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1.
Cell ; 172(3): 500-516.e16, 2018 01 25.
Artículo en Inglés | MEDLINE | ID: mdl-29275859

RESUMEN

Microglia are embryonically seeded macrophages that contribute to brain development, homeostasis, and pathologies. It is thus essential to decipher how microglial properties are temporally regulated by intrinsic and extrinsic factors, such as sexual identity and the microbiome. Here, we found that microglia undergo differentiation phases, discernable by transcriptomic signatures and chromatin accessibility landscapes, which can diverge in adult males and females. Remarkably, the absence of microbiome in germ-free mice had a time and sexually dimorphic impact both prenatally and postnatally: microglia were more profoundly perturbed in male embryos and female adults. Antibiotic treatment of adult mice triggered sexually biased microglial responses revealing both acute and long-term effects of microbiota depletion. Finally, human fetal microglia exhibited significant overlap with the murine transcriptomic signature. Our study shows that microglia respond to environmental challenges in a sex- and time-dependent manner from prenatal stages, with major implications for our understanding of microglial contributions to health and disease.


Asunto(s)
Vida Libre de Gérmenes , Microbiota , Microglía/citología , Efectos Tardíos de la Exposición Prenatal/microbiología , Transcriptoma , Animales , Encéfalo/citología , Encéfalo/embriología , Encéfalo/metabolismo , Diferenciación Celular , Células Cultivadas , Ensamble y Desensamble de Cromatina , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Microglía/metabolismo , Embarazo , Factores Sexuales
2.
Immunity ; 48(6): 1160-1171.e5, 2018 06 19.
Artículo en Inglés | MEDLINE | ID: mdl-29858009

RESUMEN

Hematopoiesis occurs in distinct waves. "Definitive" hematopoietic stem cells (HSCs) with the potential for all blood lineages emerge in the aorta-gonado-mesonephros, while "primitive" progenitors, whose potential is thought to be limited to erythrocytes, megakaryocytes, and macrophages, arise earlier in the yolk sac (YS). Here, we questioned whether other YS lineages exist that have not been identified, partially owing to limitations of current lineage tracing models. We established the use of Cdh5-CreERT2 for hematopoietic fate mapping, which revealed the YS origin of mast cells (MCs). YS-derived MCs were replaced by definitive MCs, which maintained themselves independently from the bone marrow in the adult. Replacement occurred with tissue-specific kinetics. MCs in the embryonic skin, but not other organs, remained largely YS derived prenatally and were phenotypically and transcriptomically distinct from definite adult MCs. We conclude that within myeloid lineages, dual hematopoietic origin is shared between macrophages and MCs.


Asunto(s)
Linaje de la Célula/inmunología , Hematopoyesis/fisiología , Mastocitos/citología , Animales , Hemangioblastos/citología , Células Madre Hematopoyéticas/citología , Macrófagos/citología , Macrófagos/inmunología , Mastocitos/inmunología , Ratones , Piel/citología , Piel/inmunología , Saco Vitelino/citología , Saco Vitelino/embriología
3.
Nature ; 594(7861): 94-99, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-34012116

RESUMEN

Inflammation is a defence response to tissue damage that requires tight regulation in order to prevent impaired healing. Tissue-resident macrophages have a key role in tissue repair1, but the precise molecular mechanisms that regulate the balance between inflammatory and pro-repair macrophage responses during healing remain poorly understood. Here we demonstrate a major role for sensory neurons in promoting the tissue-repair function of macrophages. In a sunburn-like model of skin damage in mice, the conditional ablation of sensory neurons expressing the Gαi-interacting protein (GINIP) results in defective tissue regeneration and in dermal fibrosis. Elucidation of the underlying molecular mechanisms revealed a crucial role for the neuropeptide TAFA4, which is produced in the skin by C-low threshold mechanoreceptors-a subset of GINIP+ neurons. TAFA4 modulates the inflammatory profile of macrophages directly in vitro. In vivo studies in Tafa4-deficient mice revealed that TAFA4 promotes the production of IL-10 by dermal macrophages after UV-induced skin damage. This TAFA4-IL-10 axis also ensures the survival and maintenance of IL-10+TIM4+ dermal macrophages, reducing skin inflammation and promoting tissue regeneration. These results reveal a neuroimmune regulatory pathway driven by the neuropeptide TAFA4 that promotes the anti-inflammatory functions of macrophages and prevents fibrosis after tissue damage, and could lead to new therapeutic perspectives for inflammatory diseases.


