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1.
Immunity ; 55(8): 1431-1447.e11, 2022 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-35830859

RESUMO

Conventional dendritic cells (cDCs) consist of two major functionally and phenotypically distinct subsets, cDC1 and cDC2, whose development is dependent on distinct sets of transcription factors. Interferon regulatory factor 8 (IRF8) is required at multiple stages of cDC1 development, but its role in committed cDC1 remains unclear. Here, we used Xcr1-cre to delete Irf8 in committed cDC1 and demonstrate that Irf8 is required for maintaining the identity of cDC1. In the absence of Irf8, committed cDC1 acquired the transcriptional, functional, and chromatin accessibility properties of cDC2. This conversion was independent of Irf4 and was associated with the decreased accessibility of putative IRF8, Batf3, and composite AP-1-IRF (AICE)-binding elements, together with increased accessibility of cDC2-associated transcription-factor-binding elements. Thus, IRF8 expression by committed cDC1 is required for preventing their conversion into cDC2-like cells.


Assuntos
Células Dendríticas , Fatores Reguladores de Interferon , Células Dendríticas/metabolismo , Epigênese Genética , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/metabolismo
2.
Nat Immunol ; 15(10): 929-937, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25151491

RESUMO

The paradigm that macrophages that reside in steady-state tissues are derived from embryonic precursors has never been investigated in the intestine, which contains the largest pool of macrophages. Using fate-mapping models and monocytopenic mice, together with bone marrow chimera and parabiotic models, we found that embryonic precursor cells seeded the intestinal mucosa and demonstrated extensive in situ proliferation during the neonatal period. However, these cells did not persist in the intestine of adult mice. Instead, they were replaced around the time of weaning by the chemokine receptor CCR2-dependent influx of Ly6C(hi) monocytes that differentiated locally into mature, anti-inflammatory macrophages. This process was driven largely by the microbiota and had to be continued throughout adult life to maintain a normal intestinal macrophage pool.


Assuntos
Mucosa Intestinal/imunologia , Intestinos/imunologia , Macrófagos/imunologia , Monócitos/imunologia , Animais , Animais Recém-Nascidos , Antígenos de Diferenciação/genética , Antígenos de Diferenciação/imunologia , Antígenos de Diferenciação/metabolismo , Antígenos Ly/imunologia , Antígenos Ly/metabolismo , Transplante de Medula Óssea , Antígeno CD11b/genética , Antígeno CD11b/imunologia , Antígeno CD11b/metabolismo , Receptor 1 de Quimiocina CX3C , Diferenciação Celular/imunologia , Proliferação de Células , Citometria de Fluxo , Expressão Gênica/imunologia , Mucosa Intestinal/citologia , Mucosa Intestinal/metabolismo , Intestinos/citologia , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Modelos Imunológicos , Monócitos/metabolismo , Parabiose , Receptores CCR2/genética , Receptores CCR2/imunologia , Receptores CCR2/metabolismo , Receptores de Quimiocinas/genética , Receptores de Quimiocinas/imunologia , Receptores de Quimiocinas/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Tempo
3.
Nat Immunol ; 18(6): 599-600, 2017 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-28518159

Assuntos
Monócitos , Humanos
4.
Immunity ; 40(3): 311-2, 2014 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-24656043

RESUMO

In this issue of Immunity, Kim et al. (2014) propose that CD103(+) DCs in mouse lung selectively generate effector CD8(+) T cells by binding the alarmin HMGB1 via CD24 and presenting it to RAGE(+) T cells.


