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1.
Int J Mol Sci ; 20(14)2019 Jul 17.
Artículo en Inglés | MEDLINE | ID: mdl-31319604

RESUMEN

Altered adaptive immunity involving T lymphocytes has been found in depressed patients and in stress-induced depression-like behavior in animal models. Peripheral T cells play important roles in homeostasis and function of the central nervous system and thus modulate behavior. However, the T cell phenotype and function associated with susceptibility and resilience to depression remain largely unknown. Here, we characterized splenic T cells in susceptible and resilient mice after 10 days of social defeat stress (SDS). We found equally decreased T cell frequencies and comparably altered expression levels of genes associated with T helper (Th) cell function in resilient and susceptible mice. Interleukin (IL)-17 producing CD4+ and CD8+ T cell numbers in the spleen were significantly increased in susceptible mice. These animals further exhibited significantly reduced numbers of regulatory T cells (Treg) and decreased gene expression levels of TGF-ß. Mice with enhanced Th17 differentiation induced by conditional deletion of PPARγ in CD4+ cells (CD4-PPARγKO), an inhibitor of Th17 development, were equally susceptible to SDS when compared to CD4-PPARγWT controls. These data indicate that enhanced Th17 differentiation alone does not alter stress vulnerability. Thus, SDS promotes Th17 cell and suppresses Treg cell differentiation predominantly in susceptible mice with yet unknown effects in immune responses after stress exposure.


Asunto(s)
Diferenciación Celular/inmunología , Estrés Psicológico/inmunología , Linfocitos T Reguladores/inmunología , Células Th17/inmunología , Animales , Susceptibilidad a Enfermedades , Masculino , Ratones , Estrés Psicológico/patología , Linfocitos T Reguladores/patología , Células Th17/patología
2.
J Biol Chem ; 291(37): 19517-31, 2016 09 09.
Artículo en Inglés | MEDLINE | ID: mdl-27474745

RESUMEN

Cerebral malaria is a severe and often fatal complication of Plasmodium falciparum infection. It is characterized by parasite sequestration, a breakdown of the blood-brain barrier, and a strong inflammation in the brain. We investigated the role of the cannabinoid receptor 2 (CB2), an important modulator of neuroinflammatory responses, in experimental cerebral malaria (ECM). Strikingly, mice with a deletion of the CB2-encoding gene (Cnr2(-/-)) inoculated with Plasmodium berghei ANKA erythrocytes exhibited enhanced survival and a diminished blood-brain barrier disruption. Therapeutic application of a specific CB2 antagonist also conferred increased ECM resistance in wild type mice. Hematopoietic derived immune cells were responsible for the enhanced protection in bone marrow (BM) chimeric Cnr2(-/-) mice. Mixed BM chimeras further revealed that CB2-expressing cells contributed to ECM development. A heterogeneous CD11b(+) cell population, containing macrophages and neutrophils, expanded in the Cnr2(-/-) spleen after infection and expressed macrophage mannose receptors, arginase-1 activity, and IL-10. Also in the Cnr2(-/-) brain, CD11b(+) cells that expressed selected anti-inflammatory markers accumulated, and expression of inflammatory mediators IFN-γ and TNF-α was reduced. Finally, the M2 macrophage chemokine CCL17 was identified as an essential factor for enhanced survival in the absence of CB2, because CCL17 × Cnr2 double-deficient mice were fully susceptible to ECM. Thus, targeting CB2 may be promising for the development of alternative treatment regimes of ECM.


Asunto(s)
Barrera Hematoencefálica/inmunología , Quimiocina CCL17/inmunología , Malaria Cerebral/inmunología , Plasmodium berghei/inmunología , Receptor Cannabinoide CB2/inmunología , Animales , Arginasa/genética , Arginasa/inmunología , Barrera Hematoencefálica/parasitología , Barrera Hematoencefálica/patología , Quimiocina CCL17/genética , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Femenino , Interleucina-10/genética , Interleucina-10/inmunología , Lectinas Tipo C/genética , Lectinas Tipo C/inmunología , Macrófagos/inmunología , Macrófagos/patología , Malaria Cerebral/genética , Malaria Cerebral/patología , Masculino , Receptor de Manosa , Lectinas de Unión a Manosa/genética , Lectinas de Unión a Manosa/inmunología , Ratones , Ratones Noqueados , Neutrófilos/inmunología , Neutrófilos/patología , Receptor Cannabinoide CB2/genética , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/inmunología
3.
Brain Behav Immun ; 66: 382-393, 2017 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-28642092

