scholarly journals Deficiency of LRRC4 Accelerates Experimental Autoimmune Encephalomyelitis by Disrupting Th1/Treg Cell Balance

2019 ◽  
Author(s):  
Yan Zhang ◽  
Di Li ◽  
Qiuming Zeng ◽  
Jianbo Feng ◽  
Haijuan Fu ◽  
...  
Keyword(s):  
Experimental Autoimmune Encephalomyelitis ◽  
Clinical Symptoms ◽  
Critical Role ◽  
Ectopic Expression ◽  
Treg Cells ◽  
Autism Spectrum ◽  
Th1 Cells ◽  
Autoimmune Encephalomyelitis ◽  
Experimental Autoimmune

Abstract Background Leucine rich repeat containing 4 (LRRC4), also known as netrin-G ligand-2 (NGL-2), belongs to the superfamily of LRR proteins and serves as a receptor for netrin-G2. LRRC4 regulates the formation of excitatory synapses and promotes axon differentiation. Mutations in LRRC4 occur in Autism Spectrum Disorder (ASD) and intellectual disability. Multiple sclerosis (MS) is a chronic autoimmune disease characterized by immune-mediated demyelination and neurodegeneration of the central nervous system (CNS). Here, we investigated the role of LRRC4 in the pathological process of experimental autoimmune encephalomyelitis (EAE), a widely used mouse model of MS.Methods LRRC4 was detected in the CNS of EAE mice by the use of real-time PCR and western blotting. LRRC4 -/- mice were created and immunized with myelin oligodendrocyte glycoprotein peptide (MOG) 35–55 . Pathological changes in spinal cords of LRRC4 -/- and WT mice 15 days after immunization were examined by using hematoxylin and eosin (H&E), Luxol Fast Blue (LFB) staining and immunohistochemistry. The number of Th1/Th2/Th17/Treg cells in spleens and blood were measured with flow cytometry. Differential gene expression in the spinal cords from WT and LRRC4 -/- mice was analyzed by using RNA sequencing (RNA-seq). Adeno-associated virus (AAV) vectors were used to overexpress LRRC4 (AAV-LRRC4) and were injected into EAE mice to assess the therapeutic effect of AAV-LRRC4 ectopic expression on EAE.Results We discovered that the level of LRRC4 decreases in the spinal cords of the EAE mice. Deletion of LRRC4 accelerates infiltration of leukocytes into the spinal cords and disease exacerbation in vivo. We further showed that LRRC4 deletion disrupts the balance between Th1 cells and Treg cells and causes a shift toward Th1 cells and that the disrupted balance may be attributed to up-regulation of IL-6, IFN-γ and down-regulation of TNF-α in EAE mice. At a mechanistic level, we found that deficiency of LRRC4 induces elevated NF-κB p65 expression and does so by up-regulating Rab7b, while ectopic expression of LRRC4 alleviates the clinical symptoms of EAE mice and protects the CNS from immune damages.Conclusions We establish a critical role of LRRC4 in the progression of EAE and provide novel mechanistic insights into EAE development. Our findings also suggest that LRRC4 may be used as a potential target for therapeutic treatment of MS.

scholarly journals LRRC4 functions as a neuron-protective role in experimental autoimmune encephalomyelitis

2021 ◽  
Vol 27 (1) ◽  
Author(s):  
Yan Zhang ◽  
Di Li ◽  
Qiuming Zeng ◽  
Jianbo Feng ◽  
Haijuan Fu ◽  
...  
Keyword(s):  
Experimental Autoimmune Encephalomyelitis ◽  
Clinical Symptoms ◽  
Ectopic Expression ◽  
Treg Cells ◽  
Protective Role ◽  
Autism Spectrum ◽  
Autoimmune Encephalomyelitis ◽  
Adeno Associated Virus ◽  
Neuroinflammatory Disease ◽  
Experimental Autoimmune

Abstract Background Leucine rich repeat containing 4 (LRRC4), also known as netrin-G ligand-2 (NGL-2), belongs to the superfamily of LRR proteins and serves as a receptor for netrin-G2. LRRC4 regulates the formation of excitatory synapses and promotes axon differentiation. Mutations in LRRC4 occur in Autism Spectrum Disorder (ASD) and intellectual disability. Multiple sclerosis (MS) is a chronic neuroinflammatory disease with spinal cords demyelination and neurodegeneration. Here, we sought to investigate whether LRRC4 is involved in spinal cords neuron-associated diseases. Methods LRRC4 was detected in the CNS of experimental autoimmune encephalomyelitis (EAE) mice by the use of real-time PCR and western blotting. LRRC4−/− mice were created and immunized with myelin oligodendrocyte glycoprotein peptide (MOG)35–55. Pathological changes in spinal cords of LRRC4−/− and WT mice 15 days after immunization were examined by using hematoxylin and eosin (H&E), Luxol Fast Blue (LFB) staining and immunohistochemistry. The number of Th1/Th2/Th17/Treg cells in spleens and blood were measured with flow cytometry. Differential gene expression in the spinal cords from WT and LRRC4−/− mice was analyzed by using RNA sequencing (RNA-seq). Adeno-associated virus (AAV) vectors were used to overexpress LRRC4 (AAV-LRRC4) and were injected into EAE mice to assess the therapeutic effect of AAV-LRRC4 ectopic expression on EAE. Results We report that LRRC4 is mainly expressed in neuron of spinal cords, and is decreased in the spinal cords of the EAE mice. Knockout of LRRC4 have a disease progression quickened and exacerbated with more severe myelin degeneration and infiltration of leukocytes into the spinal cords. We also first found that Rab7b is high expressed in EAE mice, and the deficiency of LRRC4 induces the elevated NF-κB p65 by up-regulating Rab7b, and up-regulation of IL-6, IFN-γ and down-regulation of TNF-α, results in more severe Th1 immune response in LRRC4−/− mice. Ectopic expression of LRRC4 alleviates the clinical symptoms of EAE mice and protects the neurons from immune damages. Conclusions We identified a neuroprotective role of LRRC4 in the progression of EAE, which may be used as a potential target for auxiliary support therapeutic treatment of MS.