Asunto(s)
Citocinas/metabolismo , Macrófagos/metabolismo , Regeneración , Células Receptoras Sensoriales/metabolismo , Cicatrización de Heridas , Animales , Supervivencia Celular , Citocinas/deficiencia , Modelos Animales de Enfermedad , Femenino , Fibrosis/etiología , Fibrosis/metabolismo , Fibrosis/patología , Fibrosis/prevención & control , Inflamación/etiología , Inflamación/metabolismo , Inflamación/patología , Inflamación/prevención & control , Interleucina-10/biosíntesis , Interleucina-10/metabolismo , Macrófagos/efectos de la radiación , Proteínas de la Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Células Receptoras Sensoriales/efectos de la radiación , Piel/patología , Piel/efectos de la radiación , Quemadura Solar/complicaciones , Quemadura Solar/etiología , Quemadura Solar/metabolismo , Quemadura Solar/patología , Rayos Ultravioleta/efectos adversos
4.
Brain Behav Immun ; 119: 750-766, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38710336

RESUMEN

Chronic pain is a heavily debilitating condition and a huge socio-economic burden, with no efficient treatment. Over the past decade, the gut microbiota has emerged as an important regulator of nervous system's health and disease states. Yet, its contribution to the pathogenesis of chronic somatic pain remains poorly documented. Here, we report that male but not female mice lacking Myosin1a (KO) raised under single genotype housing conditions (KO-SGH) are predisposed to develop chronic pain in response to a peripheral tissue injury. We further underscore the potential of MYO1A loss-of-function to alter the composition of the gut microbiota and uncover a functional connection between the vulnerability to chronic pain and the dysbiotic gut microbiota of KO-SGH males. As such, parental antibiotic treatment modifies gut microbiota composition and completely rescues the injury-induced pain chronicity in male KO-SGH offspring. Furthermore, in KO-SGH males, this dysbiosis is accompanied by a transcriptomic activation signature in the dorsal root ganglia (DRG) macrophage compartment, in response to tissue injury. We identify CD206+CD163- and CD206+CD163+ as the main subsets of DRG resident macrophages and show that both are long-lived and self-maintained and exhibit the capacity to monitor the vasculature. Consistently, in vivo depletion of DRG macrophages rescues KO-SGH males from injury-induced chronic pain underscoring a deleterious role for DRG macrophages in a Myo1a-loss-of function context. Together, our findings reveal gene-sex-microbiota interactions in determining the predisposition to injury-induced chronic pain and point-out DRG macrophages as potential effector cells.


Asunto(s)
Dolor Crónico , Disbiosis , Ganglios Espinales , Microbioma Gastrointestinal , Ratones Noqueados , Miosina Tipo I , Animales , Femenino , Masculino , Ratones , Dolor Crónico/metabolismo , Dolor Crónico/microbiología , Disbiosis/metabolismo , Ganglios Espinales/metabolismo , Microbioma Gastrointestinal/fisiología , Macrófagos/metabolismo , Ratones Endogámicos C57BL , Miosina Tipo I/metabolismo
5.
Immunity ; 42(4): 665-78, 2015 Apr 21.
Artículo en Inglés | MEDLINE | ID: mdl-25902481

RESUMEN

Although classified as hematopoietic cells, tissue-resident macrophages (MFs) arise from embryonic precursors that seed the tissues prior to birth to generate a self-renewing population, which is maintained independently of adult hematopoiesis. Here we reveal the identity of these embryonic precursors using an in utero MF-depletion strategy and fate-mapping of yolk sac (YS) and fetal liver (FL) hematopoiesis. We show that YS MFs are the main precursors of microglia, while most other MFs derive from fetal monocytes (MOs). Both YS MFs and fetal MOs arise from erythro-myeloid progenitors (EMPs) generated in the YS. In the YS, EMPs gave rise to MFs without monocytic intermediates, while EMP seeding the FL upon the establishment of blood circulation acquired c-Myb expression and gave rise to fetal MOs that then seeded embryonic tissues and differentiated into MFs. Thus, adult tissue-resident MFs established from hematopoietic stem cell-independent embryonic precursors arise from two distinct developmental programs.


