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1.
Cell ; 166(1): 88-101, 2016 Jun 30.
Artículo en Inglés | MEDLINE | ID: mdl-27293190

RESUMEN

Antibodies to DNA and chromatin drive autoimmunity in systemic lupus erythematosus (SLE). Null mutations and hypomorphic variants of the secreted deoxyribonuclease DNASE1L3 are linked to familial and sporadic SLE, respectively. We report that DNASE1L3-deficient mice rapidly develop autoantibodies to DNA and chromatin, followed by an SLE-like disease. Circulating DNASE1L3 is produced by dendritic cells and macrophages, and its levels inversely correlate with anti-DNA antibody response. DNASE1L3 is uniquely capable of digesting chromatin in microparticles released from apoptotic cells. Accordingly, DNASE1L3-deficient mice and human patients have elevated DNA levels in plasma, particularly in circulating microparticles. Murine and human autoantibody clones and serum antibodies from human SLE patients bind to DNASE1L3-sensitive chromatin on the surface of microparticles. Thus, extracellular microparticle-associated chromatin is a potential self-antigen normally digested by circulating DNASE1L3. The loss of this tolerance mechanism can contribute to SLE, and its restoration may represent a therapeutic opportunity in the disease.


Asunto(s)
Autoanticuerpos/inmunología , Micropartículas Derivadas de Células/química , Cromatina/inmunología , ADN/inmunología , Endodesoxirribonucleasas/genética , Lupus Eritematoso Sistémico/inmunología , Animales , Micropartículas Derivadas de Células/metabolismo , Modelos Animales de Enfermedad , Endodesoxirribonucleasas/deficiencia , Endodesoxirribonucleasas/metabolismo , Humanos , Células Jurkat , Lupus Eritematoso Sistémico/enzimología , Lupus Eritematoso Sistémico/genética , Ratones , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Noqueados
2.
Immunity ; 54(12): 2698-2700, 2021 12 14.
Artículo en Inglés | MEDLINE | ID: mdl-34910939

RESUMEN

The gut houses one of the largest populations of glia in the nervous system, yet their essential functions remain unclear. New work by Progatzky et al. (2021) in Nature reveals that these enteric glia orchestrate an IFNγ-dependent immune response to helminth infection that promotes tissue repair.


Asunto(s)
Intestino Delgado , Neuroglía
3.
Cell ; 158(2): 300-313, 2014 Jul 17.
Artículo en Inglés | MEDLINE | ID: mdl-25036630

RESUMEN

Intestinal peristalsis is a dynamic physiologic process influenced by dietary and microbial changes. It is tightly regulated by complex cellular interactions; however, our understanding of these controls is incomplete. A distinct population of macrophages is distributed in the intestinal muscularis externa. We demonstrate that, in the steady state, muscularis macrophages regulate peristaltic activity of the colon. They change the pattern of smooth muscle contractions by secreting bone morphogenetic protein 2 (BMP2), which activates BMP receptor (BMPR) expressed by enteric neurons. Enteric neurons, in turn, secrete colony stimulatory factor 1 (CSF1), a growth factor required for macrophage development. Finally, stimuli from microbial commensals regulate BMP2 expression by macrophages and CSF1 expression by enteric neurons. Our findings identify a plastic, microbiota-driven crosstalk between muscularis macrophages and enteric neurons that controls gastrointestinal motility. PAPERFLICK:


Asunto(s)
Motilidad Gastrointestinal , Tracto Gastrointestinal/citología , Tracto Gastrointestinal/microbiología , Macrófagos/metabolismo , Animales , Proteína Morfogenética Ósea 2/metabolismo , Receptores de Proteínas Morfogenéticas Óseas de Tipo II/metabolismo , Tracto Gastrointestinal/inervación , Tracto Gastrointestinal/fisiología , Técnicas In Vitro , Factor Estimulante de Colonias de Macrófagos , Ratones , Neuronas/metabolismo , Peristaltismo , Receptor de Factor Estimulante de Colonias de Macrófagos/metabolismo , Transducción de Señal
4.
Immunity ; 45(2): 238-9, 2016 08 16.
Artículo en Inglés | MEDLINE | ID: mdl-27533011

RESUMEN

Type 3 innate lymphoid cells (ILC3s) and enteric glia, an essential structural component of gut innervation, are well-known regulators of intestinal homeostasis. Ibiza et al. (2016) uncover a new link between commensal bacteria, enteric glial cells, and ILC3s that is required for intestinal homeostasis and defense.


