Papel de la glía en la enfermedad de Alzheimer. Futuras implicaciones terapéuticas / The role of glial cells in Alzheimer disease: potential therapeutic implications

Introducción: La enfermedad de Alzheimer (EA) es una compleja enfermedad neurodegenerativa caracterizada por inflamación, neurotoxicidad, estrés oxidativo y gliosis reactiva. La microglía y los astrocitos no solo actúan como células presentadoras de antígenos, sino que constituyen células efectoras, liberando moléculas proinflamatorias que promueven la excitotoxicidad y la neurodegeneración. Objetivo: En la presente revisión bibliográfica se discute el papel de la glía, específicamente de la microglía y el astrocito en la fisiopatología de la EA y las posibles implicaciones terapéuticas. Desarrollo: La emergente evidencia del papel patogénico y la activación de vías de inflamación a partir de la microglía y el astrocito, los factores neurotóxicos liberados por estas células cuando están activadas, y cómo estos pueden desestabilizar la homeostasis del sistema nervioso central, sostienen la idea de que la inflamación inducida por la glía amplifica la EA. Conclusiones: La inhibición de la inflamación por inactivación de la glía, pudiera reducir la producción de factores que contribuyen con la toxicidad, resultando ser un beneficio clínico. La microglía y el astrocito constituyen blancos terapéuticos en el desarrollo de nuevos fármacos para combatir esta enfermedad. Estrategias terapéuticas diseñadas para contrarrestar el efecto perjudicial de la sobreactivación de estas poblaciones celulares deben ser investigadas

Introduction: Alzheimer (AD) disease is a complex neurodegenerative disease characterised by inflammation, neurotoxicity, oxidative stress, and reactive gliosis. Microglia and astrocytes not only act as antigen-presenting cells, but also function as effector cells releasing pro-inflammatory molecules that promote excitotoxicity and neurodegeneration Objective: In the present review we discuss the role of glia, specifically microglia and astrocytes, in the pathophysiology of AD and possible therapeutic implications. Development: The growing body of evidence suggesting that microglia and astrocytes play a pathogenic role and activate inflammation pathways, the neurotoxic factors released by these cells when activated, and the way these factors may disrupt the homeostasis of the central nervous system all support the hypothesis that glia-induced inflammation exacerbates AD. Conclusions: Inhibiting inflammation by deactivating glial cells may reduce the production of factors which contribute to neurotoxicity, and therefore result in clinical improvement. Microglia and astrocytes are therapeutic targets for the development of new drugs to combat this disease. Therapeutic strategies designed to counter the detrimental effects of overactivation of these cell populations should be investigated

The role of glial cells in Alzheimer disease: potential therapeutic implications.

INTRODUCTION: Alzheimer (AD) disease is a complex neurodegenerative disease characterised by inflammation, neurotoxicity, oxidative stress, and reactive gliosis. Microglia and astrocytes not only act as antigen-presenting cells, but also function as effector cells releasing pro-inflammatory molecules that promote excitotoxicity and neurodegeneration. OBJECTIVE: In the present review we discuss the role of glia, specifically microglia and astrocytes, in the pathophysiology of AD and possible therapeutic implications. DEVELOPMENT: The growing body of evidence suggesting that microglia and astrocytes play a pathogenic role and activate inflammation pathways, the neurotoxic factors released by these cells when activated, and the way these factors may disrupt the homeostasis of the central nervous system all support the hypothesis that glia-induced inflammation exacerbates AD. CONCLUSIONS: Inhibiting inflammation by deactivating glial cells may reduce the production of factors which contribute to neurotoxicity, and therefore result in clinical improvement. Microglia and astrocytes are therapeutic targets for the development of new drugs to combat this disease. Therapeutic strategies designed to counter the detrimental effects of overactivation of these cell populations should be investigated.

