肿瘤坏死因子-α在实验性自身免疫性神经炎的作用
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摘要
肿瘤坏死因子-α(Tumor necrosis factor-α, TNF-α)是具有潜在神经损害作用的多效性细胞因子,在自身免疫性脱髓鞘疾病中起到很重要的作用。为了研究TNF-α在实验性自身免疫性神经炎(experimental autoimmune neuritis, EAN)中的作用及其机制,本研究探讨了TNF-α受体1基因敲除(TNF-αreceptor 1 deficient, TNFR1-/-)小鼠在P0蛋白106~125(P0 106~125)多肽诱发的EAN模型中施万细胞(又称雪旺细胞)的抗原呈递能力及诱导型一氧化氮合酶(inducible nitric oxide synthase, iNOS)的表达水平。实验通过检测激活的施万细胞上主要组织相容性复合物-II (Major histo-compatibility complexⅡ, MHC-Ⅱ),CD40, CD80和CD86的表达以及P0106~125多肽诱发的特异性T细胞与激活的施万细胞共培养后T细胞的增殖来反应施万细胞抗原呈递能力。除此以外,通过流式细胞术分析了iNOS在激活的施万细胞内的表达。实验结果显示TNFR1-/- EAN小鼠较野生型EAN小鼠起病延迟,且临床症状严重度弱于后者。体外实验来源于TNFR1-/-EAN小鼠坐骨神经原代培养的施万细胞上MHC-Ⅱ, CD80和iNOS表达较野生型EAN小鼠降低。与此同时,施万细胞与T细胞共培养增殖实验提示TNFR1-/-EAN小鼠特异性T细胞的增殖也低于野生型EAN小鼠。因此,我们认为,TNF-α在EAN中可能通过TNFR1上调施万细胞抗原呈递能力和iNOS的合成发挥促炎作用。
To address the role of TNF-αand its receptors in the pathogenesis of experimental autoimmune neuritis (EAN) and Guillain-Barr? syndrome (GBS), we established EAN, an animal model for GBS in human in TNF-a receptor1 (TNFR1) deficient mice.
GBS is an immune-mediated inflammatory disease of the peripheral nervous system (PNS), involving the damage to both myelin and axons. However, the exact mechanism of GBS is still unclear and remains to be clarified. EAN shares clinical, histopathological and electrophysiological features with GBS and is therefore used as an animal model to explore the pathogenesis of GBS. Numerous inflammatory cytokines play pivotal roles in initiating, enhancing perpetuating the pathogenic events in EAN. After stimulation with inflammatory cytokines, Schwann cells can express MHC-Ⅰand MHC-Ⅱmolecules, and are able to stimulate antigen specific T cell proliferation and secrete cytokines like, TNF-α, IL-1, IL-6 and complements as well as nitrite oxide (NO). TNF-α, as a pleiotropic pro-inflammatory cytokine, has been identified as a key player in the pathogenesis of EAN and GBS. Experimental strategies blocking TNF-? processing significantly reduced disease severity in EAN. TNF-αcan mediate the induction of demyelination and/or neuronal degeneration either directly or indirectly via the production of other pro-inflammatory cytokines, but the exact role of TNF-? in EAN pathogenesis is still unclear. TNFR1 is the predominant receptor involved in a wide variety of TNF-a mediated effects, including cytotoxicity, antiviral activity, induction of nuclear factor kappa B (NF-κB), modulation of MHC-Ⅱexpression and activation of macrophages in autoimmune diseases. Blockade of TNFR1 in autoimmunity could inhibit activities of TNF-α. A gene knockout (abbreviation: KO) is a genetic technique in which an organism is engineered to carry genes that have been made inoperative. It has been used in learning about a gene that has been sequenced, but which has an unknown or incompletely known function. Researchers draw inferences from the difference between the knockout organism and normal individuals, which is the best way to study the unknown function of gene in vivo. Knockout mice are considered as the ideal animals for studying human disease. By using TNF-αR1 deficient (TNFR1-/-) mice to induce EAN by P0 protein peptide 106-125, the current study investigated the antigen-presenting capacity and cytokine production of Schwann cells in EAN. The antigen-presenting capacity of Schwann cells were assessed by the expression of MHC-Ⅱ, CD40, CD80 and CD86 on activated Schwann cells as well as the induction of T cell proliferation in co-cultures of P0 protein peptide 106-125 specific T cells with activated Schwann cells. In addition, the expression of inducible nitric oxide synthase (iNOS) was measured in activated Schwann cells by flow cytometry. In gene level or molecular level, current study addressed the role of TNF-αin the pathogenesis of EAN, thus to further clarify the pathogenesis of GBS and provide experimental and theoretical basis for clinical treatment of the patients with GBS. Compared to wild type EAN mice, the onset of disease