Asunto(s)
Disbiosis/genética , Microbioma Gastrointestinal/inmunología , Inmunidad Innata , Intestinos/inmunología , Linfocitos/inmunología , Neuroglía/inmunología , Proteínas Proto-Oncogénicas c-ret/metabolismo , Animales , Técnicas de Silenciamiento del Gen , Factores Neurotróficos Derivados de la Línea Celular Glial/metabolismo , Homeostasis , Humanos , Interleucinas/metabolismo , Intestinos/inervación , Ratones , Neuroglía/microbiología , Proteínas Proto-Oncogénicas c-ret/genética , Simbiosis , Interleucina-22
5.
Nat Immunol ; 13(9): 888-99, 2012 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-22797772

RESUMEN

Although much progress has been made in the understanding of the ontogeny and function of dendritic cells (DCs), the transcriptional regulation of the lineage commitment and functional specialization of DCs in vivo remains poorly understood. We made a comprehensive comparative analysis of CD8(+), CD103(+), CD11b(+) and plasmacytoid DC subsets, as well as macrophage DC precursors and common DC precursors, across the entire immune system. Here we characterized candidate transcriptional activators involved in the commitment of myeloid progenitor cells to the DC lineage and predicted regulators of DC functional diversity in tissues. We identified a molecular signature that distinguished tissue DCs from macrophages. We also identified a transcriptional program expressed specifically during the steady-state migration of tissue DCs to the draining lymph nodes that may control tolerance to self tissue antigens.


Asunto(s)
Diferenciación Celular/inmunología , Linaje de la Célula/inmunología , Células Dendríticas/inmunología , Transcripción Genética , Diferenciación Celular/genética , Células Dendríticas/citología , Perfilación de la Expresión Génica , Humanos
7.
Trends Immunol ; 41(5): 359-362, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-32249062

RESUMEN

There is a major gap in our understanding of how the intestinal immune and nervous systems are integrated to regulate protective adaptations to enteric infections while maintaining tissue homeostasis. Three recent complementary reports published in Cell (2020) provide new mechanistic insights into how this enteric neuro-immune crosstalk may occur.


Asunto(s)
Homeostasis , Enfermedades Intestinales , Intestinos , Sistema Nervioso , Animales , Homeostasis/inmunología , Humanos , Enfermedades Intestinales/inmunología , Enfermedades Intestinales/microbiología , Intestinos/inmunología , Sistema Nervioso/inmunología
8.
Immunity ; 36(6): 1031-46, 2012 Jun 29.
Artículo en Inglés | MEDLINE | ID: mdl-22749353

RESUMEN

GM-CSF (Csf-2) is a critical cytokine for the in vitro generation of dendritic cells (DCs) and is thought to control the development of inflammatory DCs and resident CD103(+) DCs in some tissues. Here we showed that in contrast to the current understanding, Csf-2 receptor acts in the steady state to promote the survival and homeostasis of nonlymphoid tissue-resident CD103(+) and CD11b(+) DCs. Absence of Csf-2 receptor on lung DCs abrogated the induction of CD8(+) T cell immunity after immunization with particulate antigens. In contrast, Csf-2 receptor was dispensable for the differentiation and innate function of inflammatory DCs during acute injuries. Instead, inflammatory DCs required Csf-1 receptor for their development. Thus, Csf-2 is important in vaccine-induced CD8(+) T cell immunity through the regulation of nonlymphoid tissue DC homeostasis rather than control of inflammatory DCs in vivo.


