RESUMEN
Although glucocorticoids (GCs) are a mainstay in the clinical management of asthma, the target cells that mediate their therapeutic effects are unknown. Contrary to our expectation, we found that GC receptor (GR) expression in immune cells was dispensable for successful therapy of allergic airway inflammation (AAI) with dexamethasone. Instead, GC treatment was compromised in mice expressing a defective GR in the nonhematopoietic compartment or selectively lacking the GR in airway epithelial cells. Further, we found that an intact GR dimerization interface was a prerequisite for the suppression of AAI and airway hyperresponsiveness by GCs. Our observation that the ability of dexamethasone to modulate gene expression in airway epithelial cells coincided with its potency to resolve AAI supports a crucial role for transcriptional regulation by the GR in this cell type. Taken together, we identified an unknown mode of GC action in the treatment of allergic asthma that might help to develop more specific therapies in the future.
Asunto(s)
Asma/tratamiento farmacológico , Dexametasona/farmacología , Células Epiteliales/efectos de los fármacos , Glucocorticoides/farmacología , Receptores de Glucocorticoides/metabolismo , Mucosa Respiratoria/efectos de los fármacos , Animales , Asma/inmunología , Asma/fisiopatología , Dexametasona/uso terapéutico , Modelos Animales de Enfermedad , Células Epiteliales/inmunología , Células Epiteliales/metabolismo , Regulación de la Expresión Génica , Glucocorticoides/uso terapéutico , Inflamación/tratamiento farmacológico , Inflamación/inmunología , Ratones , Receptores de Glucocorticoides/química , Receptores de Glucocorticoides/genética , Mucosa Respiratoria/inmunología , Mucosa Respiratoria/metabolismo , Transducción de SeñalRESUMEN
Glucocorticoids (GCs) are the standard therapy for treating multiple sclerosis (MS) patients suffering from an acute relapse. One of the main mechanisms of GC action is held to be the induction of T cell apoptosis leading to reduced lymphocyte infiltration into the CNS, yet our analysis of experimental autoimmune encephalomyelitis (EAE) in three different strains of genetically manipulated mice has revealed that the induction of T cell apoptosis is not essential for the therapeutic efficacy of GCs. Instead, we identified the redirection of T cell migration in response to chemokines as a new therapeutic principle of GC action. GCs inhibited the migration of T cells towards CCL19 while they enhanced their responsiveness towards CXCL12. Importantly, blocking CXCR4 signaling in vivo by applying Plerixafor(®) strongly impaired the capacity of GCs to interfere with EAE, as revealed by an aggravated disease course, more pronounced CNS infiltration and a more dispersed distribution of the infiltrating T cells throughout the parenchyma. Our observation that T cells lacking the GC receptor were refractory to CXCL12 further underscores the importance of this pathway for the treatment of EAE by GCs. Importantly, methylprednisolone pulse therapy strongly increased the capacity of peripheral blood T cells from MS patients of different subtypes to migrate towards CXCL12. This indicates that modulation of T cell migration is an important mechanistic principle responsible for the efficacy of high-dose GC therapy not only of EAE but also of MS.
