RESUMEN
The prion protein (PrP(C)) is a cell surface protein expressed mainly in the nervous system. In addition to the role of its abnormal conformer in transmissible spongiform encephalopathies, normal PrP(C) may be implicated in other degenerative conditions often associated with inflammation. PrP(C) is also present in cells of hematopoietic origin, including T cells, dendritic cells, and macrophages, and it has been shown to modulate their functions. Here, we investigated the impact of inflammation and stress on the expression and function of PrP(C) in neutrophils, a cell type critically involved in both acute and chronic inflammation. We found that systemic injection of LPS induced transcription and translation of PrP(C) in mouse neutrophils. Up-regulation of PrP(C) was dependent on the serum content of TGF-ß and glucocorticoids (GC), which, in turn, are contingent on the activation of the hypothalamic-pituitary-adrenal axis in response to systemic inflammation. GC and TGF-ß, either alone or in combination, directly up-regulated PrP(C) in neutrophils, and accordingly, the blockade of GC receptors in vivo curtailed the LPS-induced increase in the content of PrP(C). Moreover, GC also mediated up-regulation of PrP(C) in neutrophils following noninflammatory restraint stress. Finally, neutrophils with up-regulated PrP(C) presented enhanced peroxide-dependent cytotoxicity to endothelial cells. The data demonstrate a novel interplay of the nervous, endocrine, and immune systems upon both the expression and function of PrP(C) in neutrophils, which may have a broad impact upon the physiology and pathology of various organs and systems.
Asunto(s)
Regulación de la Expresión Génica , Sistema Hipotálamo-Hipofisario/metabolismo , Neutrófilos/metabolismo , Sistema Hipófiso-Suprarrenal/metabolismo , Proteínas PrPC/biosíntesis , Estrés Fisiológico , Animales , Glucocorticoides/genética , Glucocorticoides/inmunología , Glucocorticoides/metabolismo , Sistema Hipotálamo-Hipofisario/inmunología , Sistema Hipotálamo-Hipofisario/patología , Inflamación/inducido químicamente , Inflamación/genética , Inflamación/inmunología , Inflamación/metabolismo , Inflamación/patología , Lipopolisacáridos/farmacología , Ratones , Ratones Noqueados , Neutrófilos/inmunología , Neutrófilos/patología , Sistema Hipófiso-Suprarrenal/inmunología , Sistema Hipófiso-Suprarrenal/patología , Proteínas PrPC/genética , Proteínas PrPC/inmunología , Enfermedades por Prión/genética , Enfermedades por Prión/inmunología , Enfermedades por Prión/metabolismo , Biosíntesis de Proteínas/efectos de los fármacos , Biosíntesis de Proteínas/genética , Biosíntesis de Proteínas/inmunología , Transcripción Genética/efectos de los fármacos , Transcripción Genética/genética , Transcripción Genética/inmunología , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/inmunología , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
Graft versus host disease (GVHD) is the major limitation of allogeneic hematopoietic stem cell transplantation (HSCT) presenting high mortality and morbidity rates. However, the exact cause of death is not completely understood and does not correlate with specific clinical and histological parameters of disease. Here we show, by using a semi-allogeneic mouse model of GVHD, that mortality and morbidity can be experimentally separated. We injected bone marrow-derived dendritic cells (BMDC) from NOD2/CARD15-deficient donors into semi-allogeneic irradiated chimaeras and observed that recipients were protected from death. However, no protection was observed regarding clinical or pathological scores up to 20 days after transplantation. Protection from death was associated with decreased bacterial translocation, faster hematologic recovery and epithelial integrity maintenance despite mononuclear infiltration at day 20 post-GVHD induction with no skew towards different T helper phenotypes. The protected mice recovered from aGVHD and progressively reached scores compatible with healthy animals. Altogether, our data indicate that severity and mortality can be separate events providing a model to study transplant-related mortality.
Asunto(s)
Modelos Animales de Enfermedad , Enfermedad Injerto contra Huésped/mortalidad , Animales , Células de la Médula Ósea/citología , Células Dendríticas/citología , Células Dendríticas/inmunología , Progresión de la Enfermedad , Técnicas de Inactivación de Genes , Enfermedad Injerto contra Huésped/inmunología , Ratones , Células Mieloides/inmunología , Proteína Adaptadora de Señalización NOD2/deficiencia , Proteína Adaptadora de Señalización NOD2/genética , Fenotipo , Linfocitos T Reguladores/inmunología , Trasplante Homólogo/efectos adversosRESUMEN
It has been shown that in vivo and in vitro treatment with G-CSF induces the generation of low-density granulocytes (LDGs), which copurify with PBMCs and inhibit IFN-gamma production by human T cells. These results prompted us to postulate an immunomodulatory role for LDGs in acute graft-versus-host disease (aGVHD). Here it is shown that in the mouse experimental model, in vivo and in vitro G-CSF treatment generates LDGs capable of inhibiting 80% of T-cell IFN-gamma production. To assess the role of these LDGs in aGVHD, lethally irradiated (C57BL/6 x BALB/c) F1 hosts were reconstituted with T cell-depleted bone marrow cells plus nylon wool-purified spleen cells from G-CSF-treated (G-NWS) or -nontreated (NWS) C57BL/6 donors. Recipients of G-NWS had a 75% survival rate in contrast to a rate of 25% in the NWS recipients. The protective effect was completely abolished, and the mortality rate was 100% if donor-cell infusion was treated with anti-Gr1. Moreover, if LDGs were infused with NWS, full protection of aGVHD was observed, and no signs of disease were evidenced by mortality rate, weight loss, or histopathology of target organs. These results revealed the unexpected immunosuppressive capacity of G-CSF based on the generation of LDGs, leading to the possibility of using these cells as inhibitors of aGVHD.