq and CODEX data to link predicted cellular signaling with spatial proximity. Our analysis revealed a hyperoxygenated arterio-endosteal neighborhood for early myelopoiesis, and an adipocytic localization for early hematopoietic stem and progenitor cells (HSPCs). We used our CODEX atlas to annotate new images and uncovered mesenchymal stromal cell (MSC) expansion and spatial neighborhoods co-enriched for leukemic blasts and MSCs in acute myeloid leukemia (AML) patient samples. This spatially resolved, multiomic atlas of human bone marrow provides a reference for investigation of cellular interactions that drive hematopoiesis.
Asunto(s)
Médula Ósea , Células Madre Hematopoyéticas , Células Madre Mesenquimatosas , Proteómica , Análisis de la Célula Individual , Transcriptoma , Humanos , Análisis de la Célula Individual/métodos , Médula Ósea/metabolismo , Células Madre Hematopoyéticas/metabolismo , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/citología , Proteómica/métodos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Hematopoyesis , Nicho de Células Madre , Células de la Médula Ósea/metabolismo , Células de la Médula Ósea/citologíaRESUMEN
FMS-related tyrosine kinase 3 ligand (FLT3L), encoded by FLT3LG, is a hematopoietic factor essential for the development of natural killer (NK) cells, B cells, and dendritic cells (DCs) in mice. We describe three humans homozygous for a loss-of-function FLT3LG variant with a history of various recurrent infections, including severe cutaneous warts. The patients' bone marrow (BM) was hypoplastic, with low levels of hematopoietic progenitors, particularly myeloid and B cell precursors. Counts of B cells, monocytes, and DCs were low in the patients' blood, whereas the other blood subsets, including NK cells, were affected only moderately, if at all. The patients had normal counts of Langerhans cells (LCs) and dermal macrophages in the skin but lacked dermal DCs. Thus, FLT3L is required for B cell and DC development in mice and humans. However, unlike its murine counterpart, human FLT3L is required for the development of monocytes but not NK cells.
Asunto(s)
Células Asesinas Naturales , Proteínas de la Membrana , Animales , Femenino , Humanos , Masculino , Ratones , Linfocitos B/metabolismo , Linfocitos B/citología , Médula Ósea/metabolismo , Linaje de la Célula , Células Dendríticas/metabolismo , Hematopoyesis , Células Madre Hematopoyéticas/metabolismo , Células Madre Hematopoyéticas/citología , Células Asesinas Naturales/metabolismo , Células Asesinas Naturales/inmunología , Células de Langerhans/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Monocitos/metabolismo , Piel/metabolismo , Ratones Endogámicos C57BLRESUMEN
Channels connecting the skull bone marrow and the meninges have recently been discovered as a path for immune cell and molecule trafficking. In this issue of Cell, Kolabas, Kuemmerle, Perneczky, Förstera, and colleagues characterize these channels in humans and mice, revealing unique features of skull bone marrow and localized activation in human pathology.
Asunto(s)
Médula Ósea , Cráneo , Animales , Humanos , Ratones , MeningesRESUMEN
The bone marrow in the skull is important for shaping immune responses in the brain and meninges, but its molecular makeup among bones and relevance in human diseases remain unclear. Here, we show that the mouse skull has the most distinct transcriptomic profile compared with other bones in states of health and injury, characterized by a late-stage neutrophil phenotype. In humans, proteome analysis reveals that the skull marrow is the most distinct, with differentially expressed neutrophil-related pathways and a unique synaptic protein signature. 3D imaging demonstrates the structural and cellular details of human skull-meninges connections (SMCs) compared with veins. Last, using translocator protein positron emission tomography (TSPO-PET) imaging, we show that the skull bone marrow reflects inflammatory brain responses with a disease-specific spatial distribution in patients with various neurological disorders. The unique molecular profile and anatomical and functional connections of the skull show its potential as a site for diagnosing, monitoring, and treating brain diseases.