Asunto(s)
Quimiocinas/metabolismo , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Glucocorticoides/uso terapéutico , Esclerosis Múltiple/tratamiento farmacológico , Fármacos Neuroprotectores/uso terapéutico , Linfocitos T/efectos de los fármacos , Adulto , Anciano , Animales , Apoptosis/efectos de los fármacos , Apoptosis/fisiología , Movimiento Celular/efectos de los fármacos , Movimiento Celular/fisiología , Encefalomielitis Autoinmune Experimental/patología , Encefalomielitis Autoinmune Experimental/fisiopatología , Femenino , Humanos , Masculino , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Transgénicos , Persona de Mediana Edad , Esclerosis Múltiple/fisiopatología , Médula Espinal/efectos de los fármacos , Médula Espinal/patología , Médula Espinal/fisiopatología , Linfocitos T/fisiologíaRESUMEN
The activity of acid sphingomyelinase (aSMase) was previously reported to be involved in glucocorticoid-induced cell death (GICD) of T lymphocytes. This mechanism in turn is believed to contribute to the therapeutic efficacy of glucocorticoids (GCs) in the treatment of inflammatory diseases. In this study, we reassessed the role of aSMase in GICD by using aSMase knockout mice. The absence of aSMase largely abolished the partial protection that effector memory CD4(+) T cells in wild-type mice possess against GICD. Reduced IL-2 secretion by aSMase-deficient CD4(+) T cells suggested that a lack of this important survival factor might be the cause of these cells' enhanced susceptibility to GICD. Indeed, addition of IL-2 restored the protection against GICD, whereas neutralization of IL-2 abrogated the otherwise protective effect seen in wild-type effector memory CD4(+) T cells. The therapeutic implications of the altered sensitivity of aSMase-deficient T cells to GICD were assessed in models of inflammatory disorders; namely, experimental autoimmune encephalomyelitis and acute graft-versus-host disease. Surprisingly, GC treatment was equally efficient in both models in terms of ameliorating the diseases, regardless of the genotype of the T cells. Thus, our data reveal a hitherto unrecognized contribution of aSMase to the sensitivity of effector memory CD4(+) T cells to GICD and call into question the traditionally attributed importance of GICD of T cells to the treatment of inflammatory diseases by GCs.
Asunto(s)
Dexametasona/toxicidad , Memoria Inmunológica , Esfingomielina Fosfodiesterasa/fisiología , Subgrupos de Linfocitos T/enzimología , Subgrupos de Linfocitos T/inmunología , Animales , Apoptosis/genética , Apoptosis/inmunología , Muerte Celular/efectos de los fármacos , Muerte Celular/genética , Muerte Celular/inmunología , Células Cultivadas , Dexametasona/antagonistas & inhibidores , Dexametasona/uso terapéutico , Enfermedad Injerto contra Huésped/enzimología , Enfermedad Injerto contra Huésped/genética , Enfermedad Injerto contra Huésped/inmunología , Humanos , Memoria Inmunológica/efectos de los fármacos , Memoria Inmunológica/genética , Interleucina-2/antagonistas & inhibidores , Interleucina-2/metabolismo , Coriomeningitis Linfocítica/enzimología , Coriomeningitis Linfocítica/genética , Coriomeningitis Linfocítica/inmunología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Esfingomielina Fosfodiesterasa/deficiencia , Esfingomielina Fosfodiesterasa/genética , Subgrupos de Linfocitos T/efectos de los fármacosRESUMEN
Glucocorticoids (GCs) are widely used to treat acute relapses of multiple sclerosis (MS). In this study, we demonstrate that liposomal encapsulation augments the therapeutic potency of GCs as they ameliorate experimental autoimmune encephalomyelitis (EAE) to the same extent as free GC, but at strongly reduced dosage and application frequency. Importantly, this is accompanied by an altered mode of action. Unlike free GCs, which mainly target T lymphocytes during EAE therapy, liposomal GCs only marginally affect T cell apoptosis and function. In contrast, liposomal GCs efficiently repress proinflammatory macrophage functions and upregulate anti-inflammatory genes associated with the alternatively activated M2 phenotype. The GC receptor (GR) per se is indispensable for the therapeutic efficacy of liposomal GC. In contrast to free GCs, however, the individual deletion of the GR either in T cells or myeloid cells has little effect on the efficacy of liposomal GCs in the treatment of EAE. Only the combined deletion of the GR in both cellular compartments markedly compromises the therapeutic effect of liposomal GCs on disease progression. In conclusion, encapsulation of GC does not only enhance their efficacy in the treatment of EAE but also alters their target cell specificity and their mode of action compared with free GCs.