Respuesta inmune en la neuromielitis óptica / Immune response in optic neuromyelitis

La neuromielitis óptica es una enfermedad inflamatoria, desmielinizante y autoinmune del sistema nervioso central. En el presente trabajo se realiza una revisión de los diferentes mecanismos involucrados en la patogénesis de la neuromielitis óptica, se analiza el papel de los eosinófilos, de los anticuerpos contra antígenos propios y de las células T reguladoras en la enfermedad. En la neuromielitis óptica existe un predominio de la respuesta inmune humoral, la enfermedad se caracteriza por el depósito de inmunocomplejos, activación del complemento, producción de anticuerpos contra proteínas de la mielina y reclutamiento de eosinófilos en las lesiones. Existe además un aumento de la expresión de receptores de quimiocinas como el CCR3, específico de células TH2, la enfermedad está asociada predominantemente a una respuesta TH2(AU)

The Optic Neuromyelitis is an inflammatory and autoimmune illness of the central nervous system. Presently work is carried out a revision of the different mechanisms involved in the pathogenesis of the Optic Neuromyelitis, the paper of the eosinophils is analyzed, of the antibodies against own antigens and of the regulatory T cells in the illness. In the Optic Neuromyelitis is very important the humoral response, the illness exists it is characterized by the immunocomplex deposit, activation of the complement, production of antibodies against proteins of the myelin and eosinophils recruitment in the lesions. It also exists an increase of the expression of chemokines receptors like the CCR3, specific of TH2 cells; the illness is associate predominantly to a TH2 response(AU)

Respuesta inmune en la neuromielitis óptica / Immune response in optic neuromyelitis

La neuromielitis óptica es una enfermedad inflamatoria, desmielinizante y autoinmune del sistema nervioso central. En el presente trabajo se realiza una revisión de los diferentes mecanismos involucrados en la patogénesis de la neuromielitis óptica, se analiza el papel de los eosinófilos, de los anticuerpos contra antígenos propios y de las células T reguladoras en la enfermedad. En la neuromielitis óptica existe un predominio de la respuesta inmune humoral, la enfermedad se caracteriza por el depósito de inmuno complejos, activación del complemento, producción de anticuerpos contra proteínas de la mielina y reclutamiento de eosinófilos en las lesiones. Existe además un aumento de la expresión de receptores de quimiocinas como el CCR3, específico de células TH2, la enfermedad está asociada predominantemente a una respuesta TH2

The Optic Neuromyelitis is an inflammatory and autoimmune illness of the central nervous system. Presently work is carried out a revision of the different mechanisms involved in the pathogenesis of the Optic Neuromyelitis, the paper of the eosinophils is analyzed, of the antibodies against own antigens and of the regulatory T cells in the illness. In the Optic Neuromyelitis is very important the humoral response, the illnes sexists it is characterized by the immunocomplex deposit, activation of the complement, production of antibodies against proteins of the myelin and eosinophils recruitment in the lesions. It also exists an increase of the expression of chemokines receptors like the CCR3, specific of TH2 cells; the illness is associate predominantly to a TH2 response

Neuromielitis óptica. Principales diferencias con la esclerosis múltiple / Optic neuromyelitis. Main differences with multiple sclerosis

La neuromielitis optica o síndrome de Devic es una enfermedad inflamatoria, desmielinizante y autoinmune del sistema nervioso central. Se caracteriza por ataques de neuritis óptica y mielitis, pudiendo producir ceguera, gran invalidez neurológica e incluso la muerte a corto plazo. Hasta el momento no existe un tratamiento efectivo, la terapia se centra en el tratamiento de los ataques agudos, la prevención médica de las complicaciones y la rehabilitación. Se realiza una revisión de esta enfermedad poco común, considerando que su prevalencia en nuestro país ha ido en aumento y se establece una comparación entre la neuromiel itisóptica y la esclerosis múltiple, basándose en las principales características clínico-epidemiológicas, que distinguen estas dos patologías, consideradas por muchos variantes clínicas de una misma enfermedad