Asunto(s)
Médula Ósea , Enfermedades del Sistema Nervioso , Cráneo , Animales , Humanos , Ratones , Médula Ósea/metabolismo , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Proteínas Portadoras/metabolismo , Enfermedades del Sistema Nervioso/metabolismo , Enfermedades del Sistema Nervioso/patología , Tomografía de Emisión de Positrones/métodos , Receptores de GABA/metabolismo , Cráneo/citología , Cráneo/diagnóstico por imagenRESUMEN
The heterogeneity of tissue macrophages, in health and in disease, has become increasingly transparent over the last decade. But with the plethora of data comes a natural need for organization and the design of a conceptual framework for how we can better understand the origins and functions of different macrophages. We propose that the ontogeny of a macrophage-beyond its fundamental derivation as either embryonically or bone marrow-derived, but rather inclusive of the course of its differentiation, amidst steady-state cues, disease-associated signals, and time-constitutes a critical piece of information about its contribution to homeostasis or the progression of disease.
Asunto(s)
Médula Ósea , Macrófagos , Homeostasis , Diferenciación CelularRESUMEN
Multiple sclerosis (MS) is a T cell-mediated autoimmune disease of the central nervous system (CNS). Bone marrow hematopoietic stem and progenitor cells (HSPCs) rapidly sense immune activation, yet their potential interplay with autoreactive T cells in MS is unknown. Here, we report that bone marrow HSPCs are skewed toward myeloid lineage concomitant with the clonal expansion of T cells in MS patients. Lineage tracing in experimental autoimmune encephalomyelitis, a mouse model of MS, reveals remarkable bone marrow myelopoiesis with an augmented output of neutrophils and Ly6Chigh monocytes that invade the CNS. We found that myelin-reactive T cells preferentially migrate into the bone marrow compartment in a CXCR4-dependent manner. This aberrant bone marrow myelopoiesis involves the CCL5-CCR5 axis and augments CNS inflammation and demyelination. Our study suggests that targeting the bone marrow niche presents an avenue to treat MS and other autoimmune disorders.
Asunto(s)
Encefalomielitis Autoinmune Experimental , Esclerosis Múltiple , Animales , Médula Ósea , Hematopoyesis , Humanos , Ratones , Ratones Endogámicos C57BLRESUMEN
Antibody-secreting plasma cells (PCs) are generated in secondary lymphoid organs but are reported to reside in an emerging range of anatomical sites. Analysis of the transcriptome of different tissue-resident (Tr)PC populations revealed that they each have their own transcriptional signature indicative of functional adaptation to the host tissue environment. In contrast to expectation, all TrPCs were extremely long-lived, regardless of their organ of residence, with longevity influenced by intrinsic factors like the immunoglobulin isotype. Analysis at single-cell resolution revealed that the bone marrow is unique in housing a compendium of PCs generated all over the body that retain aspects of the transcriptional program indicative of their tissue of origin. This study reveals that extreme longevity is an intrinsic property of TrPCs whose transcriptome is imprinted by signals received both at the site of induction and within the tissue of residence.
Asunto(s)
Médula Ósea , Células Plasmáticas , Células de la Médula ÓseaRESUMEN
Analysis of the human hematopoietic progenitor compartment is being transformed by single-cell multimodal approaches. Cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) enables coupled surface protein and transcriptome profiling, thereby revealing genomic programs underlying progenitor states. To perform CITE-seq systematically on primary human bone marrow cells, we used titrations with 266 CITE-seq antibodies (antibody-derived tags) and machine learning to optimize a panel of 132 antibodies. Multimodal analysis resolved >80 stem, progenitor, immune, stromal and transitional cells defined by distinctive surface markers and transcriptomes. This dataset enables flow cytometry solutions for in silico-predicted cell states and identifies dozens of cell surface markers consistently detected across donors spanning race and sex. Finally, aligning annotations from this atlas, we nominate normal marrow equivalents for acute myeloid leukemia stem cell populations that differ in clinical response. This atlas serves as an advanced digital resource for hematopoietic progenitor analyses in human health and disease.
