Identifying the origin and mechanisms of pathological angiogenesis in neuroinflammatory diseases
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE210776 | GEO | 2023/03/14
REPOSITORIES: GEO
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Project description:Objective: We previously reported that white matter connexin43 (Cx43) may related to the severity of the multiple sclerosis (MS), whereas the role of gray matter Cx43 in demyelinating disease is unknown. It was considered MS lesions were only exist in white matter, but recent studies revealed that demyelinating lesions are also exist in the cerebral cortex. This fact suggest the possibility that gray matter is somewhat related to the pathophysiology of MS. In this study, we aimed to clarify the role of gray matter Cx43 in a mouse model of MS (experimental autoimmune encephalomyelitis [EAE]). Methods: We developed Cx43F/F;Glutamate aspartate transporter (GLAST)-CreER(T2)KI/+ mice as gray matter specific Cx43 conditional knock-out (Cx43cKO) mice. We induced MOG-EAE 10 days after tamoxifen injection, and analyze its clinical course and pathology. We used Cx43F/F mice as controls. Results: EAE was significantly milder in gray matter astrocyte-specific Cx43cKO mice from acute phase to chronic phase, as compared with control mice. Pathology demonstrated less demyelinating lesions and infiltrating cells. Infiltrating immune cells did not express Cx43 in the active demyelinating lesions of the lumbar cord in both groups. The expression level of Cx43 was similar between these two groups in the spleen and the inguinal lymph nodes. Interpretation: Acute KO of gray matter specific Cx43 before induction of EAE reduce its aggressiveness. This finding may suggest the possibility that gray matter Cx43 modify the MS pathophysiology.
2021-04-20 | GSE148929 | GEO
Project description:Objective: We previously reported that white matter connexin43 (Cx43) may related to the severity of the multiple sclerosis (MS), whereas the role of gray matter Cx43 in demyelinating disease is unknown. It was considered MS lesions were only exist in white matter, but recent studies revealed that demyelinating lesions are also exist in the cerebral cortex. This fact suggest the possibility that gray matter is somewhat related to the pathophysiology of MS. In this study, we aimed to clarify the role of gray matter Cx43 in a mouse model of MS (experimental autoimmune encephalomyelitis [EAE]). Methods: We developed Cx43F/F;Glutamate aspartate transporter (GLAST)-CreER(T2)KI/+ mice as gray matter specific Cx43 conditional knock-out (Cx43cKO) mice. We induced MOG-EAE 10 days after tamoxifen injection, and analyze its clinical course and pathology. We used Cx43F/F mice as controls. Results: EAE was significantly milder in gray matter astrocyte-specific Cx43cKO mice from acute phase to chronic phase, as compared with control mice. Pathology demonstrated less demyelinating lesions and infiltrating cells. Infiltrating immune cells did not express Cx43 in the active demyelinating lesions of the lumbar cord in both groups. The expression level of Cx43 was similar between these two groups in the spleen and the inguinal lymph nodes. Interpretation: Acute KO of gray matter specific Cx43 before induction of EAE reduce its aggressiveness. This finding may suggest the possibility that gray matter Cx43 modify the MS pathophysiology.
2021-04-20 | GSE148931 | GEO
Project description:Multiple sclerosis (MS) is an autoimmune disease associated with inflammatory demyelination in the central nervous system (CNS). Autologous hematopoietic cell transplantation (HCT) is under investigation as a promising therapy for treatment-refractory MS. Here we show that the enhancement of a reactive myeloid response following HCT is neuroprotective in chronic experimental autoimmune encephalitis (EAE). Myeloid cells are the CNS population with the strongest transcriptional changes in chronic EAE, which are further promoted by HCT. HCT leads to clinical improvement, reduction in demyelinated lesions, and amelioration of reactive astrogliosis reflected in reduced expression of EAE-associated gene signatures in oligodendrocytes and astrocytes. Enhanced incorporation of circulation-derived myeloid cells into the CNS results in a more consistent therapeutic effect corroborated by additional amplification of HCT-induced transcriptional changes, underlining myeloid-derived beneficial effects in the chronic phase of EAE. Replacement or manipulation of CNS myeloid cells thus represents an intriguing therapeutic direction for inflammatory demyelinating disease.