Assuntos
Antígeno CD24/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Diferenciação Celular/imunologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Memória Imunológica , Animais , Feminino
5.
Eur J Immunol ; 51(12): 3228-3238, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34633664

RESUMO

The use of bacteria as an alternative cancer therapy has been reinvestigated in recent years. SL7207: an auxotrophic Salmonella enterica serovar Typhimurium aroA mutant with immune-stimulatory potential has proven a promising strain for this purpose. Here, we show that systemic administration of SL7207 induces melanoma tumor growth arrest in vivo, with greater survival of the SL7207-treated group compared to control PBS-treated mice. Administration of SL7207 is accompanied by a change in the immune phenotype of the tumor-infiltrating cells toward pro-inflammatory, with expression of the TH 1 cytokines IFN-γ, TNF-α, and IL-12 significantly increased. Interestingly, Ly6C+ MHCII+ monocytes were recruited to the tumors following SL7207 treatment and were pro-inflammatory. Accordingly, the abrogation of these infiltrating monocytes using clodronate liposomes prevented SL7207-induced tumor growth inhibition. These data demonstrate a previously unappreciated role for infiltrating inflammatory monocytes underlying bacterial-mediated tumor growth inhibition. This information highlights a possible novel role for monocytes in controlling tumor growth, contributing to our understanding of the immune responses required for successful immunotherapy of cancer.


Assuntos
Imunoterapia , Melanoma Experimental , Monócitos/imunologia , Salmonella typhimurium/imunologia , Células Th1/imunologia , Animais , Citocinas/imunologia , Feminino , Melanoma Experimental/imunologia , Melanoma Experimental/terapia , Camundongos , Salmonella typhimurium/genética
6.
J Immunol ; 201(1): 215-229, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29760193

RESUMO

Atypical chemokine receptors (ACKRs) are expressed by discrete populations of stromal cells at specific anatomical locations where they control leukocyte migration by scavenging or transporting chemokines. ACKR4 is an atypical receptor for CCL19, CCL21, and CCL25. In skin, ACKR4 plays indispensable roles in regulating CCR7-dependent APC migration, and there is a paucity of migratory APCs in the skin-draining lymph nodes of Ackr4-deficient mice under steady-state and inflammatory conditions. This is caused by loss of ACKR4-mediated CCL19/21 scavenging by keratinocytes and lymphatic endothelial cells. In contrast, we show in this study that Ackr4 deficiency does not affect dendritic cell abundance in the small intestine and mesenteric lymph nodes, at steady state or after R848-induced mobilization. Moreover, Ackr4 expression is largely restricted to mesenchymal cells in the intestine, where it identifies a previously uncharacterized population of fibroblasts residing exclusively in the submucosa. Compared with related Ackr4- mesenchymal cells, these Ackr4+ fibroblasts have elevated expression of genes encoding endothelial cell regulators and lie in close proximity to submucosal blood and lymphatic vessels. We also provide evidence that Ackr4+ fibroblasts form physical interactions with lymphatic endothelial cells, and engage in molecular interactions with these cells via the VEGFD/VEGFR3 and CCL21/ACKR4 pathways. Thus, intestinal submucosal fibroblasts in mice are a distinct population of intestinal mesenchymal cells that can be identified by their expression of Ackr4 and have transcriptional and anatomical properties that strongly suggest roles in endothelial cell regulation.


Assuntos
Células Endoteliais/metabolismo , Fibroblastos/metabolismo , Mucosa Intestinal/metabolismo , Receptores CCR/metabolismo , Animais , Movimento Celular/fisiologia , Quimiocina CCL21/metabolismo , Colite/induzido quimicamente , Colite/patologia , Células Dendríticas/citologia , Sulfato de Dextrana/toxicidade , Feminino , Mucosa Intestinal/citologia , Leucócitos/fisiologia , Mesoderma/citologia , Mesoderma/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores CCR/genética , Fator D de Crescimento do Endotélio Vascular/metabolismo , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/metabolismo
7.
Eur J Immunol ; 48(7): 1181-1187, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29676784