Asunto(s)
Células Madre Hematopoyéticas , Transcriptoma , Humanos , Médula Ósea , Perfilación de la Expresión Génica , Células de la Médula ÓseaRESUMEN
Human bone marrow permanently harbors high numbers of neutrophils, and a tumor-supportive bias of these cells could significantly impact bone marrow-confined malignancies. In individuals with multiple myeloma, the bone marrow is characterized by inflammatory stromal cells with the potential to influence neutrophils. We investigated myeloma-associated alterations in human marrow neutrophils and the impact of stromal inflammation on neutrophil function. Mature neutrophils in myeloma marrow are activated and tumor supportive and transcribe increased levels of IL1B and myeloma cell survival factor TNFSF13B (BAFF). Interactions with inflammatory stromal cells induce neutrophil activation, including BAFF secretion, in a STAT3-dependent manner, and once activated, neutrophils gain the ability to reciprocally induce stromal activation. After first-line myeloid-depleting antimyeloma treatment, human bone marrow retains residual stromal inflammation, and newly formed neutrophils are reactivated. Combined, we identify a neutrophil-stromal cell feed-forward loop driving tumor-supportive inflammation that persists after treatment and warrants novel strategies to target both stromal and immune microenvironments in multiple myeloma.
Asunto(s)
Factor Activador de Células B , Interleucina-1beta , Mieloma Múltiple , Neutrófilos , Células del Estroma , Microambiente Tumoral , Mieloma Múltiple/inmunología , Mieloma Múltiple/patología , Humanos , Microambiente Tumoral/inmunología , Neutrófilos/inmunología , Neutrófilos/metabolismo , Células del Estroma/metabolismo , Células del Estroma/inmunología , Factor Activador de Células B/metabolismo , Interleucina-1beta/metabolismo , Activación Neutrófila , Factor de Transcripción STAT3/metabolismo , Médula Ósea/inmunología , Médula Ósea/patologíaRESUMEN
Clonal hematopoiesis, a condition in which individual hematopoietic stem cell clones generate a disproportionate fraction of blood leukocytes, correlates with higher risk for cardiovascular disease. The mechanisms behind this association are incompletely understood. Here, we show that hematopoietic stem cell division rates are increased in mice and humans with atherosclerosis. Mathematical analysis demonstrates that increased stem cell proliferation expedites somatic evolution and expansion of clones with driver mutations. The experimentally determined division rate elevation in atherosclerosis patients is sufficient to produce a 3.5-fold increased risk of clonal hematopoiesis by age 70. We confirm the accuracy of our theoretical framework in mouse models of atherosclerosis and sleep fragmentation by showing that expansion of competitively transplanted Tet2-/- cells is accelerated under conditions of chronically elevated hematopoietic activity. Hence, increased hematopoietic stem cell proliferation is an important factor contributing to the association between cardiovascular disease and clonal hematopoiesis.
Asunto(s)
Aterosclerosis/patología , Hematopoyesis Clonal , Células Madre Hematopoyéticas/patología , Envejecimiento/patología , Animales , Apolipoproteínas E/genética , Aterosclerosis/genética , Médula Ósea/metabolismo , Proliferación Celular , Evolución Clonal , Modelos Animales de Enfermedad , Femenino , Humanos , Ratones , Ratones Endogámicos C57BL , Modelos Biológicos , Privación de Sueño/patologíaRESUMEN
High-dimensional approaches have revealed heterogeneity amongst dendritic cells (DCs), including a population of transitional DCs (tDCs) in mice and humans. However, the origin and relationship of tDCs to other DC subsets has been unclear. Here we show that tDCs are distinct from other well-characterized DCs and conventional DC precursors (pre-cDCs). We demonstrate that tDCs originate from bone marrow progenitors shared with plasmacytoid DCs (pDCs). In the periphery, tDCs contribute to the pool of ESAM+ type 2 DCs (DC2s), and these DC2s have pDC-related developmental features. Different from pre-cDCs, tDCs have less turnover, capture antigen, respond to stimuli and activate antigen-specific naïve T cells, all characteristics of differentiated DCs. Different from pDCs, viral sensing by tDCs results in IL-1ß secretion and fatal immune pathology in a murine coronavirus model. Our findings suggest that tDCs are a distinct pDC-related subset with a DC2 differentiation potential and unique proinflammatory function during viral infections.