Asunto(s)
Envejecimiento/inmunología , Macrófagos/inmunología , Monocitos/inmunología , Células Progenitoras Mieloides/inmunología , Proteínas Proto-Oncogénicas c-myb/inmunología , Animales , Biomarcadores/metabolismo , Diferenciación Celular , Linaje de la Célula/inmunología , Rastreo Celular , Embrión de Mamíferos , Femenino , Feto , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/inmunología , Riñón/citología , Riñón/inmunología , Hígado/citología , Hígado/inmunología , Pulmón/citología , Pulmón/inmunología , Macrófagos/citología , Ratones , Microglía/citología , Microglía/inmunología , Monocitos/citología , Células Progenitoras Mieloides/citología , Embarazo , Cultivo Primario de Células , Proteínas Proto-Oncogénicas c-myb/metabolismo , Piel/citología , Piel/inmunología , Saco Vitelino/citología , Saco Vitelino/inmunología
6.
Immunity ; 38(5): 970-83, 2013 May 23.
Artículo en Inglés | MEDLINE | ID: mdl-23706669

RESUMEN

Mouse and human dendritic cells (DCs) are composed of functionally specialized subsets, but precise interspecies correlation is currently incomplete. Here, we showed that murine lung and gut lamina propria CD11b+ DC populations were comprised of two subsets: FLT3- and IRF4-dependent CD24(+)CD64(-) DCs and contaminating CSF-1R-dependent CD24(-)CD64(+) macrophages. Functionally, loss of CD24(+)CD11b(+) DCs abrogated CD4+ T cell-mediated interleukin-17 (IL-17) production in steady state and after Aspergillus fumigatus challenge. Human CD1c+ DCs, the equivalent of murine CD24(+)CD11b(+) DCs, also expressed IRF4, secreted IL-23, and promoted T helper 17 cell responses. Our data revealed heterogeneity in the mouse CD11b+ DC compartment and identifed mucosal tissues IRF4-expressing DCs specialized in instructing IL-17 responses in both mouse and human. The demonstration of mouse and human DC subsets specialized in driving IL-17 responses highlights the conservation of key immune functions across species and will facilitate the translation of mouse in vivo findings to advance DC-based clinical therapies.


Asunto(s)
Aspergillus fumigatus/inmunología , Células Dendríticas/metabolismo , Factores Reguladores del Interferón/metabolismo , Interleucina-17/metabolismo , Células Th17/metabolismo , Animales , Antígeno CD11b/metabolismo , Antígeno CD24/metabolismo , Diferenciación Celular/inmunología , Células Dendríticas/inmunología , Humanos , Interleucina-17/biosíntesis , Interleucina-23/metabolismo , Mucosa Intestinal/citología , Mucosa Intestinal/inmunología , Macrófagos/metabolismo , Ratones , Receptores de IgG/metabolismo , Mucosa Respiratoria/citología , Mucosa Respiratoria/inmunología , Tirosina Quinasa 3 Similar a fms/metabolismo
7.
Immunity ; 37(6): 1050-1060, 2012 Dec 14.
Artículo en Inglés | MEDLINE | ID: mdl-23177320

RESUMEN

Colony stimulating factor-1 (Csf-1) receptor and its ligand Csf-1 control macrophage development, maintenance, and function. The development of both Langerhans cells (LCs) and microglia is highly dependent on Csf-1 receptor signaling but independent of Csf-1. Here we show that in both mice and humans, interleukin-34 (IL-34), an alternative ligand for Csf-1 receptor, is produced by keratinocytes in the epidermis and by neurons in the brain. Mice lacking IL-34 displayed a marked reduction of LCs and a decrease of microglia, whereas monocytes, dermal, and lymphoid tissue macrophages and DCs were unaffected. We identified IL-34 as a nonredundant cytokine for the development of LCs during embryogenesis as well as for their homeostasis in the adult skin. Whereas inflammation-induced repopulation of LCs appears to be dependent on Csf-1, once inflammation is resolved, LC survival is again IL-34-dependent. In contrast, microglia and their yolk sac precursors develop independently of IL-34 but rely on it for their maintenance in the adult brain.