Asunto(s)
Subunidad beta Común de los Receptores de Citocinas/fisiología , Células Dendríticas/inmunología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/fisiología , Inflamación/inmunología , Animales , Linfocitos T CD8-positivos/inmunología , Diferenciación Celular , Linaje de la Célula , Subunidad beta Común de los Receptores de Citocinas/antagonistas & inhibidores , Subunidad beta Común de los Receptores de Citocinas/deficiencia , Subunidad beta Común de los Receptores de Citocinas/genética , Células Dendríticas/clasificación , Células Dendríticas/citología , Encefalomielitis Autoinmune Experimental/inmunología , Endotoxemia/inmunología , Perfilación de la Expresión Génica , Factor Estimulante de Colonias de Granulocitos y Macrófagos/deficiencia , Factor Estimulante de Colonias de Granulocitos y Macrófagos/genética , Homeostasis , Lipopolisacáridos/toxicidad , Listeriosis/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Monocitos/trasplante , Especificidad de Órganos , Infecciones por Orthomyxoviridae/inmunología , Infecciones Neumocócicas/inmunología , Quimera por Radiación , Bazo/inmunología , Tamoxifeno/farmacología
9.
Immunity ; 35(5): 780-91, 2011 Nov 23.
Artículo en Inglés | MEDLINE | ID: mdl-22018469

RESUMEN

Dendritic cells (DCs) in tissues and lymphoid organs comprise distinct functional subsets that differentiate in situ from circulating progenitors. Tissue-specific signals that regulate DC subset differentiation are poorly understood. We report that DC-specific deletion of the Notch2 receptor caused a reduction of DC populations in the spleen. Within the splenic CD11b(+) DC subset, Notch signaling blockade ablated a distinct population marked by high expression of the adhesion molecule Esam. The Notch-dependent Esam(hi) DC subset required lymphotoxin beta receptor signaling, proliferated in situ, and facilitated CD4(+) T cell priming. The Notch-independent Esam(lo) DCs expressed monocyte-related genes and showed superior cytokine responses. In addition, Notch2 deletion led to the loss of CD11b(+)CD103(+) DCs in the intestinal lamina propria and to a corresponding decrease of IL-17-producing CD4(+) T cells in the intestine. Thus, Notch2 is a common differentiation signal for T cell-priming CD11b(+) DC subsets in the spleen and intestine.


Asunto(s)
Diferenciación Celular , Células Dendríticas/citología , Células Dendríticas/inmunología , Intestinos/inmunología , Receptor Notch2/metabolismo , Transducción de Señal , Bazo/inmunología , Animales , Diferenciación Celular/inmunología , Células Cultivadas , Células Dendríticas/metabolismo , Femenino , Perfilación de la Expresión Génica , Regulación del Desarrollo de la Expresión Génica , Proteína de Unión a la Señal Recombinante J de las Inmunoglobulinas/metabolismo , Mucosa Intestinal/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Fenotipo , Bazo/metabolismo , Tirosina Quinasa 3 Similar a fms/genética
10.
Proc Natl Acad Sci U S A ; 114(18): E3709-E3718, 2017 05 02.
Artículo en Inglés | MEDLINE | ID: mdl-28420791

RESUMEN

According to current dogma, there is little or no ongoing neurogenesis in the fully developed adult enteric nervous system. This lack of neurogenesis leaves unanswered the question of how enteric neuronal populations are maintained in adult guts, given previous reports of ongoing neuronal death. Here, we confirm that despite ongoing neuronal cell loss because of apoptosis in the myenteric ganglia of the adult small intestine, total myenteric neuronal numbers remain constant. This observed neuronal homeostasis is maintained by new neurons formed in vivo from dividing precursor cells that are located within myenteric ganglia and express both Nestin and p75NTR, but not the pan-glial marker Sox10. Mutation of the phosphatase and tensin homolog gene in this pool of adult precursors leads to an increase in enteric neuronal number, resulting in ganglioneuromatosis, modeling the corresponding disorder in humans. Taken together, our results show significant turnover and neurogenesis of adult enteric neurons and provide a paradigm for understanding the enteric nervous system in health and disease.


Asunto(s)
Apoptosis , Sistema Nervioso Entérico/metabolismo , Nestina/metabolismo , Neurogénesis , Receptores de Factor de Crecimiento Nervioso/metabolismo , Factores de Transcripción SOXE/metabolismo , Animales , Humanos , Ratones , Ratones Transgénicos , Nestina/genética , Receptores de Factor de Crecimiento Nervioso/genética , Factores de Transcripción SOXE/genética
11.
J Neurosci ; 38(44): 9346-9354, 2018 10 31.
Artículo en Inglés | MEDLINE | ID: mdl-30381426

RESUMEN

The enteric nervous system (ENS) is a large, complex division of the peripheral nervous system that regulates many digestive, immune, hormonal, and metabolic functions. Recent advances have elucidated the dynamic nature of the mature ENS, as well as the complex, bidirectional interactions among enteric neurons, glia, and the many other cell types that are important for mediating gut behaviors. Here, we provide an overview of ENS development and maintenance, and focus on the latest insights gained from the use of novel model systems and live-imaging techniques. We discuss major advances in the understanding of enteric glia, and the functional interactions among enteric neurons, glia, and enteroendocrine cells, a large class of sensory epithelial cells. We conclude by highlighting recent work on muscularis macrophages, a group of immune cells that closely interact with the ENS in the gut wall, and the importance of neurological-immune system communication in digestive health and disease.