Asunto(s)
Médula Ósea , Células Dendríticas , Animales , Ratones , Antivirales , Médula Ósea/inmunología , Diferenciación Celular , Células Dendríticas/clasificación , Células Dendríticas/inmunologíaRESUMEN
Here we report the identification of human CD66b-CD64dimCD115- neutrophil-committed progenitor cells (NCPs) within the SSCloCD45dimCD34+ and CD34dim/- subsets in the bone marrow. NCPs were either CD45RA+ or CD45RA-, and in vitro experiments showed that CD45RA acquisition was not mandatory for their maturation process. NCPs exclusively generated human CD66b+ neutrophils in both in vitro differentiation and in vivo adoptive transfer experiments. Single-cell RNA-sequencing analysis indicated NCPs fell into four clusters, characterized by different maturation stages and distributed along two differentiation routes. One of the clusters was characterized by an interferon-stimulated gene signature, consistent with the reported expansion of peripheral mature neutrophil subsets that express interferon-stimulated genes in diseased individuals. Finally, comparison of transcriptomic and phenotypic profiles indicated NCPs represented earlier neutrophil precursors than the previously described early neutrophil progenitors (eNePs), proNeus and COVID-19 proNeus. Altogether, our data shed light on the very early phases of neutrophil ontogeny.
Asunto(s)
Antígenos CD , Médula Ósea , Moléculas de Adhesión Celular , Diferenciación Celular , Neutrófilos , Receptor de Factor Estimulante de Colonias de Macrófagos , Receptores de IgG , Células de la Médula Ósea , COVID-19 , Proteínas Ligadas a GPI , Humanos , Interferones , Neutrófilos/citologíaRESUMEN
Much has been learned about how cells enter lymphoid tissues. But how do they leave? Sphingosine-1-phosphate (S1P) has emerged over the past decade as a central mediator of lymphocyte egress. In this review, we summarize the current understanding of how S1P promotes exit from the secondary lymphoid organs and thymus. We review what is known about additional requirements for emigration and summarize the mostly distinct requirements for exit from the bone marrow. Egress from lymphoid organs is limited during immune responses, and we examine how this regulation works. There is accumulating evidence for roles of S1P in directing immune cell behavior within lymphoid tissues. How such actions can fit together with the egress-promoting role of S1P is discussed. Finally, we examine current understanding of how FTY720, a drug that targets S1P receptors and is approved for the treatment of multiple sclerosis, causes immune suppression.
Asunto(s)
Linfocitos/inmunología , Linfocitos/metabolismo , Tejido Linfoide/inmunología , Tejido Linfoide/metabolismo , Lisofosfolípidos/metabolismo , Esfingosina/análogos & derivados , Animales , Médula Ósea/efectos de los fármacos , Médula Ósea/inmunología , Médula Ósea/metabolismo , Clorhidrato de Fingolimod , Humanos , Inmunosupresores/farmacología , Ganglios Linfáticos/efectos de los fármacos , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/metabolismo , Linfocitos/efectos de los fármacos , Tejido Linfoide/efectos de los fármacos , Lisofosfolípidos/inmunología , Modelos Biológicos , Glicoles de Propileno/farmacología , Esfingosina/inmunología , Esfingosina/metabolismo , Esfingosina/farmacología , Timo/efectos de los fármacos , Timo/inmunología , Timo/metabolismoRESUMEN
Baryawno et al. provide a comprehensive atlas of the mouse bone marrow stroma based on single-cell RNA-sequencing data. Their analysis reveals a taxonomy of 17 distinct cell types with diverse functions that highlights the complexity of the bone marrow stroma and paves the way for future in vivo assessment.
Asunto(s)
Médula Ósea , Leucemia , Animales , Células de la Médula Ósea , Homeostasis , Ratones , Análisis de Secuencia de ARNRESUMEN
This year's Lasker Basic Medical Research Award honors Max Cooper and Jacques Miller for discoveries that revealed the organizing principles of adaptive immunity. Their collective contributions have had broad clinical impact in the treatment of immune disease.