Asunto(s)
Interleucinas/fisiología , Células de Langerhans/inmunología , Microglía/inmunología , Células del Estroma/metabolismo , Animales , Encéfalo/inmunología , Encéfalo/metabolismo , Diferenciación Celular/genética , Epidermis/inmunología , Epidermis/metabolismo , Homeostasis , Humanos , Inflamación/genética , Inflamación/inmunología , Inflamación/metabolismo , Interleucinas/genética , Interleucinas/inmunología , Interleucinas/metabolismo , Queratinocitos/inmunología , Queratinocitos/metabolismo , Células de Langerhans/citología , Células de Langerhans/metabolismo , Ratones , Microglía/citología , Microglía/metabolismo , Psoriasis/inducido químicamente , Psoriasis/inmunología , Receptor de Factor Estimulante de Colonias de Macrófagos/metabolismo , Transducción de Señal , Piel/inmunología , Piel/metabolismo
8.
Cell Immunol ; 330: 5-15, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-29475558

RESUMEN

Tissue-resident macrophages have pivotal functions for tissue defense and homeostasis. Two main discoveries have changed our current understanding of macrophage development: Their embryonic origin and their ability to self-renew throughout the lifespan. It is now well accepted that most tissue-resident macrophages are long-lived cells derived from a transient hematopoietic wave of erythro-myeloid progenitors (EMPs) emerging in the yolk sac. At least two distinct pathways derived from EMPs have been implicated in macrophage development. The first one, c-Myb-independent is giving rise to yolk sac macrophages also called primitive macrophages, and bypassing the classical monocytic intermediates. The second requires c-Myb expression and start once EMPs seed the fetal liver where they generate fetal monocytes. Sequentially, primitive macrophages seed every tissue and will ultimately give rise to microglia in the brain, rapidly isolated by the blood brain barrier, while EMP-derived fetal monocytes infiltrate every other tissues and gradually generate the major pool of adult tissue-resident macrophages by diluting the initial primitive macrophage contribution. A third wave of hematopoietic stem cells (HSC)-derived monocytes is also emerging from the fetal liver to contribute to the long-lived macrophage pool established at birth while the adult hematopoiesis is only starting in the bone marrow. We propose here to review recent insights about the different embryonic hematopoietic programs responsible for the generation of long-lived tissue-resident macrophages and their maintenance after birth.


Asunto(s)
Células Madre Hematopoyéticas/citología , Macrófagos/citología , Monocitos/citología , Saco Vitelino/citología , Animales , Linaje de la Célula , Femenino , Células Madre Hematopoyéticas/metabolismo , Humanos , Hígado/citología , Hígado/embriología , Microglía/citología , Proteínas Proto-Oncogénicas c-myb/metabolismo , Saco Vitelino/embriología
9.
Adv Exp Med Biol ; 1003: 251-272, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28667562

RESUMEN

Following myocardial infarction (MI), resident innate immune cells such as macrophages, innate lymphoid cells, and mast cells rapidly coordinate their function to contain inflammation by removing dying cells and promoting cardiomyocyte replenishment. To sustain local tissue repair functions, hematopoietic progenitors are mobilized from the bone marrow to the spleen to generate subsequent myeloid cells such as monocytes and neutrophils, which are rapidly recruited at the site of MI. A finely tuned balance between local adaptation and recruitment controls the overall outcome of the cardiac tissue regeneration versus repair and scar formation.In this chapter, the (potential) roles of the innate immune system residing in the heart are discussed in the context of recent findings about macrophage ontogeny and their homeostasis with circulating monocytes during cardiac tissue growth and after myocardial infarction. Their interactions with other members of the innate immune system are also discussed with a particular emphasis on the potential involvement of mast cells and innate lymphoid cells during MI, largely underestimated until recently. Understanding the development and the functions of the different protagonists responding to MI as well as their potential cross talk could help design new strategies for regenerative medicine intervention.