RESUMO

Macrophages play a crucial role in maintaining homeostasis in the intestine, but the underlying mechanisms have not yet been elucidated fully. Here, we show for the first time that mature intestinal macrophages in mouse intestine express high levels of αvß5 integrin, which acts as a receptor for the uptake of apoptotic cells and can activate molecules involved in several aspects of tissue homeostasis such as angiogenesis and remodeling of the ECM. αvß5 is not expressed by other immune cells in the intestine, is already present on intestinal macrophages soon after birth, and its expression is not dependent on the microbiota. In adults, αvß5 is induced during the differentiation of monocytes in response to the local environment and it confers intestinal macrophages with the ability to promote engulfment of apoptotic cells via engagement of the bridging molecule milk fat globule EGF-like molecule 8. In the absence of αvß5, there are fewer monocytes in the mucosa and mature intestinal macrophages have decreased expression of metalloproteases and IL 10. Mice lacking αvß5 on haematopoietic cells show increased susceptibility to chemical colitis and we conclude that αvß5 contributes to the tissue repair by regulating the homeostatic properties of intestinal macrophages.


Assuntos
Colite/imunologia , Integrina alfa5/metabolismo , Mucosa Intestinal/metabolismo , Intestinos/imunologia , Macrófagos/metabolismo , Animais , Células Cultivadas , Colite/induzido quimicamente , Fator de Crescimento Epidérmico/metabolismo , Regulação da Expressão Gênica , Homeostase , Humanos , Integrina alfa5/genética , Macrófagos/imunologia , Metaloproteases/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fagocitose , Receptores de Vitronectina/genética , Receptores de Vitronectina/metabolismo , Quimeras de Transplante
8.
Immunol Rev ; 260(1): 102-17, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24942685

RESUMO

The intestine contains the largest pool of macrophages in the body which are essential for maintaining mucosal homeostasis in the face of the microbiota and the constant need for epithelial renewal but are also important components of protective immunity and are involved in the pathology of inflammatory bowel disease (IBD). However, defining the biological roles of intestinal macrophages has been impeded by problems in defining the phenotype and origins of different populations of myeloid cells in the mucosa. Here, we discuss how multiple parameters can be used in combination to discriminate between functionally distinct myeloid cells and discuss the roles of macrophages during homeostasis and how these may change when inflammation ensues. We also discuss the evidence that intestinal macrophages do not fit the current paradigm that tissue-resident macrophages are derived from embryonic precursors that self-renew in situ, but require constant replenishment by blood monocytes. We describe our recent work demonstrating that classical monocytes constantly enter the intestinal mucosa and how the environment dictates their subsequent fate. We believe that understanding the factors that drive intestinal macrophage development in the steady state and how these may change in response to pathogens or inflammation could provide important insights into the treatment of IBD.


Assuntos
Homeostase , Inflamação/imunologia , Mucosa Intestinal/imunologia , Intestinos/imunologia , Macrófagos/imunologia , Animais , Modelos Animais de Doenças , Humanos , Tolerância Imunológica , Inflamação/genética , Inflamação/metabolismo , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/metabolismo , Mucosa Intestinal/metabolismo , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Ativação de Macrófagos/genética , Ativação de Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Monócitos/imunologia , Monócitos/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
9.
Eur J Immunol ; 44(12): 3658-68, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25236797

RESUMO

Signal regulatory protein alpha (SIRPα/CD172a) is a conserved transmembrane protein thought to play an inhibitory role in immune function by binding the ubiquitous ligand CD47. SIRPα expression has been used to identify dendritic cell subsets across species and here we examined its expression and function on intestinal DCs in mice. Normal mucosa contains four subsets of DCs based on their expression of CD103 and CD11b and three of these express SIRPα. However, loss of SIRPα signaling in mice leads to a selective reduction in the CD103(+) CD11b(+) subset of DCs in the small intestine, colon, and among migratory DCs in the mesenteric lymph node. In parallel, these mice have reduced numbers of TH 17 cells in steady-state intestinal mucosa, and a defective TH 17 response to Citrobacter infection. Identical results were obtained in CD47KO mice. DC precursors from SIRPα mutant mice had an enhanced ability to generate CD103(+) CD11b(+) DCs in vivo, but CD103(+) CD11b(+) DCs from mutant mice were more prone to die by apoptosis. These data show a previously unappreciated and crucial role for SIRPα in the homeostasis of CD103(+) CD11b(+) DCs in the intestine, as well as providing further evidence that this subset of DCs is critical for the development of mucosal TH 17 responses.