Asunto(s)
Inmunidad Adaptativa/inmunología , Comunicación Celular/inmunología , Células Plasmáticas/inmunología , Linfocitos T/inmunología , Animales , Formación de Anticuerpos/inmunología , Presentación de Antígeno , Médula Ósea/inmunología , Pollos , Humanos , Hibridomas/inmunología , Cambio de Clase de Inmunoglobulina/inmunología , Ganglios Linfáticos/inmunología , Ratones , Premio Nobel , Autotolerancia/inmunología , Timo/inmunologíaRESUMEN
Nutritional status potentially influences immune responses; however, how nutritional signals regulate cellular dynamics and functionality remains obscure. Herein, we report that temporary fasting drastically reduces the number of lymphocytes by â¼50% in Peyer's patches (PPs), the inductive site of the gut immune response. Subsequent refeeding seemingly restored the number of lymphocytes, but whose cellular composition was conspicuously altered. A large portion of germinal center and IgA+ B cells were lost via apoptosis during fasting. Meanwhile, naive B cells migrated from PPs to the bone marrow during fasting and then back to PPs during refeeding when stromal cells sensed nutritional signals and upregulated CXCL13 expression to recruit naive B cells. Furthermore, temporal fasting before oral immunization with ovalbumin abolished the induction of antigen-specific IgA, failed to induce oral tolerance, and eventually exacerbated food antigen-induced diarrhea. Thus, nutritional signals are critical in maintaining gut immune homeostasis.
Asunto(s)
Linfocitos B/fisiología , Inmunidad Mucosa , Animales , Antígenos/inmunología , Linfocitos B/inmunología , Linfocitos B/metabolismo , Médula Ósea/inmunología , Médula Ósea/metabolismo , Quimiocina CXCL13/genética , Quimiocina CXCL13/metabolismo , Ayuno , Regulación de la Expresión Génica , Glucólisis , Inmunoglobulina A/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Estado Nutricional , Ovalbúmina/inmunología , Ganglios Linfáticos Agregados/inmunología , Ganglios Linfáticos Agregados/metabolismo , Ganglios Linfáticos Agregados/patología , Receptores CXCR5/genética , Receptores CXCR5/metabolismo , Transducción de Señal , Células del Estroma/citología , Células del Estroma/metabolismo , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Mammals evolved in the face of fluctuating food availability. How the immune system adapts to transient nutritional stress remains poorly understood. Here, we show that memory T cells collapsed in secondary lymphoid organs in the context of dietary restriction (DR) but dramatically accumulated within the bone marrow (BM), where they adopted a state associated with energy conservation. This response was coordinated by glucocorticoids and associated with a profound remodeling of the BM compartment, which included an increase in T cell homing factors, erythropoiesis, and adipogenesis. Adipocytes, as well as CXCR4-CXCL12 and S1P-S1P1R interactions, contributed to enhanced T cell accumulation in BM during DR. Memory T cell homing to BM during DR was associated with enhanced protection against infections and tumors. Together, this work uncovers a fundamental host strategy to sustain and optimize immunological memory during nutritional challenges that involved a temporal and spatial reorganization of the memory pool within "safe haven" compartments.
Asunto(s)
Médula Ósea/metabolismo , Memoria Inmunológica , Animales , Médula Ósea/inmunología , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Restricción Calórica/veterinaria , Línea Celular Tumoral , Quimiocina CXCL12/metabolismo , Dieta Reductora/veterinaria , Metabolismo Energético , Regulación de la Expresión Génica , Glucocorticoides , Melanoma Experimental/mortalidad , Melanoma Experimental/patología , Ratones , Ratones Endogámicos C57BL , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptores CXCR4/metabolismo , Tasa de Supervivencia , Linfocitos T/inmunología , Linfocitos T/metabolismo , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Acute myeloid leukemia (AML) is a heterogeneous disease that resides within a complex microenvironment, complicating efforts to understand how different cell types contribute to disease progression. We combined single-cell RNA sequencing and genotyping to profile 38,410 cells from 40 bone marrow aspirates, including 16 AML patients and five healthy donors. We then applied a machine learning classifier to distinguish a spectrum of malignant cell types whose abundances varied between patients and between subclones in the same tumor. Cell type compositions correlated with prototypic genetic lesions, including an association of FLT3-ITD with abundant progenitor-like cells. Primitive AML cells exhibited dysregulated transcriptional programs with co-expression of stemness and myeloid priming genes and had prognostic significance. Differentiated monocyte-like AML cells expressed diverse immunomodulatory genes and suppressed T cell activity in vitro. In conclusion, we provide single-cell technologies and an atlas of AML cell states, regulators, and markers with implications for precision medicine and immune therapies. VIDEO ABSTRACT.