Asunto(s)
Encéfalo/metabolismo , Sistema Nervioso Entérico/metabolismo , Enfermedades Gastrointestinales/metabolismo , Tracto Gastrointestinal/metabolismo , Animales , Encéfalo/inmunología , Encéfalo/patología , Sistema Nervioso Entérico/inmunología , Sistema Nervioso Entérico/patología , Enfermedades Gastrointestinales/inmunología , Enfermedades Gastrointestinales/patología , Tracto Gastrointestinal/inmunología , Tracto Gastrointestinal/patología , Humanos , Neurobiología
12.
Trends Immunol ; 37(7): 487-501, 2016 07.
Artículo en Inglés | MEDLINE | ID: mdl-27289177

RESUMEN

The gastrointestinal (GI) tract is the largest immune organ; in vertebrates, it is the only organ whose function is controlled by its own intrinsic enteric nervous system (ENS), but it is additionally regulated by extrinsic (sympathetic and parasympathetic) innervation. The GI nervous and immune systems are highly integrated in their common goal, which is to unite digestive functions with protection from ingested environmental threats. This review discusses the physiological relevance of enteric neuroimmune integration by summarizing the current knowledge of evolutionary and developmental pathways, cellular organization, and molecular mechanisms of neuroimmune interactions in health and disease.


Asunto(s)
Tracto Gastrointestinal/inmunología , Sistema Inmunológico , Inmunidad Mucosa , Sistema Nervioso , Neuroinmunomodulación , Animales , Evolución Biológica , Tracto Gastrointestinal/inervación , Homeostasis , Humanos , Tolerancia Inmunológica
13.
Immunity ; 33(4): 597-606, 2010 Oct 29.
Artículo en Inglés | MEDLINE | ID: mdl-20933441

RESUMEN

Dendritic cells (DCs) comprise distinct functional subsets including CD8⁻ and CD8(+) classical DCs (cDCs) and interferon-secreting plasmacytoid DCs (pDCs). The cytokine Flt3 ligand (Flt3L) controls the development of DCs and is particularly important for the pDC and CD8(+) cDC and their CD103(+) tissue counterparts. We report that mammalian target of rapamycin (mTOR) inhibitor rapamycin impaired Flt3L-driven DC development in vitro, with the pDCs and CD8(+)-like cDCs most profoundly affected. Conversely, deletion of the phosphoinositide 3-kinase (PI3K)-mTOR negative regulator Pten facilitated Flt3L-driven DC development in culture. DC-specific Pten targeting in vivo caused the expansion of CD8(+) and CD103(+) cDC numbers, which was reversible by rapamycin. The increased CD8(+) cDC numbers caused by Pten deletion correlated with increased susceptibility to the intracellular pathogen Listeria. Thus, PI3K-mTOR signaling downstream of Flt3L controls DC development, and its restriction by Pten ensures optimal DC pool size and subset composition.


Asunto(s)
Células Dendríticas/fisiología , Péptidos y Proteínas de Señalización Intracelular/fisiología , Proteínas de la Membrana/fisiología , Proteínas Serina-Treonina Quinasas/fisiología , Transducción de Señal/fisiología , Animales , Antígenos CD/análisis , Linfocitos T CD8-positivos/inmunología , Células Cultivadas , Cadenas alfa de Integrinas/análisis , Listeriosis/inmunología , Ratones , Ratones Endogámicos C57BL , Fosfohidrolasa PTEN/fisiología , Fosfatidilinositol 3-Quinasas/fisiología , Sirolimus/farmacología , Serina-Treonina Quinasas TOR
14.
Immunity ; 31(3): 513-25, 2009 Sep 18.
Artículo en Inglés | MEDLINE | ID: mdl-19733489