Assuntos
Antígenos CD/imunologia , Antígeno CD11b/imunologia , Células Dendríticas/imunologia , Homeostase/fisiologia , Imunidade nas Mucosas/fisiologia , Cadeias alfa de Integrinas/imunologia , Mucosa Intestinal/imunologia , Receptores Imunológicos/imunologia , Animais , Antígenos CD/genética , Apoptose/genética , Apoptose/imunologia , Antígeno CD11b/genética , Citrobacter/genética , Citrobacter/imunologia , Células Dendríticas/citologia , Infecções por Enterobacteriaceae/genética , Infecções por Enterobacteriaceae/imunologia , Cadeias alfa de Integrinas/genética , Mucosa Intestinal/citologia , Linfonodos/citologia , Linfonodos/imunologia , Mesentério/citologia , Mesentério/imunologia , Camundongos , Camundongos Mutantes , Receptores Imunológicos/genética , Células Th17/citologia , Células Th17/imunologia
10.
Nat Rev Immunol ; 3(4): 331-41, 2003 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-12669023

RESUMO

The intestinal immune system has to discriminate between harmful and beneficial antigens. Although strong protective immunity is essential to prevent invasion by pathogens, equivalent responses against dietary proteins or commensal bacteria can lead to chronic disease. These responses are normally prevented by a complex interplay of regulatory mechanisms. This article reviews the unique aspects of the local microenvironment of the intestinal immune system and discuss how these promote the development of regulatory responses that ensure the maintenance of homeostasis in the gut.


Assuntos
Tolerância Imunológica , Intestinos/anatomia & histologia , Intestinos/imunologia , Administração Oral , Animais , Antígenos/administração & dosagem , Células Dendríticas/imunologia , Humanos , Mucosa Intestinal/anatomia & histologia , Mucosa Intestinal/imunologia , Linfonodos/anatomia & histologia , Linfonodos/imunologia , Tecido Linfoide/anatomia & histologia , Tecido Linfoide/imunologia , Camundongos , Modelos Imunológicos , Nódulos Linfáticos Agregados/anatomia & histologia , Nódulos Linfáticos Agregados/imunologia , Linfócitos T/imunologia
11.
Eur J Immunol ; 43(12): 3098-107, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23966272

RESUMO

The intestinal mucosa is exposed to large amounts of foreign antigen (Ag) derived from commensal bacteria, dietary Ags, and intestinal pathogens. Dendritic cells (DCs) are believed to be involved in the induction of tolerance to harmless Ags and in mounting protective immune responses to pathogens and, as such, to play key roles in regulating intestinal immune homeostasis. The characterization of classical DCs (cDCs) in the intestinal lamina propria has been under intense investigation in recent years but the use of markers (including CD11c, CD11b, MHC class II), which are also expressed by intestinal MΦs, has led to some controversy regarding their definition. Here we review recent studies that help to distinguish cDCs subsets from monocyte-derived cells in the intestinal mucosa. We address the phenotype and ontogeny of these cDC subsets and highlight recent findings indicating that these subsets play distinct roles in the regulation of mucosal immune responses in vivo.