Asunto(s)
Sistema Inmunológico/inmunología , Inmunidad Innata , Infarto del Miocardio/inmunología , Miocardio/inmunología , Cicatrización de Heridas , Animales , Humanos , Sistema Inmunológico/metabolismo , Sistema Inmunológico/patología , Infarto del Miocardio/metabolismo , Infarto del Miocardio/patología , Infarto del Miocardio/fisiopatología , Miocardio/metabolismo , Miocardio/patología , Recuperación de la Función , Regeneración , Transducción de Señal
10.
Traffic ; 11(4): 455-67, 2010 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-20070608

RESUMEN

Macrophages are among the major targets of HIV-1 infection and play a key role in viral pathogenesis. Identification of the cellular cofactors involved in the production of infectious HIV-1 from macrophages is thus crucial. Here, we investigated the role of the cellular cofactor TIP47 in HIV-1 morphogenesis in primary macrophages. Using siRNA approach, we show that TIP47 is essential for HIV-1 infectivity and propagation. TIP47 silencing disrupts Gag and Env colocalization in macrophages. Moreover, mutations in HIV-1 Gag or Env, which abolish interaction with TIP47, impair HIV-1 propagation and infectivity preventing colocalization of Gag and Env, Gag and Env coimmunoprecipitation. Interestingly, disruption of Gag-TIP47 interaction by matrix mutation or TIP47 depletion also causes Gag to localize in scattered dots in the vicinity of the plasma membrane of macrophages. Therefore, TIP47 is required for the encounter between Gag and Env, and thus for the generation of infectious HIV-1 particles from primary macrophages.


Asunto(s)
Proteínas de Unión al ADN/metabolismo , VIH-1/fisiología , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Macrófagos/virología , Proteínas Gestacionales/metabolismo , Ensamble de Virus , Proteínas de Unión al ADN/genética , VIH-1/metabolismo , Células HeLa , Humanos , Inmunoprecipitación , Péptidos y Proteínas de Señalización Intracelular/genética , Macrófagos/metabolismo , Mutación , Perilipina-3 , Proteínas Gestacionales/genética , ARN Interferente Pequeño/genética , Proteínas de Transporte Vesicular , Productos del Gen env del Virus de la Inmunodeficiencia Humana/genética , Productos del Gen env del Virus de la Inmunodeficiencia Humana/metabolismo , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/genética , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/metabolismo
11.
Blood ; 115(22): 4412-20, 2010 Jun 03.
Artículo en Inglés | MEDLINE | ID: mdl-20308597

RESUMEN

Cross-presentation is an essential mechanism that allows dendritic cells (DCs) to efficiently present exogenous antigens to CD8(+) T cells. Among cellular antigen sources, apoptotic cells are commonly considered as the best for cross-presentation by DCs. However, the potential of live cells as a source of antigen has been overlooked. Here we explored whether DCs were able to capture and cross-present antigens from live cells. DCs internalized cytosolic and membrane material into vesicles from metabolically labeled live cells. Using time-lapse confocal microscopy in whole spleens, we showed that DCs internalized material from live cells in vivo. After ovalbumin uptake from live cells, DCs cross-primed ovalbumin-specific naive OT-I CD8(+) T cells in vitro. Injected into mice previously transferred with naive OT-I T cells, they also cross-primed in vivo, even in the absence of endogenous DCs able to present the epitope in the recipient mice. Interestingly, DCs induced stronger natural CD8(+) T-cell responses and protection against a lethal tumor challenge after capture of antigens from live melanoma cells than from apoptotic melanoma cells. The potential for cross-presentation from live cells uncovers a new type of cellular intercommunication and must be taken into account for induction of tolerance or immunity against self, tumors, grafts, or pathogens.


Asunto(s)
Reactividad Cruzada , Células Dendríticas/inmunología , Animales , Presentación de Antígeno , Apoptosis/inmunología , Linfocitos T CD8-positivos/inmunología , Línea Celular Tumoral , Supervivencia Celular , Inmunidad Celular , Técnicas In Vitro , Melanoma Experimental/inmunología , Melanoma Experimental/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Mutantes , Ovalbúmina/inmunología
12.
Curr Opin Immunol ; 77: 102212, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35644113

RESUMEN

With its unique structure and large numbers of immune cells, the skin is one of the body's first lines of defense against attacks from the environment. It is also innervated by a dense meshwork of primary sensory neurons, including nociceptive fibers specializing in the detection and transduction of harmful stimuli that can elicit pain. This tissue is, therefore, a key organ for studies of neuroimmune interactions and their impact on the host response to environmental challenges. Neuroimmune crosstalk in the skin is crucial for the regulation of inflammation, tissue repair, and host defense against pathogens. A better understanding of this regulation would facilitate the identification of new molecular targets for the treatment of skin diseases.


