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Spermidine alleviates experimental autoimmune encephalomyelitis through inducing inhibitory macrophages.

ABSTRACT: Multiple sclerosis (MS) is a chronic and debilitating autoimmune disease, characterized by chronic inflammatory demyelination in the nervous tissue and subsequent neurological dysfunction. Spermidine, a natural polyamine, has been shown to affect inflammation in some experimental models. We show here that spermidine could alleviate experimental autoimmune encephalomyelitis (EAE), a model for MS, through regulating the infiltration of CD4+ T cells and macrophages in central nervous system. Unexpectedly, we found that spermidine treatment of MOG-specific T cells did not affect their pathogenic potency upon adaptive transfer; however, spermidine diminished the ability of macrophages in activating MOG-specific T cells ex vivo. Depletion of macrophages in diseased mice completely abolished the therapeutic effect of spermidine, indicating a critical role of spermidine-activated macrophages. Mechanistically, spermidine was found to specifically suppress the expression of interleukin-1beta (IL-1?), IL-12 and CD80 while enhance the expression of arginase 1 in macrophages. Interestingly, macrophages from spermidine-treated mice could also reverse EAE progression, while pretreatment of those macrophages with the arginase 1 inhibitor abrogated the therapeutic effect. Therefore, our studies revealed a critical role of macrophages in spermidine-mediated treatment on EAE and provided novel information for better management of MS.

SUBMITTER: Yang Q

PROVIDER: S-EPMC5071574 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Spermidine alleviates experimental autoimmune encephalomyelitis through inducing inhibitory macrophages.

Yang Q Q Zheng C C Cao J J Cao G G Shou P P Lin L L Velletri T T Jiang M M Chen Q Q Han Y Y Li F F Wang Y Y Cao W W Shi Y Y

Cell death and differentiation 20160722 11

Multiple sclerosis (MS) is a chronic and debilitating autoimmune disease, characterized by chronic inflammatory demyelination in the nervous tissue and subsequent neurological dysfunction. Spermidine, a natural polyamine, has been shown to affect inflammation in some experimental models. We show here that spermidine could alleviate experimental autoimmune encephalomyelitis (EAE), a model for MS, through regulating the infiltration of CD4<sup>+</sup> T cells and macrophages in central nervous sys ...[more]

PMID: 27447115

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Project description:AimsDaphnetin, a coumarin derivative extracted from Daphne odora var. marginata, has been reported to have antiinflammatory and immunosuppressive properties. Our previous study indicated that it was able to remarkably suppress the neuroinflammation and suggested its potential application in treating neuroinflammatory diseases. Multiple sclerosis (MS), a Th cell-mediated autoimmune disease, is the most common inflammatory demyelinating disease of the central nervous system (CNS). We examined whether daphnetin treatment can protect mice against experimental autoimmune encephalomyelitis (EAE), an animal model for MS.MethodsTo assess the effect of daphnetin in neuroinflammatory diseases, the EAE mice were established and treated with daphnetin at 8 mg/kg for 28 days. The severity of neuroinflammation and demyelination in the spinal cords was examined histopathologically. Infiltration of CD4(+) T cells into the CNS was assessed by immunohistochemistry, and the cytokine production was determined by ELISA. Meanwhile, the effect of daphnetin on the activity of dendritic cells (DCs) was evaluated, as assessed by DCs' capability to express surface markers, secrete cytokines, and activate naïve CD4(+) T cells. Furthermore, we explored the molecular mechanisms whereby DAPH regulated DCs' activity and thereby CD4(+) T cell responses.ResultsThe administration of daphnetin markedly alleviated the clinical symptoms of EAE and reduced the CNS inflammation and demyelination in experimental mice. Th1 and Th17 cell responses were profoundly repressed in daphnetin-treated EAE mice. Mechanistically, daphnetin treatment significantly repressed the activation, maturation, and antigen-presenting capability of DCs. NF-κB signaling was significantly reduced in daphnetin-treated DCs, along with a concomitant induction of heme oxygenase-1, a negative regulator of inflammatory signaling.ConclusionsOur findings for the first time demonstrate the property of daphnetin in regulating DCs' function and subsequently Th development. Given the low or absent toxicity associated with daphnetin, our data may suggest a novel safe and effective approach to control autoimmune neuroinflammation.