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Project description:Multiple sclerosis (MS) is an autoimmune disease associated with inflammatory demyelination in the central nervous system (CNS). Autologous hematopoietic cell transplantation (HCT) is under investigation as a promising therapy for treatment-refractory MS. Here we identify a reactive myeloid state in chronic experimental autoimmune encephalitis (EAE) that is surprisingly associated with neuroprotection and immune suppression. HCT in EAE mice leads to an enhancement of this myeloid state, as well as clinical improvement, reduction of demyelinated lesions, decrease in effector T cells, and amelioration of reactive astrogliosis reflected in reduced expression of EAE-associated gene signatures in oligodendrocytes and astrocytes. Further enhancement of myeloid cell incorporation into the CNS following a modified HCT protocol results in an even more consistent therapeutic effect corroborated by additional amplification of HCT-induced transcriptional changes, hence underlining myeloid-derived beneficial effects in the chronic phase of EAE. Replacement or manipulation of CNS myeloid cells thus represents an intriguing therapeutic direction for inflammatory demyelinating disease.
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Project description:Multiple Sclerosis (MS) is a complex disease of the CNS believed to require one or more environmental triggers and is characterized by episodic formation of inflammatory demyelinating lesions in the brain and spinal cord. Gut dysbiosis is a common feature in MS and here, using enhanced and quantitative PCR detection, we show that people with MS are more likely to harbor and have higher abundance of epsilon toxin (ETX)-producing strains of Clostridium perfringens within their gut microbiome compared to healthy controls (HC). MS patient-derived isolates produce functional ETX and have a genetic architecture typical of highly conjugative plasmids. In the active immunization model of experimental autoimmune encephalomyelitis (EAE), where pertussis toxin (PTX) is used to overcome CNS immune privilege, we find that ETX can substitute for PTX in disease induction. In contrast to PTX-induced EAE, where inflammatory demyelination is largely restricted to the spinal cord, ETX-induced EAE results in multifocal demyelination in the corpus callosum, thalamus, cerebellum, brainstem, and spinal cord, more akin to the lesion distribution observed in MS. Transcriptional profiles from CNS endothelial cells reveal ETX-induced genes that are known to play a role in overcoming CNS immune privilege. Together, these findings support ETX-producing strains of C. perfringens as biologically plausible pathogens in MS to trigger inflammatory demyelination in the context of circulating myelin autoreactive lymphocytes.
2023-03-31 | GSE223137 | GEO
Project description:We asked whether combining Notch and VEGF blockade would enhance suppression of tumor angiogenesis and growth, using the NGP neuroblastoma model. NGP tumors were engineered to express a Notch1 decoy construct (N1D), which restricts Notch signaling, and then treated with either the anti-VEGF antibody bevacizumab or vehicle. Combining Notch and VEGF blockade led to blood vessel regression, increasing endothelial cell apoptosis and disrupting pericyte coverage of endothelial cells. Combined Notch and VEGF blockade did not affect tumor weight, but did additively reduce tumor viability. Our results indicate that Notch and VEGF pathways play distinct but complementary roles in tumor angiogenesis, and show that concurrent blockade disrupts primary tumor vasculature and viability further than inhibition of either pathway alone. 6 neuroblastoma tumors were transfected with Notch1 decoy, 6 with Notch1 decoy and treated with bevacizumab, 6 tumors treated with bevacizumab, and 6 control tumors were profiled by human 133A 2.0 arrays
2013-12-01 | E-GEOD-48880 | biostudies-arrayexpress
Project description:Multiple sclerosis (MS) is a severe chronic inflammatory disease of the central nervous system (CNS) that leads to disability in young adults. T lymphocytes are a key component of lesion pathology throughout the disease course. Here we used the animal model experimental autoimmune encephalomyelitis (EAE) to conduct an unbiased characterization of CD4+ T cells in acute and chronic EAE.