RESUMEN

CX(3)CR1(+) and CD103(+) dendritic cells (DCs) in intestinal lamina propria play a key role in mucosal immunity. However, the origin and the developmental pathways that regulate their differentiation in the lamina propria remain unclear. We showed that monocytes gave rise exclusively to CD103(-)CX(3)CR1(+) lamina propria DCs under the control of macrophage-colony-stimulating factor receptor (M-CSFR) and Fms-like thyrosine kinase 3 (Flt3) ligands. In contrast, common DC progenitors (CDP) and pre-DCs, which give rise to lymphoid organ DCs but not to monocytes, differentiated exclusively into CD103(+)CX(3)CR1(-) lamina propria DCs under the control of Flt3 and granulocyte-macrophage-colony-stimulating factor receptor (GM-CSFR) ligands. CD103(+)CX(3)CR1(-) DCs but not CD103(-)CX(3)CR1(+) DCs in the lamina propria constitutively expressed CCR7 and were the first DCs to transport pathogenic Salmonella from the intestinal tract to the mesenteric lymph nodes. Altogether, these results underline the diverse origin of the lamina propria DC network and identify mucosal DCs that arise from pre-DCs as key sentinels of the gut immune system.


Asunto(s)
Linaje de la Célula , Células Dendríticas/citología , Células Dendríticas/inmunología , Mucosa Intestinal/citología , Mucosa Intestinal/inmunología , Animales , Antígenos CD/inmunología , Receptor 1 de Quimiocinas CX3C , Diferenciación Celular , Movimiento Celular , Cadenas alfa de Integrinas/inmunología , Ganglios Linfáticos/inmunología , Ratones , Ratones Noqueados , Fenotipo , Receptor de Factor Estimulante de Colonias de Macrófagos/inmunología , Receptores de Quimiocina/inmunología , Salmonella/inmunología , Salmonella/patogenicidad , Tirosina Quinasa 3 Similar a fms/deficiencia , Tirosina Quinasa 3 Similar a fms/genética , Tirosina Quinasa 3 Similar a fms/inmunología
15.
J Immunol ; 189(5): 2614-24, 2012 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-22855714

RESUMEN

Although peroxisome proliferator-activated receptor γ (PPARγ) has anti-inflammatory actions in macrophages, which macrophage populations express PPARγ in vivo and how it regulates tissue homeostasis in the steady state and during inflammation remains unclear. We now show that lung and spleen macrophages selectively expressed PPARγ among resting tissue macrophages. In addition, Ly-6C(hi) monocytes recruited to an inflammatory site induced PPARγ as they differentiated to macrophages. When PPARγ was absent in Ly-6C(hi)-derived inflammatory macrophages, initiation of the inflammatory response was unaffected, but full resolution of inflammation failed, leading to chronic leukocyte recruitment. Conversely, PPARγ activation favored resolution of inflammation in a macrophage PPARγ-dependent manner. In the steady state, PPARγ deficiency in red pulp macrophages did not induce overt inflammation in the spleen. By contrast, PPARγ deletion in lung macrophages induced mild pulmonary inflammation at the steady state and surprisingly precipitated mortality upon infection with Streptococcus pneumoniae. This accelerated mortality was associated with impaired bacterial clearance and inability to sustain macrophages locally. Overall, we uncovered critical roles for macrophage PPARγ in promoting resolution of inflammation and maintaining functionality in lung macrophages where it plays a pivotal role in supporting pulmonary host defense. In addition, this work identifies specific macrophage populations as potential targets for the anti-inflammatory actions of PPARγ agonists.


Asunto(s)
Resistencia a la Enfermedad/inmunología , Mediadores de Inflamación/fisiología , Pulmón/inmunología , Pulmón/patología , Macrófagos Alveolares/inmunología , Macrófagos Alveolares/patología , PPAR gamma/fisiología , Animales , Regulación de la Expresión Génica/inmunología , Inflamación/inmunología , Inflamación/microbiología , Inflamación/prevención & control , Mediadores de Inflamación/metabolismo , Mediadores de Inflamación/uso terapéutico , Pulmón/microbiología , Macrófagos Alveolares/microbiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , PPAR gamma/biosíntesis , PPAR gamma/deficiencia , Streptococcus pneumoniae/inmunología
16.
Immunol Rev ; 234(1): 55-75, 2010 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-20193012