Asunto(s)
Células Receptoras Sensoriales , Piel , Humanos , Inflamación , Neuroinmunomodulación/fisiología , Dolor , Células Receptoras Sensoriales/fisiología
13.
Nat Commun ; 12(1): 2936, 2021 05 18.
Artículo en Inglés | MEDLINE | ID: mdl-34006861

RESUMEN

Host protection against cutaneous herpes simplex virus 1 (HSV-1) infection relies on the induction of a robust adaptive immune response. Here, we show that Nav1.8+ sensory neurons, which are involved in pain perception, control the magnitude of CD8 T cell priming and expansion in HSV-1-infected mice. The ablation of Nav1.8-expressing sensory neurons is associated with extensive skin lesions characterized by enhanced inflammatory cytokine and chemokine production. Mechanistically, Nav1.8+ sensory neurons are required for the downregulation of neutrophil infiltration in the skin after viral clearance to limit the severity of tissue damage and restore skin homeostasis, as well as for eliciting robust CD8 T cell priming in skin-draining lymph nodes by controlling dendritic cell responses. Collectively, our data reveal an important role for the sensory nervous system in regulating both innate and adaptive immune responses to viral infection, thereby opening up possibilities for new therapeutic strategies.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Herpes Simple/inmunología , Herpesvirus Humano 1/inmunología , Dolor Nociceptivo/inmunología , Células Receptoras Sensoriales/inmunología , Animales , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/virología , Citocinas/inmunología , Citocinas/metabolismo , Femenino , Herpes Simple/genética , Herpes Simple/virología , Herpesvirus Humano 1/fisiología , Humanos , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Canal de Sodio Activado por Voltaje NAV1.8/genética , Canal de Sodio Activado por Voltaje NAV1.8/inmunología , Canal de Sodio Activado por Voltaje NAV1.8/metabolismo , Infiltración Neutrófila/inmunología , Dolor Nociceptivo/genética , Dolor Nociceptivo/metabolismo , Células Receptoras Sensoriales/metabolismo , Células Receptoras Sensoriales/virología , Piel/inmunología , Piel/metabolismo , Piel/virología
14.
FASEB J ; 21(14): 4038-46, 2007 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-17627030

RESUMEN

The chemokine receptor CCR5 plays an important role as an entry gate for the human immunodeficiency virus-1 (HIV-1) and for viral postentry events. Among signal transducers used by chemoattractant receptors, the phosphatidylcholine-specific phospholipase D (PLD) produces large amounts of second messengers in most cell types. However, the relevance of PLD isoforms to CCR5 signaling and HIV-1 infection process remains unexplored. We show here that CCR5 activation by MIP-1beta in HeLa-MAGI cells triggered a rapid and substantial PLD activity, as assessed by mass choline production. This activity required the activation of ERK1/2-MAP kinases and involved both PLD1 and PLD2. MIP-1beta also promoted the activation of an HIV-1 long terminal repeat (LTR) by the transactivator Tat in HeLa P4.2 cells through a process involving ERK1/2. Expression of wild-type and catalytically inactive PLDs dramatically boosted and inhibited the LTR activation, respectively, without altering Tat expression. Wild-type and inactive PLDs also respectively potentiated and inhibited HIV-1(BAL) replication in MAGI cells. Finally, in monocytic THP-1 cells, antisense oligonucleotides to both PLDs dramatically inhibited the HIV-1 replication. Thus, PLD is activated downstream of ERK1/2 upon CCR5 activation and plays a major role in promoting HIV-1 LTR transactivation and virus replication, which may open novel perspectives to anti-HIV-1 strategies.