2023-09-09 | GSE156196 | GEO
Project description:Objective: Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS), characterized by a global increasing incidence driven by relapsing-remitting disease in females. p38 MAP kinase (MAPK) has been described as a key regulator of inflammatory responses in autoimmunity, but its role in the sexual dimorphism in MS or MS models remains unexplored. Methods: Toward this end, we used experimental autoimmune encephalomyelitis (EAE), the principal animal model of MS, combined with pharmacologic and genetic inhibition of p38 MAPK activity and transcriptomic analyses. Results: Pharmacologic inhibition of p38 MAPK selectively ameliorated EAE in female mice. Conditional deletion studies demonstrated that p38M-NM-1 signaling in macrophages/myeloid cells, but not T cells or dendritic cells, recapitulated this sexual dimorphism. Analysis of CNS inflammatory infiltrates showed that female, but not male mice lacking p38M-NM-1 in myeloid cells exhibited reduced immune cell activation compared with controls, while peripheral T cell priming was unaffected in both sexes. Transcriptomic analyses of myeloid cells revealed differences in p38M-NM-1-controlled transcripts comprising female- and male-specific gene modules, with greater p38M-NM-1 dependence of pro-inflammatory gene expression in females. Interpretation: Our findings demonstrate a key role for p38M-NM-1 in myeloid cells in CNS autoimmunity and uncover important molecular mechanisms underlying sex differences in disease pathogenesis. Taken together, our results suggest that the p38 MAPK signaling pathway represents a novel target for much needed disease modifying therapies for MS WT vs. p38alphaCKO macrophages, male vs. female
2013-10-29 | E-GEOD-51707 | biostudies-arrayexpress
Project description:Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system, representing the leading cause of non-traumatic neurologic disease in young adults. This disease is three times more common in women, yet more severe in men, but the mechanisms underlying these sex differences remain largely unknown. MS is initiated by autoreactive T helper cells, but CNS-resident and CNS-infiltrating myeloid cells are the key proximal effector cells regulating disease pathology. We have previously shown that genetic ablation of p38α MAP kinase broadly in the myeloid lineage is protective in the autoimmune model of MS, experimental autoimmune encephalomyelitis (EAE), but only in females, and not males. To precisely define the mechanisms responsible, we used multiple genetic approaches and bone marrow chimeras to ablate p38α in microglial cells, peripheral myeloid cells, or both. Deletion of p38α in both cell types recapitulated the previous sex difference, with reduced EAE severity in females. Unexpectedly, deletion of p38α in the periphery was protective in both sexes. In contrast, deletion of p38α in microglia exacerbated EAE in males only, revealing opposing roles of p38α in microglia vs. periphery. Bulk transcriptional profiling revealed that p38α regulated the expression of distinct gene modules in male vs. female microglia. Single-cell transcriptional analysis of WT and p38α-deficient microglia isolated from the inflamed CNS revealed a diversity of complex microglial states, connected by distinct convergent transcriptional trajectories. Microglial p38α deficiency in males resulted in enhanced transition from homeostatic to disease-associated microglial states, with the downregulation of regulatory genes such as Atf3, Rgs1, Socs3, and Btg2, and increased expression of inflammatory genes such as Cd74, Trem2, and MHC class I and II genes. Taken together, these results reveal the presence of a p38α-dependent male-specific molecular pathway in microglia that is protective in CNS autoimmunity, suggesting that autoimmunity in males and females is driven by distinct cellular and molecular pathways, thus informing the design of novel future sex-specific therapeutic approaches.
2021-07-28 | GSE180864 | GEO
Project description:Objective: Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS), characterized by a global increasing incidence driven by relapsing-remitting disease in females. p38 MAP kinase (MAPK) has been described as a key regulator of inflammatory responses in autoimmunity, but its role in the sexual dimorphism in MS or MS models remains unexplored. Methods: Toward this end, we used experimental autoimmune encephalomyelitis (EAE), the principal animal model of MS, combined with pharmacologic and genetic inhibition of p38 MAPK activity and transcriptomic analyses. Results: Pharmacologic inhibition of p38 MAPK selectively ameliorated EAE in female mice. Conditional deletion studies demonstrated that p38α signaling in macrophages/myeloid cells, but not T cells or dendritic cells, recapitulated this sexual dimorphism. Analysis of CNS inflammatory infiltrates showed that female, but not male mice lacking p38α in myeloid cells exhibited reduced immune cell activation compared with controls, while peripheral T cell priming was unaffected in both sexes. Transcriptomic analyses of myeloid cells revealed differences in p38α-controlled transcripts comprising female- and male-specific gene modules, with greater p38α dependence of pro-inflammatory gene expression in females. Interpretation: Our findings demonstrate a key role for p38α in myeloid cells in CNS autoimmunity and uncover important molecular mechanisms underlying sex differences in disease pathogenesis. Taken together, our results suggest that the p38 MAPK signaling pathway represents a novel target for much needed disease modifying therapies for MS
2013-10-29 | GSE51707 | GEO