Project description:Myelin-associated inhibitory factors within the central nervous system (CNS) are considered to be one of the main obstacles for axonal regeneration following disease or injury. The nogo receptor 1 (NgR1) has been well documented to play a key role in limiting axonal regrowth in the injured and diseased mammalian CNS. However, the role of nogo receptor in immune cell activation during CNS inflammation is yet to be mechanistically elucidated. Microglia/macrophages are immune cells that are regarded as pathogenic contributors to inflammatory demyelinating lesions in multiple sclerosis (MS). In this study, the animal model of MS, experimental autoimmune encephalomyelitis (EAE) was induced in ngr1+/+ and ngr1-/- female mice following injection with the myelin oligodendrocyte glycoprotein (MOG35-55) peptide. A fate-map analysis of microglia/macrophages was performed throughout spinal cord sections of EAE-induced mice at clinical scores of 0, 1, 2 and 3, respectively (increasing locomotor disability) from both genotypes, using the CD11b and Iba1 cell markers. Western immunoblotting using lysates from isolated spinal cord microglia/macrophages, along with immunohistochemistry and flow cytometric analysis, was performed to demonstrate the expression of nogo receptor and its two homologs during EAE progression. Myelin protein engulfment during EAE progression in ngr1+/+ and ngr1-/- mice was demonstrated by western immunblotting of lysates from isolated spinal cord microglia/macrophages, detecting levels of Nogo-A and MOG. The numbers of M1 and M2 microglia/macrophage phenotypes present in the spinal cords of EAE-induced ngr1+/+ and ngr1-/- mice, were assessed by flow cytometric analysis using CD38 and Erg-2 markers. A significant difference in microglia/macrophage numbers between ngr1+/+ and ngr1-/- mice was identified during the progression of the clinical symptoms of EAE, in the white versus gray matter regions of the spinal cord. This difference was unrelated to the expression of NgR on these macrophage/microglial cells. We have identified that as EAE progresses, the phagocytic activity of microglia/macrophages with myelin debris, in ngr1-/- mice, was enhanced. Moreover, we show a modulation from a predominant M1-pathogenic to the M2-neurotrophic cell phenotype in the ngr1-/- mice during EAE progression. These findings suggest that CNS-specific macrophages and microglia of ngr1-/- mice may exhibit an enhanced capacity to clear inhibitory molecules that are sequestered in inflammatory lesions.

Project description:Compelling evidence has shown that interferon (IFN)-γ has dual effects in multiple sclerosis and in its animal model of experimental autoimmune encephalomyelitis (EAE), with results supporting both a pathogenic and beneficial function. However, the mechanisms whereby IFN-γ may promote neuroprotection in EAE and its effects on central nervous system (CNS)-resident cells have remained an enigma for more than 30 years. In this study, the impact of IFN-γ at the peak of EAE, its effects on CNS infiltrating myeloid cells (MC) and microglia (MG), and the underlying cellular and molecular mechanisms were investigated. IFN-γ administration resulted in disease amelioration and attenuation of neuroinflammation associated with significantly lower frequencies of CNS CD11b+ myeloid cells and less infiltration of inflammatory cells and demyelination. A significant reduction in activated MG and enhanced resting MG was determined by flow cytometry and immunohistrochemistry. Primary MC/MG cultures obtained from spinal cord of IFN-γ-treated EAE mice that were ex vivo re-stimulated with a low dose (1 ng/ml) of IFN-γ and neuroantigen promoted a significantly higher induction of CD4+ regulatory T (Treg) cells associated with increased transforming growth factor (TGF)-β secretion. Additionally, IFN-γ-treated primary MC/MG cultures produced significantly lower nitrite in response to LPS challenge than control MC/MG. IFN-γ-treated EAE mice had a significantly higher frequency of CX3CR1high MC/MG and expressed lower levels of program death ligand 1 (PD-L1) than PBS-treated mice. Most CX3CR1highPD-L1lowCD11b+Ly6G- cells expressed MG markers (Tmem119, Sall2, and P2ry12), indicating that they represented an enriched MG subset (CX3CR1highPD-L1low MG). Amelioration of clinical symptoms and induction of CX3CR1highPD-L1low MG by IFN-γ were dependent on STAT-1. RNA-seq analyses revealed that in vivo treatment with IFN-γ promoted the induction of homeostatic CX3CR1highPD-L1low MG, upregulating the expression of genes associated with tolerogenic and anti-inflammatory roles and down-regulating pro-inflammatory genes. These analyses highlight the master role that IFN-γ plays in regulating microglial activity and provide new insights into the cellular and molecular mechanisms involved in the therapeutic activity of IFN-γ in EAE.

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Spermidine alleviates experimental autoimmune encephalomyelitis through inducing inhibitory macrophages.

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Spermidine alleviates experimental autoimmune encephalomyelitis through inducing inhibitory macrophages.

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