Asunto(s)
Regulación Viral de la Expresión Génica/fisiología , Duplicado del Terminal Largo de VIH/fisiología , VIH-1/genética , Sistema de Señalización de MAP Quinasas/fisiología , Proteína Quinasa 1 Activada por Mitógenos/fisiología , Proteína Quinasa 3 Activada por Mitógenos/fisiología , Fosfolipasa D/fisiología , Receptores CCR5/fisiología , Colina/biosíntesis , VIH-1/enzimología , VIH-1/fisiología , Células HeLa , Humanos , Fosfolipasa D/metabolismo , Receptores CCR5/metabolismo , Transducción de Señal/fisiología , Activación Transcripcional/genética , Replicación Viral/fisiología
15.
Med Sci (Paris) ; 34(5): 432-438, 2018 May.
Artículo en Francés | MEDLINE | ID: mdl-29900846

RESUMEN

Upon infection, our ability to eliminate pathogens depends mostly on our immune system. However, recent studies have shown that the nervous system plays a role in controlling infectious and inflammatory processes. Bidirectional functional interactions are established between the nervous and immune systems to protect tissue integrity. The skin is one of the first lines of defense against external threats and has a particularly well-developed neuroimmune system. Challenges to the skin activate neurons specialized in pain perception, which regulate immune cell functions and recruitment to tissues. We illustrate the importance of such neuroimmune regulation here, through the example of several skin diseases.


Asunto(s)
Inmunidad/fisiología , Neuroinmunomodulación/fisiología , Dolor/etiología , Fenómenos Fisiológicos de la Piel , Piel/inmunología , Piel/inervación , Animales , Comunicación Celular/inmunología , Humanos , Sistema Inmunológico/fisiopatología , Dolor/inmunología , Dolor/fisiopatología , Fenómenos Fisiológicos de la Piel/inmunología
16.
J Exp Med ; 215(12): 2994-3005, 2018 12 03.
Artículo en Inglés | MEDLINE | ID: mdl-30409784

RESUMEN

The murine epidermis harbors two immune cell lineages, Langerhans cells (LCs) and γδ T cells known as dendritic epidermal T cells (DETCs). LCs develop from both early yolk sac (YS) progenitors and fetal liver monocytes before locally self-renewing in the adult. For DETCs, the mechanisms of homeostatic maintenance and their hematopoietic origin are largely unknown. Here, we exploited multicolor fate mapping systems to reveal that DETCs slowly turn over at steady state. Like for LCs, homeostatic maintenance of DETCs is achieved by clonal expansion of tissue-resident cells assembled in proliferative units. The same mechanism, albeit accelerated, facilitates DETC replenishment upon injury. Hematopoietic lineage tracing uncovered that DETCs are established independently of definitive hematopoietic stem cells and instead originate from YS hematopoiesis, again reminiscent of LCs. DETCs thus resemble LCs concerning their maintenance, replenishment mechanisms, and hematopoietic development, suggesting that the epidermal microenvironment exerts a lineage-independent influence on the initial seeding and homeostatic maintenance of its resident immune cells.


Asunto(s)
Linaje de la Célula/inmunología , Embrión de Mamíferos/inmunología , Epidermis/inmunología , Hematopoyesis Extramedular/inmunología , Células Madre Hematopoyéticas/inmunología , Receptores de Antígenos de Linfocitos T gamma-delta/inmunología , Linfocitos T/inmunología , Saco Vitelino/inmunología , Animales , Embrión de Mamíferos/citología , Células Madre Hematopoyéticas/citología , Ratones , Ratones Transgénicos , Receptores de Antígenos de Linfocitos T gamma-delta/genética , Linfocitos T/citología , Saco Vitelino/citología
17.
Front Immunol ; 6: 486, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26441990

RESUMEN

The origin of tissue-resident macrophages, crucial for homeostasis and immunity, has remained controversial until recently. Originally described as part of the mononuclear phagocyte system, macrophages were long thought to derive solely from adult blood circulating monocytes. However, accumulating evidence now shows that certain macrophage populations are in fact independent from monocyte and even from adult bone marrow hematopoiesis. These tissue-resident macrophages derive from sequential seeding of tissues by two precursors during embryonic development. Primitive macrophages generated in the yolk sac (YS) from early erythro-myeloid progenitors (EMPs), independently of the transcription factor c-Myb and bypassing monocytic intermediates, first give rise to microglia. Later, fetal monocytes, generated from c-Myb(+) EMPs that initially seed the fetal liver (FL), then give rise to the majority of other adult macrophages. Thus, hematopoietic stem cell-independent embryonic precursors transiently present in the YS and the FL give rise to long-lasting self-renewing macrophage populations.