Assuntos
Antígenos de Diferenciação/imunologia , Células Dendríticas/imunologia , Imunidade nas Mucosas/fisiologia , Macrófagos/imunologia , Monócitos/imunologia , Mucosa/imunologia , Animais , Antígenos/imunologia , Células Dendríticas/citologia , Humanos , Tolerância Imunológica/fisiologia , Macrófagos/citologia , Monócitos/citologia , Mucosa/citologia
12.
Cell Immunol ; 291(1-2): 41-8, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24726741

RESUMO

Macrophages are one of the most abundant leucocytes in the intestinal mucosa where they are essential for maintaining homeostasis. However, they are also implicated in the pathogenesis of disorders such as inflammatory bowel disease (IBD), offering potential targets for novel therapies. Here we discuss the function of intestinal monocytes and macrophages during homeostasis and describe how these populations and their functions change during infection and inflammation. Furthermore, we review the current evidence that the intestinal macrophage pool requires continual renewal from circulating blood monocytes, unlike most other tissue macrophages which appear to derive from primitive precursors that subsequently self-renew.


Assuntos
Gastroenteropatias/imunologia , Inflamação/imunologia , Mucosa Intestinal/imunologia , Macrófagos/imunologia , Monócitos/imunologia , Imunidade Adaptativa , Animais , Diferenciação Celular/imunologia , Gastroenteropatias/sangue , Homeostase , Humanos , Inflamação/sangue , Inflamação/patologia , Mucosa Intestinal/patologia , Macrófagos/citologia , Macrófagos/patologia , Camundongos , Monócitos/citologia , Monócitos/patologia
13.
Trends Immunol ; 32(9): 412-9, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21816673

RESUMO

CD103(+) dendritic cells (DCs) in the intestinal mucosa play a crucial role in tolerance to commensal bacteria and food antigens. These cells originate in the lamina propria (LP) and migrate to the mesenteric lymph nodes (MLNs), where they drive the differentiation of gut-homing FoxP3(+) regulatory T cells by producing retinoic acid from dietary vitamin A. Local 'conditioning' factors in the LP might also contribute to this tolerogenic profile of CD103(+) DCs. Considerably less is understood about the generation of active immunity or inflammation in the intestinal mucosa. This might require alterations in pre-existing CD103(+) DCs, arrival of new DCs, or the action of a distinct DC population. Here, we discuss our current knowledge of this as yet incompletely understood population.


Assuntos
Células Dendríticas , Tolerância Imunológica/fisiologia , Imunidade , Mucosa Intestinal/imunologia , Transdução de Sinais/imunologia , Linfócitos T Reguladores/imunologia , Tretinoína/imunologia , Animais , Antígenos CD/imunologia , Bactérias/crescimento & desenvolvimento , Bactérias/imunologia , Diferenciação Celular/imunologia , Citocinas/biossíntese , Citocinas/imunologia , Células Dendríticas/citologia , Células Dendríticas/imunologia , Fatores de Transcrição Forkhead/imunologia , Humanos , Cadeias alfa de Integrinas/imunologia , Mucosa Intestinal/citologia , Mucosa Intestinal/metabolismo , Intestinos/citologia , Intestinos/imunologia , Linfonodos/citologia , Linfonodos/imunologia , Camundongos , Polissacarídeos/imunologia , Simbiose/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/citologia , Tretinoína/metabolismo
14.
Nat Rev Immunol ; 2024 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-39242920

RESUMO

Oral tolerance is the process by which feeding of soluble proteins induces antigen-specific systemic immune unresponsiveness. Oral tolerance is thought to have a central role in suppressing immune responses to 'harmless' food antigens, and its failure can lead to development of pathologies such as food allergies or coeliac disease. However, on the basis of long-standing experimental observations, the relevance of oral tolerance in human health has achieved new prominence recently following the discovery that oral administration of peanut proteins prevents the development of peanut allergy in at-risk human infants. In this Review, we summarize the new mechanistic insights into three key processes necessary for the induction of tolerance to oral antigens: antigen uptake and transport across the small intestinal epithelial barrier to the underlying immune cells; the processing, transport and presentation of fed antigen by different populations of antigen-presenting cells; and the development of immunosuppressive T cell populations that mediate antigen-specific tolerance. In addition, we consider how related but distinct processes maintain tolerance to bacterial antigens in the large intestine. Finally, we outline the molecular mechanisms and functional consequences of failure of oral tolerance and how these may be modulated to enhance clinical outcomes and prevent disease.