RESUMEN

The CC chemokine ligand 17 (CCL17) and its cognate CC chemokine receptor 4 (CCR4) are known to control leukocyte migration, maintenance of TH17 cells, and regulatory T cell (Treg) expansion in vivo. In this study we characterized the expression and functional role of CCL17 in the pathogenesis of experimental autoimmune encephalomyelitis (EAE). Using a CCL17/EGFP reporter mouse model, we could show that CCL17 expression in the CNS can be found in a subset of classical dendritic cells (DCs) that immigrate into the CNS during the effector phase of MOG-induced EAE. CCL17 deficient (CCL17-/-) mice exhibited an ameliorated disease course upon MOG-immunization, associated with reduced immigration of IL-17 producing CD4+ T cells and peripheral DCs into the CNS. CCL17-/- DCs further showed equivalent MHC class II and costimulatory molecule expression and an equivalent capacity to secrete IL-23 and induce myelin-reactive TH17 cells when compared to wildtype DCs. In contrast, their transmigration in an in vitro model of the blood-brain barrier was markedly impaired. In addition, peripheral Treg cells were enhanced in CCL17-/- mice at peak of disease pointing towards an immunoregulatory function of CCL17 in EAE. Our study identifies CCL17 as a unique modulator of EAE pathogenesis regulating DC trafficking as well as peripheral Treg cell expansion in EAE. Thus, CCL17 operates at distinct levels and on different cell subsets during immune response in EAE, a property harboring therapeutic potential for the treatment of CNS autoimmunity.


Asunto(s)
Quimiocina CCL17/metabolismo , Células Dendríticas/metabolismo , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/metabolismo , Animales , Barrera Hematoencefálica/inmunología , Barrera Hematoencefálica/metabolismo , Movimiento Celular , Quimiocina CCL17/genética , Femenino , Interleucina-23/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Bazo/inmunología , Bazo/fisiopatología , Linfocitos T Reguladores/metabolismo , Células Th17/metabolismo
4.
Int J Mol Sci ; 18(11)2017 Nov 02.
Artículo en Inglés | MEDLINE | ID: mdl-29099057

RESUMEN

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). It affects more than two million people worldwide, mainly young adults, and may lead to progressive neurological disability. Chemokines and their receptors have been shown to play critical roles in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), a murine disease model induced by active immunization with myelin proteins or transfer of encephalitogenic CD4⁺ T cells that recapitulates clinical and neuropathological features of MS. Chemokine ligand-receptor interactions orchestrate leukocyte trafficking and influence multiple pathophysiological cellular processes, including antigen presentation and cytokine production by dendritic cells (DCs). The C-C class chemokines 17 (CCL17) and 22 (CCL22) and their C-C chemokine receptor 4 (CCR4) have been shown to play an important role in homeostasis and inflammatory responses. Here, we provide an overview of the involvement of CCR4 and its ligands in CNS autoimmunity. We review key clinical studies of MS together with experimental studies in animals that have demonstrated functional roles of CCR4, CCL17, and CCL22 in EAE pathogenesis. Finally, we discuss the therapeutic potential of newly developed CCR4 antagonists and a humanized anti-CCR4 antibody for treatment of MS.


Asunto(s)
Enfermedades Autoinmunes del Sistema Nervioso/inmunología , Autoinmunidad , Quimiocina CCL17/inmunología , Quimiocina CCL22/inmunología , Receptores CCR4/inmunología , Animales , Enfermedades Autoinmunes del Sistema Nervioso/tratamiento farmacológico , Enfermedades Autoinmunes del Sistema Nervioso/patología , Autoinmunidad/inmunología , Sistema Nervioso Central/efectos de los fármacos , Sistema Nervioso Central/inmunología , Sistema Nervioso Central/patología , Quimiocina CCL17/análisis , Quimiocina CCL22/análisis , Células Dendríticas/efectos de los fármacos , Células Dendríticas/inmunología , Células Dendríticas/patología , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/patología , Humanos , Terapia Molecular Dirigida/métodos , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/patología , Receptores CCR4/análisis
5.
Front Behav Neurosci ; 12: 141, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30057531