RESUMEN

Dendritic cells (DCs) have been extensively studied in mice lymphoid organs, but less is known about the origin and the mechanisms that regulate DC development and function in non-lymphoid tissues. Here, we discuss recent evidence establishing the contribution of the DC-restricted lineage to the non-lymphoid tissue DC pool and discuss the mechanisms that control the homeostasis of non-lymphoid tissue DCs. We also review recent results underlining the functional specialization of tissue DCs and discuss the potential implications of these findings in tissue immunity and in the development of novel vaccine strategies.


Asunto(s)
Diferenciación Celular , Linaje de la Célula , Células Dendríticas/inmunología , Células Madre Hematopoyéticas/inmunología , Animales , Diferenciación Celular/inmunología , Linaje de la Célula/inmunología , Citocinas/inmunología , Células Dendríticas/metabolismo , Células Madre Hematopoyéticas/metabolismo , Homeostasis , Mediadores de Inflamación/inmunología , Ratones , Fenotipo , Factores de Transcripción/metabolismo , Vacunas/inmunología
17.
J Exp Med ; 203(12): 2627-38, 2006 Nov 27.
Artículo en Inglés | MEDLINE | ID: mdl-17116734

RESUMEN

In this study, we explored dermal dendritic cell (DC) homeostasis in mice and humans both in the steady state and after hematopoietic cell transplantation. We discovered that dermal DCs proliferate in situ in mice and human quiescent dermis. In parabiotic mice with separate organs but shared blood circulation, the majority of dermal DCs failed to be replaced by circulating precursors for >6 mo. In lethally irradiated mice injected with donor congenic bone marrow (BM) cells, a subset of recipient DCs remained in the dermis and proliferated locally throughout life. Consistent with these findings, a large proportion of recipient dermal DCs remained in patients' skin after allogeneic hematopoietic cell transplantation, despite complete donor BM chimerism. Collectively, our results oppose the traditional view that DCs are nondividing terminally differentiated cells maintained by circulating precursors and support the new paradigm that tissue DCs have local proliferative properties that control their homeostasis in the steady state. Given the role of residual host tissue DCs in transplant immune reactions, these results suggest that dermal DC homeostasis may contribute to the development of cutaneous graft-versus-host disease in clinical transplantation.


Asunto(s)
Ciclo Celular/inmunología , Células Dendríticas/clasificación , Células Dendríticas/efectos de la radiación , Quimera por Radiación , Piel/citología , Piel/inmunología , Enfermedad Aguda , Animales , Trasplante de Médula Ósea/inmunología , Trasplante de Médula Ósea/patología , Ciclo Celular/genética , Proliferación Celular , Células Cultivadas , Células Dendríticas/citología , Células Dendríticas/inmunología , Enfermedad Injerto contra Huésped/genética , Enfermedad Injerto contra Huésped/inmunología , Enfermedad Injerto contra Huésped/patología , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Especificidad de Órganos/genética , Especificidad de Órganos/inmunología , Quimera por Radiación/genética , Quimera por Radiación/inmunología , Piel/patología
18.
Curr Opin Immunol ; 68: 64-71, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33130386

RESUMEN

The gastrointestinal (GI) tract performs a set of vital physiological functions related to food and water consumption. To help regulate these complex physiological processes, the GI tract is innervated by extensive neural networks. The GI tract also serves as the largest immune organ aimed to protect hosts from harmful microbes and toxins ingested with food. It emerges that the enteric nervous and immune systems are highly integrated to optimize digestion while reinforcing immune protection. In this review, we will discuss key cellular players involved in the neuro-immune interactions within the GI mucosa with the focus on the recently uncovered neural pathways that regulate mucosal immunity in a context relevant to GI health and disease.