18.
Sci Rep ; 5: 12554, 2015 Jul 30.
Artículo en Inglés | MEDLINE | ID: mdl-26223192

RESUMEN

T cell progenitors are known to arise from the foetal liver in embryos and the bone marrow in adults; however different studies have shown that a pool of T cell progenitors may also exist in the periphery. Here, we identified a lymphoid population resembling peripheral T cell progenitors which transiently seed the epidermis during late embryogenesis in both wild-type and T cell-deficient mice. We named these cells ELCs (Epidermal Lymphoid Cells). ELCs expressed Thy1 and CD2, but lacked CD3 and TCRαß/γδ at their surface, reminiscent of the phenotype of extra- or intra- thymic T cell progenitors. Similarly to Dendritic Epidermal T Cells (DETCs), ELCs were radioresistant and capable of self-renewal. However, despite their progenitor-like phenotype and expression of T cell lineage markers within the population, ELCs did not differentiate into conventional T cells or DETCs in in vitro, ex vivo or in vivo differentiation assays. Finally, we show that ELC expressed NK markers and secreted IFN-γ upon stimulation. Therefore we report the discovery of a unique population of lymphoid cells within the murine epidermis that appears related to NK cells with as-yet-unidentified functions.


Asunto(s)
Epidermis/metabolismo , Animales , Antígenos CD2/metabolismo , Complejo CD3/metabolismo , Diferenciación Celular , Células Cultivadas , Técnicas de Cocultivo , Células Epidérmicas , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Interferón gamma/metabolismo , Interleucina-2/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Desnudos , Microscopía de Fluorescencia por Excitación Multifotónica , Fenotipo , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismo , Linfocitos T/citología , Linfocitos T/inmunología , Antígenos Thy-1/metabolismo
19.
Cell Rep ; 8(5): 1271-9, 2014 Sep 11.
Artículo en Inglés | MEDLINE | ID: mdl-25159150

RESUMEN

Dysfunction of microglia, the tissue macrophages of the brain, has been associated with the etiology of several neuropsychiatric disorders. Consistently, microglia have been shown to regulate neurogenesis and synaptic maturation at perinatal and postnatal stages. However, microglia invade the brain during mid-embryogenesis and thus could play an earlier prenatal role. Here, we show that embryonic microglia, which display a transiently uneven distribution, regulate the wiring of forebrain circuits. Using multiple mouse models, including cell-depletion approaches and cx3cr1(-/-), CR3(-/-), and DAP12(-/-) mutants, we find that perturbing microglial activity affects the outgrowth of dopaminergic axons in the forebrain and the laminar positioning of subsets of neocortical interneurons. Since defects in both dopamine innervation and cortical networks have been linked to neuropsychiatric diseases, our study provides insights into how microglial dysfunction can impact forebrain connectivity and reveals roles for immune cells during normal assembly of brain circuits.


Asunto(s)
Microglía/metabolismo , Neurogénesis , Prosencéfalo/citología , Receptor de Factor Estimulante de Colonias de Macrófagos/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Neuronas Dopaminérgicas/citología , Neuronas Dopaminérgicas/metabolismo , Interneuronas/citología , Interneuronas/metabolismo , Ratones , Ratones Endogámicos C57BL , Prosencéfalo/embriología , Prosencéfalo/fisiología , Receptor de Factor Estimulante de Colonias de Macrófagos/genética , Receptores de Interleucina-8A/genética , Receptores de Interleucina-8A/metabolismo
20.
Front Cell Neurosci ; 7: 45, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23616747

RESUMEN

Microglia are the resident macrophage population of the central nervous system (CNS). Adequate microglial function is crucial for a healthy CNS. Microglia are not only the first immune sentinels of infection, contributing to both innate and adaptive immune responses locally, but are also involved in the maintenance of brain homeostasis. Emerging data are showing new and fundamental roles for microglia in the control of neuronal proliferation and differentiation, as well as in the formation of synaptic connections. While microglia have been studied for decades, a long history of experimental misinterpretation meant that their true origins remained debated. However, recent studies on microglial origin indicate that these cells in fact arise early during development from progenitors in the embryonic yolk sac (YS) that seed the brain rudiment and, remarkably, appear to persist there into adulthood. Here, we review the history of microglial cells and discuss the latest advances in our understanding of their origin, differentiation, and homeostasis, which provides new insights into their roles in health and disease.

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