The optic neuromyelitis or syndrome of Devic is an inflammatory and autoimmune illness of the central nervous system. It is characterized by attacks of optic neuritis and myelitis, being able to produce blindness, great neurological disability and even the short term death. Until the moment an effective treatment doesn't exist, the therapy is centred in the treatment of the acute attacks, the medical prevention of the complications and the rehabilitation. This article is a revision of this not very common illness, considering that its prevalence in our country has gone in increase. We compare between the optic neuromyelitis and the multiple sclerosis, being based on the main ones characteristic clinical-epidemic that distinguishes these two pathologies, considered by many clinical variants of oneself illness

Neuromielitis óptica: principales diferencias con la esclerosis múltiple / Optic neuromyelitis: main differences with multiple sclerosis

La neuromielitis optica o síndrome de Devic es una enfermedad inflamatoria, desmielinizante y autoinmune del sistema nervioso central. Se caracteriza por ataques de neuritis óptica y mielitis, pudiendo producir ceguera, gran invalidez neurológica e incluso la muerte a corto plazo. Hasta el momento no existe un tratamiento efectivo, la terapia se centra en el tratamiento de los ataques agudos, la prevención médica de las complicaciones y la rehabilitación. Se realiza una revisión de esta enfermedad poco común, considerando que su prevalencia en nuestro país ha ido en aumento y se establece una comparación entre la neuromielitis óptica y la esclerosis múltiple, basándose en las principales características clínico-epidemiológicas, que distinguen estas dos patologías, consideradas por muchos variantes clínicas de una misma enfermedad(AU)

The optic neuromyelitis or syndrome of Devic is an inflammatory and autoimmune illness of the central nervous system. It is characterized by attacks of optic neuritis and myelitis, being able to produce blindness, great neurological disability and even the short term death. Until the moment an effective treatment doesn't exist, the therapy is centred in the treatment of the acute attacks, the medical prevention of the complications and the rehabilitation. This article is a revision of this not very common illness, considering that its prevalence in our country has gone in increase. We compare between the optic neuromyelitis and the multiple sclerosis, being based on the main ones characteristic clinical-epidemic that distinguishes these two pathologies, considered by many clinical variants of oneself illness(AU)

Treatment with type I interferons induces a regulatory T cell subset in peripheral blood mononuclear cells from multiple sclerosis patients.

Type I Interferon (IFN-alpha/beta) therapy has altered the natural course of multiple sclerosis. In this paper we evaluate the possible molecular mechanisms involved in the in vitro effects of IFN-alpha/beta on peripheral blood mononuclear cells from patients with clinically definite Relapsing-Remitting Multiple Sclerosis. The total RNA from IFN-alpha, IFN-beta treated cells and untreated cells was extracted and amplified for CD86, CD28, CTLA-4, TNF-alpha, IFN-gamma, CCL2, CCR5, IL-13, MMP-9, TIMP-1, CD25, TGF-beta, IL-10 and the transcriptional factor Foxp3 by Reverse Transcription-Polymerase Chain Reaction and the CD4+CD25high subset was evaluated using flow cytometry. In general, there were no significant differences concerning the modulation of the genes studied in the response to IFN-alpha and IFN-beta treatments, which suggest a similar mechanism of action for both interferons. However, we found a significant increment in IFN-gamma expression after IFN-alpha but not after IFN-beta treatments. The in vitro treatment of mononuclear cells from multiple sclerosis patients with both interferons significantly increased the CD25 mRNA. Furthermore, we observed a CD25/Foxp3 correlation and an increment of the CD4+CD25high subset, indicating that the induction of regulatory T cells could be a crucial mechanism involved in the type I interferon effects.

[Optic neuromyelitis. Main differences with multiple sclerosis]. / Neuromielitis óptica. Principales diferencias con la esclerosis múltiple.