in TNFR1-/- EAN mice were delayed and the clinical signs were reduced obviously. The onset of disease in the wild type mice ranged between days 6 and 8 p.i.. In contrast, TNFR1-/- mice experienced a later onset of EAN, i.e., at days 8 to 10 p.i., with a decreased severity of the disease. The differences in clinical scores between groups were statistically significant from day 8 p.i. and onwards (p< 0.05). In parallel, in vitro primary Schwann cell culture from sciatic nerve of EAN mice, the expression of MHC-Ⅱand CD80 on Schwann cells of TNFR1-/- mice were significantly lower compared with those of wild type mice (p < 0.05). However, only a non-significant tendency of decreasing levels of MFI of CD40 and CD86 expression was seen in Schwann cells of TNFR1-/- EAN mice compared with wild type EAN mice. The level of iNOS was significantly lower in Schwann cells stimulated with rmIFN-γand LPS in TNFR1-/-EAN mice compared with wild type EAN mice. There was a similar profile of iNOS production between TNFR1-/- mice and wild type mice on na?ve background (p<0.05). Likewise, proliferation of P0 protein peptide 106-125 specific T cells simulated by activated Schwann cells of TNFR1-/- EAN mice was lower than that of wild type EAN mice. This indicates that TNFR1 deficiency reduces the antigen-presenting capacity of the Schwann cells. On the other hand, there was no significant difference of proliferative level between T cells of TNFR1-/- EAN mice co-cultured with Schwann cells from wild-type EAN mice and T cells of wild type EAN mice co-cultured with Schwann cells from the same mice, which suggested that T cell function is not impaired in TNFR1-/- mice. The main conclusion of this study is as follows: TNFR1?/? mice immunized with P0 protein peptide 106-125, developed a delayed and reduced clinical disease in parallel with decreased antigen-presenting capacity and iNOS production of schwann cells, with unimpaired T cell function. TNF-αmay exert the pro-inflammatory function through a TNFR1-dependent mechanism by up-regulating the antigen-presenting capacity and iNOS expression of SCs. The main innovation of this study is as follows:
1. In vivo, deleting TNFR1 can delay the onset of clinical signs and reduce disease severity in EAN from the study at the levels of gene and receptor, which further clarify that TNF-αexert pro-inflammatory function in EAN. 2. TNF-αmay exerts the pro-inflammatory function by up-regulating the antigen-presenting capacity and iNOS production of Schwann cells. Currently, TNF-αis a beneficial factor or destructive factor in EAN, which has been debateing. One of the reasons, the biological effects of both forms of TNF-αare mediated via its transmembrane receptors, TNFR1 and TNFR2, each of which utilizes a distinct signal pathway and exerts unique intracellular effects. The harmful and beneficial effects of TNF-αmay segregate at the level of TNFR1 and TNFR2. Besides, the differential timing, location and quantity of TNF-αexpressed and released, and the differential genetic background of the organism might also modulate to a great extent the biological function of TNF-α. The most important reason is the lack of extensive and deep-level research evidence in the gene and TNF-αreceptor levels in the EAN. Therefore, in the gene and receptor level, the current study shows TNF-αmay exert the pro-inflammatory function through a TNFR1-dependent mechanism by up-regulating the antigen-presenting capacity and iNOS expression of Schwann cells, thus to provide evidence for the pathogenesis of GBS and experimental and theoretical basis for treatment patients with GBS. But the extensive and systematic studies are still required to further demonstrate the role of TNF-αin EAN.
To address the role of TNF-αand its receptors in the pathogenesis of experimental autoimmune neuritis (EAN) and Guillain-Barr? syndrome (GBS), we established EAN, an animal model for GBS in human in TNF-a receptor1 (TNFR1) deficient mice.