15.
Eur J Immunol ; 42(12): 3150-66, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22936024

RESUMO

Dendritic cells (DCs) and monocyte-derived macrophages (MΦs) are key components of intestinal immunity. However, the lack of surface markers differentiating MΦs from DCs has hampered understanding of their respective functions. Here, we demonstrate that, using CD64 expression, MΦs can be distinguished from DCs in the intestine of both mice and humans. On that basis, we revisit the phenotype of intestinal DCs in the absence of contaminating MΦs and we delineate a developmental pathway in the healthy intestine that leads from newly extravasated Ly-6C(hi) monocytes to intestinal MΦs. We determine how inflammation impacts this pathway and show that T cell-mediated colitis is associated with massive recruitment of monocytes to the intestine and the mesenteric lymph node (MLN). There, these monocytes differentiate into inflammatory MΦs endowed with phagocytic activity and the ability to produce inducible nitric oxide synthase. In the MLNs, inflammatory MΦs are located in the T-cell zone and trigger the induction of proinflammatory T cells. Finally, T cell-mediated colitis develops irrespective of intestinal DC migration, an unexpected finding supporting an important role for MLN-resident inflammatory MΦs in the etiology of T cell-mediated colitis.


Assuntos
Colite/imunologia , Células Dendríticas/imunologia , Mucosa Intestinal/imunologia , Linfonodos/imunologia , Macrófagos/imunologia , Mesentério/imunologia , Receptores de IgG/imunologia , Células Th1/imunologia , Animais , Antígenos Ly/imunologia , Diferenciação Celular/imunologia , Colite/patologia , Células Dendríticas/patologia , Humanos , Imunidade nas Mucosas , Mucosa Intestinal/patologia , Linfonodos/patologia , Macrófagos/patologia , Mesentério/patologia , Camundongos , Camundongos Knockout , Monócitos/imunologia , Monócitos/patologia , Células Th1/patologia
17.
Nat Commun ; 14(1): 2307, 2023 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-37085516

RESUMO

The intestinal lamina propria contains a diverse network of fibroblasts that provide key support functions to cells within their local environment. Despite this, our understanding of the diversity, location and ontogeny of fibroblasts within and along the length of the intestine remains incomplete. Here we show that the small and large intestinal lamina propria contain similar fibroblast subsets that locate in specific anatomical niches. Nevertheless, we find that the transcriptional profile of similar fibroblast subsets differs markedly between the small intestine and colon suggesting region specific functions. We perform in vivo transplantation and lineage-tracing experiments to demonstrate that adult intestinal fibroblast subsets, smooth muscle cells and pericytes derive from Gli1-expressing precursors present in embryonic day 12.5 intestine. Trajectory analysis of single cell RNA-seq datasets of E12.5 and adult mesenchymal cells suggest that adult smooth muscle cells and fibroblasts derive from distinct embryonic intermediates and that adult fibroblast subsets develop in a linear trajectory from CD81+ fibroblasts. Finally, we provide evidence that colonic subepithelial PDGFRαhi fibroblasts comprise several functionally distinct populations that originate from an Fgfr2-expressing fibroblast intermediate. Our results provide insights into intestinal stromal cell diversity, location, function, and ontogeny, with implications for intestinal development and homeostasis.


Assuntos
Intestino Grosso , Células-Tronco Mesenquimais , Colo , Fibroblastos/metabolismo , Intestino Grosso/anatomia & histologia , Intestino Grosso/citologia , Intestino Delgado , Intestinos/anatomia & histologia , Intestinos/citologia , Proteína GLI1 em Dedos de Zinco/genética , Células-Tronco Mesenquimais/metabolismo
18.
Eur J Immunol ; 41(9): 2494-8, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21952804

RESUMO

Interest in intestinal mononuclear phagocytes (MPs), both DCs and macrophages (Mφs), has exploded in the recent years. In this Viewpoint we will detail how resident intestinal lamina propria (LP) Mφs possess distinctive properties that reflect adaptation to a unique microenvironment. They play quite different roles in the normal and inflamed mucosa and, as we will show, the existing paradigms of differentiated Mφ subsets and of 'resident' versus 'inflammatory' monocytes based on other tissues may not apply to the gut. Strategies for targeting Mφs as a means of dampening intestinal inflammation will need to take account of these unique characteristics.