The optic neuromyelitis or syndrome of Devic is an inflammatory and autoimmune illness of the central nervous system. It is characterized by attacks of optic neuritis and myelitis, being able to produce blindness, great neurological disability and even the short term death. Until the moment an effective treatment doesn't exist, the therapy is centred in the treatment of the acute attacks, the medical prevention of the complications and the rehabilitation. This article is a revision of this not very common illness, considering that its prevalence in our country has gone in increase. We compare between the optic neuromyelitis and the multiple sclerosis, being based on the main ones characteristic clinical-epidemic that distinguishes these two pathologies, considered by many clinical variants of oneself illness.

[Immune response in optic neuromyelitis]. / Respuesta inmune en la neuromielitis óptica.

The Optic Neuromyelitis is an inflammatory and autoimmune illness of the central nervous system. Presently work is carried out a revision of the different mechanisms involved in the pathogenesis of the Optic Neuromyelitis, the paper of the eosinophils is analyzed, of the antibodies against own antigens and of the regulatory T cells in the illness. In the Optic Neuromyelitis is very important the humoral response, the illness exists it is characterized by the immunocomplex deposit, activation of the complement, production of antibodies against proteins of the myelin and eosinophils recruitment in the lesions. It also exists an increase of the expression of chemokines receptors like the CCR3, specific of TH2 cells; the illness is associate predominantly to a TH2 response.

Differential expression and regulation of toll-like receptors (TLR) in human leukocytes: selective expression of TLR3 in dendritic cells.

Members of the Toll-like receptor (TLR) family probably play a fundamental role in pathogen recognition and activation of innate immunity. The present study used a systematic approach to analyze how different human leukocyte populations express specific transcripts for the first five characterized TLR family members. TLR1 was expressed in all leukocytes examined, including monocytes, polymorphonuclear leukocytes, T and B cells, and NK cells. In contrast TLR2, TLR4, and TLR5 were expressed in myelomonocytic elements. Exposure to bacterial products, such as LPS or lipoarabinomannan, or to proinflammatory cytokines increased TLR4 expression in monocytes and polymorphonuclear leukocytes, whereas IL-10 blocked this effect. TLR3 was only expressed in human dendritic cells (DC) wherein maturation induced by bacterial products or cytokines was associated with reduced expression. TLR3 mRNA expression was detected by in situ hybridization in DC and lymph nodes. These results demonstrate that TLR1 through TLR5 mRNAs are differentially expressed and regulated in human leukocytes. In particular, expression of TLR3 transcripts is restricted to DC that are the only elements which express the full TLR repertoire. These data suggest that TLR can be classified based on expression pattern as ubiquitous (TLR1), restricted (TLR2, TLR4, and TLR5 in myelomonocytic cells), and specific (TLR3 in DC) molecules.

Up-regulation of CCR2 chemokine receptor expression and increased susceptibility to the multitropic HIV strain 89.6 in monocytes exposed to glucocorticoid hormones.

Glucocorticoid hormones (GC) are potent antiinflammatory agents widely used in the treatment of diverse human diseases. The present study was aimed at assessing the effect of GC on chemokine receptor expression in human monocytes. Dexamethasone (Dex) up-regulated mRNA expression of the monocyte chemotactic protein (MCP-1, CCL2) chemokine receptor CCR2. The effect was selective in that other chemokine receptors were not substantially affected. Stimulation by Dex was observed after 4 h of exposure at concentrations of 10(-7) to 10(-5) M. Steroids devoid of GC activity were inactive, and the GC receptor antagonist, RU486, inhibited stimulation. Dex did not affect the rate of nuclear transcription, but augmented the CCR2 mRNA half-life. Augmentation of CCR2 expression by Dex was associated with increased chemotaxis. Finally, Dex treatment induced productive replication of the HIV strain 89.6, which utilizes CCR2 as entry coreceptor, in freshly isolated monocytes. Together with previous findings, these results indicate that at least certain pro- and antiinflammatory molecules have reciprocal and divergent effects on expression of a major monocyte chemoattractant, MCP-1, and of its receptor (CCR2). Augmentation of monocyte CCR2 expression may underlie unexplained in vivo effects of GC as well as some of their actions on HIV infection.