RESUMEN

Dysregulation of innate immune responses has frequently been reported in stress-associated psychiatric disorders such as major depression. In mice, enhanced circulating cytokine levels as well as altered innate immune cell numbers have been found after stress exposure. In addition, stress-induced recruitment of peripheral monocytes to the brain has been shown to promote anxiety-like behavior. However, it is yet unclear whether specific differences in the innate immune system are associated with stress susceptibility or resilience in mice. Utilizing chronic social defeat, a model of depression and stress vulnerability, we characterized peripheral and brain-invading myeloid cells in stress-susceptible and resilient animals. In all defeated animals, we found reduced percentages of CD11c+ dendritic cells (DCs) by flow cytometry in the spleen when compared to non-defeated controls. Exclusively in susceptible mice conventional DCs of the spleen showed up-regulated expression of MHC class II and co-stimulatory CD80 molecules pointing toward an enhanced maturation phenotype of these cells. Susceptible, but not resilient animals further exhibited an increase in inflammatory Ly6Chi monocytes and higher numbers of spleen-derived CD11b+ cells that produced the proinflammatory cytokine tumor necrosis factor (TNF) upon lipopolysaccharide (LPS) stimulation. Increased percentages of peripheral CD45hi CD11b+ cells immigrated into the brain of defeated mice, regardless of resilience or susceptibility. However, cellular infiltrates in the brain of susceptible mice contained higher percentages of CC chemokine receptor 2 (CCR2+) Ly6Chi monocytes representing an inflammatory phenotype. Thus, we defined specific stress-related immune signatures involving conventional DCs and inflammatory Ly6Chi monocytes in susceptible and resilient mice. Together, our findings suggest an impact of the innate immune system in vulnerability to stress-related disorders such as major depression.

6.
Life Sci ; 138: 29-34, 2015 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-25744392

RESUMEN

AIMS: Acute rejection of cardiac allografts is a major risk factor limiting survival of heart transplant recipients. Rejection is triggered by dendritic cell (DC) mediated activation of host T cells, amongst others CD4(+) T helper (TH)1- and TH17 cells. The cannabinoid receptor 2 (CB2) is an important modulator of cellular immune responses. However, its role in cardiac allograft rejection has not been studied so far. MAIN METHODS: Here, we examined the effect of CB2 on cytokine release by mature DCs and its impact on CD4(+) T cell differentiation by utilizing in vitro generated bone marrow-derived DCs (BM-DCs) and CD4(+) T cells from CB2 knockout (Cnr2(-/-)) mice. We further assessed the functional role of CB2 in acute allograft rejection using Cnr2(-/-) mice in a fully major histocompatibility complex-mismatched mouse cardiac transplantation model. KEY FINDINGS: Cardiac allograft rejection was accelerated in Cnr2(-/-) mice compared to wild type recipients. In vitro stimulation of BM-DCs showed enhanced secretion of the pro-inflammatory cytokines interleukin (IL)-6, IL-1ß, tumor necrosis factor (TNF) and the immunomodulatory cytokine TGF-ß. Furthermore, secretion of the TH1/TH17 promoting cytokines IL-12 and IL-23 was increased in Cnr2(-/-) BM-DCs. In addition, Cnr2(-/-) CD4(+) T cells showed an enhanced capacity to differentiate into interferon (IFN)-γ- or IL-17-producing effector cells. SIGNIFICANCE: These results demonstrate that CB2 modulates in vitro cytokine responses via DCs and directly via its influence on TH1/TH17 differentiation. These findings and the fact that allograft rejection is enhanced in Cnr2(-/-) mice suggest that CB2 may be a promising therapeutic target in organ transplantation.


Asunto(s)
Rechazo de Injerto/fisiopatología , Trasplante de Corazón , Receptor Cannabinoide CB1 , Enfermedad Aguda , Animales , Linfocitos T CD4-Positivos/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Citocinas/metabolismo , Células Dendríticas/efectos de los fármacos , Complejo Mayor de Histocompatibilidad/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Receptor Cannabinoide CB1/genética
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