GBS is an immune-mediated inflammatory disease of the peripheral nervous system (PNS), involving the damage to both myelin and axons. However, the exact mechanism of GBS is still unclear and remains to be clarified. EAN shares clinical, histopathological and electrophysiological features with GBS and is therefore used as an animal model to explore the pathogenesis of GBS. Numerous inflammatory cytokines play pivotal roles in initiating, enhancing perpetuating the pathogenic events in EAN. After stimulation with inflammatory cytokines, Schwann cells can express MHC-Ⅰand MHC-Ⅱmolecules, and are able to stimulate antigen specific T cell proliferation and secrete cytokines like, TNF-α, IL-1, IL-6 and complements as well as nitrite oxide (NO). TNF-α, as a pleiotropic pro-inflammatory cytokine, has been identified as a key player in the pathogenesis of EAN and GBS. Experimental strategies blocking TNF-? processing significantly reduced disease severity in EAN. TNF-αcan mediate the induction of demyelination and/or neuronal degeneration either directly or indirectly via the production of other pro-inflammatory cytokines, but the exact role of TNF-? in EAN pathogenesis is still unclear. TNFR1 is the predominant receptor involved in a wide variety of TNF-a mediated effects, including cytotoxicity, antiviral activity, induction of nuclear factor kappa B (NF-κB), modulation of MHC-Ⅱexpression and activation of macrophages in autoimmune diseases. Blockade of TNFR1 in autoimmunity could inhibit activities of TNF-α. A gene knockout (abbreviation: KO) is a genetic technique in which an organism is engineered to carry genes that have been made inoperative. It has been used in learning about a gene that has been sequenced, but which has an unknown or incompletely known function. Researchers draw inferences from the difference between the knockout organism and normal individuals, which is the best way to study the unknown function of gene in vivo. Knockout mice are considered as the ideal animals for studying human disease. By using TNF-αR1 deficient (TNFR1-/-) mice to induce EAN by P0 protein peptide 106-125, the current study investigated the antigen-presenting capacity and cytokine production of Schwann cells in EAN. The antigen-presenting capacity of Schwann cells were assessed by the expression of MHC-Ⅱ, CD40, CD80 and CD86 on activated Schwann cells as well as the induction of T cell proliferation in co-cultures of P0 protein peptide 106-125 specific T cells with activated Schwann cells. In addition, the expression of inducible nitric oxide synthase (iNOS) was measured in activated Schwann cells by flow cytometry. In gene level or molecular level, current study addressed the role of TNF-αin the pathogenesis of EAN, thus to further clarify the pathogenesis of GBS and provide experimental and theoretical basis for clinical treatment of the patients with GBS. Compared to wild type EAN mice, the onset of disease in TNFR1-/- EAN mice were delayed and the clinical signs were reduced obviously. The onset of disease in the wild type mice ranged between days 6 and 8 p.i.. In contrast, TNFR1-/- mice experienced a later onset of EAN, i.e., at days 8 to 10 p.i., with a decreased severity of the disease. The differences in clinical scores between groups were statistically significant from day 8 p.i. and onwards (p< 0.05). In parallel, in vitro primary Schwann cell culture from sciatic nerve of EAN mice, the expression of MHC-Ⅱand CD80 on Schwann cells of TNFR1-/- mice were significantly lower compared with those of wild type mice (p < 0.05). However, only a non-significant tendency of decreasing levels of MFI of CD40 and CD86 expression was seen in Schwann cells of TNFR1-/- EAN mice compared with wild type EAN mice. The level of iNOS was significantly lower in Schwann cells stimulated with rmIFN-γand LPS in TNFR1-/-EAN mice compared with wild type EAN mice. There was a similar profile of iNOS production between TNFR1-/- mice and wild type mice on na?ve background (p<0.05). Likewise, proliferation of P0 protein peptide 106-125 specific T cells simulated by activated Schwann cells of TNFR1-/- EAN mice was lower than that of wild type EAN mice. This indicates that TNFR1 deficiency reduces the antigen-presenting capacity of the Schwann cells. On the other hand, there was no significant difference of proliferative level between T cells of TNFR1-/- EAN mice co-cultured with Schwann cells from wild-type EAN mice and T cells of wild type EAN mice co-cultured with Schwann cells from the same mice, which suggested that T cell function is not impaired in TNFR1-/- mice. The main conclusion of this study is as follows: TNFR1?/? mice immunized with P0 protein peptide 106-125, developed a delayed and reduced clinical disease in parallel with decreased antigen-presenting capacity and iNOS production of schwann cells, with unimpaired T cell function. TNF-αmay exert the pro-inflammatory function through a TNFR1-dependent mechanism by up-regulating the antigen-presenting capacity and iNOS expression of SCs. The main innovation of this study is as follows:
1. In vivo, deleting TNFR1 can delay the onset of clinical signs and reduce disease severity in EAN from the study at the levels of gene and receptor, which further clarify that TNF-αexert pro-inflammatory function in EAN. 2. TNF-αmay exerts the pro-inflammatory function by up-regulating the antigen-presenting capacity and iNOS production of Schwann cells. Currently, TNF-αis a beneficial factor or destructive factor in EAN, which has been debateing. One of the reasons, the biological effects of both forms of TNF-αare mediated via its transmembrane receptors, TNFR1 and TNFR2, each of which utilizes a distinct signal pathway and exerts unique intracellular effects. The harmful and beneficial effects of TNF-αmay segregate at the level of TNFR1 and TNFR2. Besides, the differential timing, location and quantity of TNF-αexpressed and released, and the differential genetic background of the organism might also modulate to a great extent the biological function of TNF-α. The most important reason is the lack of extensive and deep-level research evidence in the gene and TNF-αreceptor levels in the EAN. Therefore, in the gene and receptor level, the current study shows TNF-αmay exert the pro-inflammatory function through a TNFR1-dependent mechanism by up-regulating the antigen-presenting capacity and iNOS expression of Schwann cells, thus to provide evidence for the pathogenesis of GBS and experimental and theoretical basis for treatment patients with GBS. But the extensive and systematic studies are still required to further demonstrate the role of TNF-αin EAN.
引文
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