Bacterial lipopolysaccharide causes rapid shedding, followed by inhibition of mRNA expression, of the IL-1 type II receptor, with concomitant up-regulation of the type I receptor and induction of incompletely spliced transcripts.

The IL-1 type I receptor (IL-1RI) is part of a signaling complex together with the IL-1R accessory protein, whereas available information is consistent with a "decoy" model of function for the IL-1 type II receptor (IL-1RII). The present study was designed to investigate the effect of bacterial LPS on IL-1R in human monocytes. LPS causes rapid release of the IL-1RII, an effect blocked by a metalloprotease inhibitor. Subsequently, LPS-treated monocytes showed a drastic reduction of IL-1RII mRNA. In contrast, LPS induced IL-1RI and, to a lesser extent, IL-1AcP expression. LPS-induced augmented expression of the canonical 5-kb IL-1RI mRNA was accompanied by the appearance of 2.4-kb IL-1RI transcripts. The use of probes representative of different regions of the IL-1RI mRNA, as well as cDNA cloning, revealed that the 2.4-kb inducible band includes incompletely spliced, polyadenylated transcripts potentially encoding truncated versions of the receptor. The observation that the prototypic proinflammatory molecule LPS has divergent effects on IL-1Rs, with inhibition of IL-1RII and stimulation of IL-1RI and IL-1R accessory protein, is consistent with the view that these molecules subserve opposite functions in the pathophysiology of the IL-1 system. The rapid shedding of IL-1RII by monocytes early in recruitment may serve to buffer the systemic action of IL-1 leaking from sites of inflammation. This early event, followed by prolonged inhibition of IL-1RII expression and up-regulation of IL-1RI, may render monocytes more responsive to IL-1 at sites of inflammation.

Divergent effects of LPS on expression of IL-1 receptor family members in mononuclear phagocytes in vitro and in vivo.

Three molecules, interleukin 1 (IL-1) receptor I (IL-1RI), IL-1 receptor II (IL-1RII or decoy) and IL-1 receptor accessory protein (IL-1R AcP or IL-1RIII), are involved in IL-1 binding and signal transduction. In addition, three homologous genes (T1/ST2, MyD88 and rsc786) have been identified. Expression of the signal transducing type I R and of the decoy type II R in human monocytes is regulated by pro- and anti-inflammatory signals. The present study was designed to evaluate comprehensively how a prototypic pro-inflammatory signal, bacterial lipopolysaccharide (LPS), affects expression of IL-1R family members in mononuclear phagocytes in vitro and in vivo. Resting human monocytes expressed high levels of IL-1RII, IL-1R AcP, MyD88 and rsc786, whereas low levels of IL-1RI and T1/ST2 were present. In vitro exposure to LPS augmented expression of IL-1RI, T1/ST2 and MyD88, whereas it inhibited that of IL-1RII and rsc786. Expression of IL-1R AcP in monocytes was less substantially affected by LPS. The expression of IL-1R family members was also studied in organs of mice given LPS. As expected on the basis of in vitro results, organs (e.g. spleen, lungs and peritoneal exudate cells) from LPS-treated mice showed increased levels of IL-1RI, T1/ST2 and MyD88. Intriguingly, while expression of IL-1RII was inhibited in peritoneal macrophages after LPS, in accordance with in vitro results, increased IL-1RII mRNA was observed in organs such as liver, lungs and spleen. This unexpected effect of LPS was drastically reduced in mice rendered neutropenic by 5-fluorouracil. Therefore, we conclude that the apparent induction of IL-1RII in certain organs of LPS-treated mice is due to recruitment of myeloid cells which express high levels of decoy RII. Therefore, members of IL-1R family are independently and divergently regulated in mononuclear phagocytes exposed to the prototypic pro-inflammatory signal LPS in vitro and in vivo.

Selective inhibition of expression of the chemokine receptor CCR2 in human monocytes by IFN-gamma.