Asunto(s)
Microbioma Gastrointestinal/inmunología , Neuroinmunomodulación/inmunología , Animales , Tracto Gastrointestinal/inmunología , Humanos
19.
Gastroenterology ; 137(3): 1006-18, 1018.e1-3, 2009 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-19501588

RESUMEN

BACKGROUND & AIMS: Chemokines are small proteins that direct leukocyte trafficking under homeostatic and inflammatory conditions. We analyzed the differential expression of chemokines in distinct segments of the intestine and investigated the importance of chemokines for the distribution of leukocytes in the intestine during homeostatic and inflammatory conditions. METHODS: We analyzed messenger RNA for all known chemokines in different segments of the gut by quantitative polymerase chain reaction. To study the effect of multiple-chemokine blockade in the gut, we generated transgenic mice that expressed the chemokine binding protein M3 in the intestine (V-M3 mice). We used flow cytometry to evaluate the changes in the numbers of leukocytes. RESULTS: We observed distinct chemokine expression profiles in the 6 segments of the gut. Some chemokines were expressed throughout the intestine (CCL28, CCL6, CXCL16, and CX3CL1), whereas others were expressed preferentially in the small (CCL25 and CCL5) or large intestine (CCL19, CCL21, and CXCL5). Expression of the chemokine blocker M3 in intestinal epithelial cells resulted in reduced numbers of B and T cells in Peyer's patches, reduced numbers of intraepithelial CD8alphabeta(+)/TCRalphabeta(+) and CD8alphaalpha(+)/TCRalphabeta(+) T cells, and reduced numbers of lamina propria CD8(+) T cells. Strikingly, M3 expression markedly reduced the number of eosinophils and macrophages in the small and large intestines. Dextran sulfate sodium treatment of control mice led to marked changes in the expression of chemokines and in the number of myeloid cells in the colon. These cellular changes were significantly attenuated in the presence of M3. CONCLUSIONS: Our study reveals a complex pattern of chemokine expression in the intestine and indicates that chemokines are critical for leukocyte accumulation in the intestine during homeostasis and inflammation.


Asunto(s)
Quimiocinas/metabolismo , Intestinos/inmunología , Subgrupos Linfocitarios , Receptores de Quimiocina/metabolismo , Proteínas Virales/metabolismo , Animales , Técnicas In Vitro , Mucosa Intestinal/metabolismo , Ratones , Ratones Transgénicos , Ganglios Linfáticos Agregados/citología
20.
Sci Immunol ; 5(46)2020 04 10.
Artículo en Inglés | MEDLINE | ID: mdl-32276965

RESUMEN

Intestinal mononuclear phagocytes (MPs) are composed of heterogeneous dendritic cell (DC) and macrophage subsets necessary for the initiation of immune response and control of inflammation. Although MPs in the normal intestine have been extensively studied, the heterogeneity and function of inflammatory MPs remain poorly defined. We performed phenotypical, transcriptional, and functional analyses of inflammatory MPs in infectious Salmonella colitis and identified CX3CR1+ MPs as the most prevalent inflammatory cell type. CX3CR1+ MPs were further divided into three distinct populations, namely, Nos2 +CX3CR1lo, Ccr7 +CX3CR1int (lymph migratory), and Cxcl13 +CX3CR1hi (mucosa resident), all of which were transcriptionally aligned with macrophages and derived from monocytes. In follow-up experiments in vivo, intestinal CX3CR1+ macrophages were superior to conventional DC1 (cDC1) and cDC2 in inducing Salmonella-specific mucosal IgA. We next examined spatial organization of the immune response induced by CX3CR1+ macrophage subsets and identified mucosa-resident Cxcl13 +CX3CR1hi macrophages as the antigen-presenting cells responsible for recruitment and activation of CD4+ T and B cells to the sites of Salmonella invasion, followed by tertiary lymphoid structure formation and the local pathogen-specific IgA response. Using mice we developed with a floxed Ccr7 allele, we showed that this local IgA response developed independently of migration of the Ccr7 +CX3CR1int population to the mesenteric lymph nodes and contributed to the total mucosal IgA response to infection. The differential activity of intestinal macrophage subsets in promoting mucosal IgA responses should be considered in the development of vaccines to prevent Salmonella infection and in the design of anti-inflammatory therapies aimed at modulating macrophage function in inflammatory bowel disease.


Asunto(s)
Receptor 1 de Quimiocinas CX3C/inmunología , Inmunoglobulina A/inmunología , Mucosa Intestinal/inmunología , Macrófagos/inmunología , Estructuras Linfoides Terciarias/inmunología , Animales , Femenino , Microbioma Gastrointestinal/inmunología , Inflamación/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Salmonella enterica/inmunología , Estreptomicina
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