Assuntos
Imunoterapia , Intestinos/imunologia , Macrófagos/imunologia , Mucosa/imunologia , Animais , Diferenciação Celular , Humanos , Imunidade nas Mucosas , Inflamação , Especificidade de Órgãos
19.
J Immunol ; 184(12): 6843-54, 2010 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-20483766

RESUMO

Macrophages (Mphis) in the large intestine are crucial effectors of inflammatory bowel disease, but are also essential for homeostasis. It is unclear if these reflect separate populations of Ms or if resident Ms change during inflammation. In this study, we identify two subsets of colonic Ms in mice, whose proportions differ in healthy and inflamed intestine. Under resting conditions, most F4/80+ Ms are TLR- CCR2- CX3CR1hi and do not produce TNF-alpha in response to stimulation. The lack of TLR expression is stable, affects all TLRs, and is determined both transcriptionally and posttranscriptionally. During experimental colitis, TLR2+ CCR2+ CX3CR1int Ly6Chi Gr-1+, TNF-alpha-producing Ms come to dominate, and some of these are also present in the normal colon. The TLR2+ and TLR2- subsets are phenotypically distinct and have different turnover kinetics in vivo, and these properties are not influenced by the presence of inflammation. There is preferential CCR2-dependent recruitment of the proinflammatory population during colitis, suggesting they are derived from independent myeloid precursors. CCR2 knockout mice show reduced susceptibility to colitis and lack the recruitment of TLR2+ CCR2+ Gr-1+, TNF-alpha-producing Ms. The balance between proinflammatory and resident Ms in the colon is controlled by CCR2-dependent recruitment mechanisms, which could prove useful as targets for therapy in inflammatory bowel disease.


Assuntos
Colite/imunologia , Colo/imunologia , Macrófagos/imunologia , Receptores CCR2/imunologia , Receptores Toll-Like/imunologia , Animais , Separação Celular , Quimiotaxia de Leucócito/imunologia , Citocinas/biossíntese , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Imunofluorescência , Inflamação/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , RNA Mensageiro/análise , Receptores CCR2/biossíntese , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Receptores Toll-Like/biossíntese
20.
Eur J Immunol ; 40(2): 318-20, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20039306

RESUMO

There is almost no aspect of the immune response that is not regulated by TLR. Initially described as drivers of the innate immune response to pathogens, it is now clear that the TLR family can also influence most aspects of adaptive immunity, as well as determine how tissue cells interact with microbes in their environment. In particular, the intestine and its immune system must co-exist with an enormous community of commensal bacteria and are also on constant alert against invading pathogens. Unsurprisingly, there is therefore great interest in how TLR might regulate physiological and pathological reactions in the gut. An article in this issue of the European Journal of Immunology addresses this question with some elegant experiments that indicate that TLR2 is not essential for the pathogenesis or T-cell-mediated regulation of different models of inflammatory bowel disease in mice.


Assuntos
Infecções por Helicobacter/fisiopatologia , Doenças Inflamatórias Intestinais/fisiopatologia , Transdução de Sinais , Receptor 2 Toll-Like/fisiologia , Doença Aguda , Animais , Doença Crônica , Fatores de Transcrição Forkhead/metabolismo , Infecções por Helicobacter/imunologia , Infecções por Helicobacter/microbiologia , Helicobacter hepaticus/fisiologia , Interações Hospedeiro-Patógeno , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/microbiologia , Camundongos , Camundongos Knockout , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Receptor 2 Toll-Like/genética
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