Asunto(s)
Leucemia Mieloide Aguda/genética , Transcriptoma/genética , Adulto , Secuencia de Bases/genética , Médula Ósea , Células de la Médula Ósea/citología , Línea Celular Tumoral , Progresión de la Enfermedad , Femenino , Genotipo , Humanos , Leucemia Mieloide Aguda/inmunología , Leucemia Mieloide Aguda/fisiopatología , Aprendizaje Automático , Masculino , Persona de Mediana Edad , Mutación , Pronóstico , ARN , Transducción de Señal , Análisis de la Célula Individual/métodos , Microambiente Tumoral , Secuenciación del Exoma/métodosRESUMEN
Progression and persistence of malignancies are influenced by the local tumor microenvironment, and future eradication of currently incurable tumors will, in part, hinge on our understanding of malignant cell biology in the context of their nourishing surroundings. Here, we generated paired single-cell transcriptomic datasets of tumor cells and the bone marrow immune and stromal microenvironment in multiple myeloma. These analyses identified myeloma-specific inflammatory mesenchymal stromal cells, which spatially colocalized with tumor cells and immune cells and transcribed genes involved in tumor survival and immune modulation. Inflammatory stromal cell signatures were driven by stimulation with proinflammatory cytokines, and analyses of immune cell subsets suggested interferon-responsive effector T cell and CD8+ stem cell memory T cell populations as potential sources of stromal cell-activating cytokines. Tracking stromal inflammation in individuals over time revealed that successful antitumor induction therapy is unable to revert bone marrow inflammation, predicting a role for mesenchymal stromal cells in disease persistence.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Células Madre Mesenquimatosas/inmunología , Mieloma Múltiple/inmunología , Recurrencia Local de Neoplasia/inmunología , Microambiente Tumoral/inmunología , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Médula Ósea/efectos de los fármacos , Médula Ósea/inmunología , Médula Ósea/patología , Línea Celular Tumoral , Progresión de la Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica/inmunología , Humanos , Masculino , Células Madre Mesenquimatosas/patología , Persona de Mediana Edad , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/patología , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/prevención & control , Cultivo Primario de Células , Estudios Prospectivos , RNA-Seq , Análisis de la Célula Individual , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/genéticaRESUMEN
Mutations of the CBP/p300 histone acetyltransferase (HAT) domain can be linked to leukemic transformation in humans, suggestive of a checkpoint of leukocyte compartment sizes. Here, we examined the impact of reversible inhibition of this domain by the small-molecule A485. We found that A485 triggered acute and transient mobilization of leukocytes from the bone marrow into the blood. Leukocyte mobilization by A485 was equally potent as, but mechanistically distinct from, granulocyte colony-stimulating factor (G-CSF), which allowed for additive neutrophil mobilization when both compounds were combined. These effects were maintained in models of leukopenia and conferred augmented host defenses. Mechanistically, activation of the hypothalamus-pituitary-adrenal gland (HPA) axis by A485 relayed shifts in leukocyte distribution through corticotropin-releasing hormone receptor 1 (CRHR1) and adrenocorticotropic hormone (ACTH), but independently of glucocorticoids. Our findings identify a strategy for rapid expansion of the blood leukocyte compartment via a neuroendocrine loop, with implications for the treatment of human pathologies.