IFN-gamma is a potent activator of mononuclear phagocyte function and promotes the development of Th1 responses. Moreover, it induces and modulates chemokine production in a variety of cell types, including mononuclear phagocytes. In the present study, we examined the effect of IFN-gamma on the expression of CC chemokine receptors in human monocytes. IFN-gamma selectively and rapidly inhibited expression of the monocyte chemotactic protein (MCP) receptor CCR2 with an ED50 of approximately 50 U/ml. The effect was rapid (detectable after 1 h) and reversible. Other chemokine receptors (CCR1, CCR3, CCR4, and CCR5) were not substantially affected, and CXCR4 was reduced. IFN-gamma acted in concert with LPS, TNF-alpha, and IL-1beta in inhibiting CCR2 expression. IFN-gamma-treated monocytes showed a shorter half-life of CCR2 mRNA compared with untreated cells, whereas the rate of nuclear transcription was unaffected. The inhibition of CCR2 mRNA expression by IFN-gamma was associated with a lower number of surface receptors and lower chemotactic responsiveness. Thus, IFN-gamma, an inducer of MCP-1 and MCP-3 in mononuclear phagocytes, selectively inhibits expression of the MCP receptor CCR2 in monocytes. These results are consistent with an emerging paradigm of divergent regulation by several agents of chemokine production and receptor expression in monocytes. The inhibition of MCP-1R expression may serve as a means of retaining mononuclear phagocytes at sites of inflammation and as a feedback mechanism in the regulation of recruitment from the blood.

Gene transfer-mediated expression of physiological numbers of the type II decoy receptor in a myelomonocytic cellular context dampens the response to interleukin-1.

Available information suggests that the type II IL-1 receptor (RII) is a nonsignaling molecule which acts as a decoy for IL-1. The decoy function model for RII was supported by gene transfer experiments in fibroblasts and keratinocytes. Therefore, inhibition of IL-1 responsiveness after decoy RII gene transfer could reflect a non-physiological cellular context and receptor number. In the present study, constructs encoding RII or a cytoplasmic deletion mutant (delta 372-398) were transfected into U937 cells which express only low levels of RI detectable by RT-PCR. Gene transfer resulted in receptor numbers (approximately equal to 10(3)/cell) of the same order of magnitude as that found in normal myelomonocytic cells. Transfer of RII or a cytoplasmic deletion mutant into U937 did not increase responsiveness to IL-1, as assessed by IL-8 expression and production; it actually considerably dampened it. These results are consistent with the view that in a myelomonocytic cellular context, RII does not contribute to signaling and represents a unique pathway of negative regulation of the IL-1 system.

Inhibition of interleukin-1 responsiveness by type II receptor gene transfer: a surface "receptor" with anti-interleukin-1 function.

The hypothesis that the type II receptor (RII) acts as a decoy for interleukin-1 (IL-1) was tested by gene transfer in cells expressing only the type I receptor (8387 fibroblasts). RII-transfected cells showed defective responsiveness to IL-1 in terms of NFkappaB activation, cytokine gene expression and production. Blocking monoclonal antibodies against RII restored the capacity of RII-transfected cells to respond to IL-1 beta. Hence defective IL-1 responsiveness of RII-transfected cells requires surface expression of the molecule. RII-transfected cells showed normal responsiveness to TNF, which shares functional properties and elements in the signal transduction pathway with IL-1. Cells transfected with a deletion mutant of RII missing 26 of 29 amino acids of the cytoplasmic portion of the molecule showed impaired responsiveness to IL-2. Cells transfected with full-length or the cytoplasmic deletion mutant of RII released copious amounts of RII in the supernatant. However, transfected cells showed defective responsiveness to brief exposure to IL-1, in the absence of measurable released RII. These results indicate that impairment of the responsiveness to IL-1 following RII gene transfer was dependent upon surface expression of the molecule, specific for IL-1 and unaffected by truncation of the cytoplasmic portion. Thus, the type II "receptor" is a decoy surface molecule, regulated by antiinflammatory signals, whose only known function is to capture and block IL-1.