scholarly journals A new mouse model to study restoration of interleukin-6 (IL-6) expression in a Cre-dependent manner: microglial IL-6 regulation of experimental autoimmune encephalomyelitis

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Paula Sanchis ◽  
Olaya Fernández-Gayol ◽  
Gemma Comes ◽  
Kevin Aguilar ◽  
Anna Escrig ◽  
...  
Keyword(s):  
Mouse Model ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Interleukin 6 ◽  
Clinical Symptoms ◽  
Recovery Of Function ◽  
Cell Types ◽  
Dependent Manner ◽  
Autoimmune Encephalomyelitis ◽  
Experimental Autoimmune

Abstract Background Interleukin-6 (IL-6) is a pleiotropic cytokine that controls numerous physiological processes both in basal and neuroinflammatory conditions, including the inflammatory response to experimental autoimmune encephalomyelitis (EAE). IL-6 is produced by multiple peripheral and central cells, and until now, the putative roles of IL-6 from different cell types have been evaluated through conditional cell-specific IL-6 knockout mice. Nevertheless, these mice probably undergo compensatory responses of IL-6 from other cells, which makes it difficult to assess the role of each source of IL-6. Methods To give some insight into this problem, we have produced a novel mouse model: a conditional reversible IL-6 KO mouse (IL6-DIO-KO). By using double-inverted, open-reading-frame (DIO) technology, we created a mouse line with the loss of Il6 expression in all cells that can be restored by the action of Cre recombinase. Since microglia are one of the most important sources and targets of IL-6 into the central nervous system, we have recovered microglial Il6 expression in IL6-DIO-KO mice through breeding to Cx3cr1-CreER mice and subsequent injection of tamoxifen (TAM) when mice were 10–16 weeks old. Then, they were immunized with myelin oligodendrocyte glycoprotein 35-55 peptide (MOG35-55) 7 weeks after TAM treatment to induce EAE. Clinical symptoms and demyelination, CD3 infiltration, and gliosis in the spinal cord were evaluated. Results IL6-DIO-KO mice were resistant to EAE, validating the new model. Restoration of microglial Il6 was sufficient to develop a mild version of EAE-related clinical symptoms and neuropathology. Conclusions IL6-DIO-KO mouse is an excellent model to understand in detail the role of specific cellular sources of IL-6 within a recovery-of-function paradigm in EAE.

scholarly journals Role of SOCS2 in the Regulation of Immune Response and Development of the Experimental Autoimmune Encephalomyelitis

2019 ◽  
Vol 2019 ◽  
pp. 1-11
Author(s):  
Allysson Cramer ◽  
Bruno Cabral de Lima Oliveira ◽  
Paulo Gaio Leite ◽  
David Henrique Rodrigues ◽  
Fatima Brant ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Immune Response ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Acute Phase ◽  
Critical Role ◽  
Recovery Phase ◽  
Cytokine Signaling ◽  
Autoimmune Encephalomyelitis ◽  
Experimental Autoimmune

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS). Experimental Autoimmune Encephalomyelitis (EAE) is the most widely used animal model for the study of MS. The Suppressor of Cytokine Signaling (SOCS) 2 protein plays a critical role in regulating the immune responses. The role of SOCS2 during EAE has not been explored. EAE was induced in WT and SOCS2-/- mice using myelin oligodendrocyte glycoprotein (MOG35-55) peptide. Brain and spinal cord were examined during the peak (day 14) and recovery phase (day 28) of the disease. SOCS2 was upregulated in the brain of WT mice at the peak and recovery phase of EAE. The development of the acute phase was slower in onset in SOCS2-/- mice and was associated with reduced number of Th1 (CD3+CD4+IFN-γ+) cells in the spinal cord and brain. However, while in WT mice, maximal clinical EAE score was followed by a progressive recovery; the SOCS2-/- mice were unable to recover from locomotor impairment that occurred during the acute phase. There was a prolonged inflammatory response (increased Th1 and decreased Th2 and T regulatory cells) in the late phase of EAE in the CNS of SOCS2-/- mice. Transplantation of bone marrow cells from SOCS2-/- into irradiated WT mice resulted in higher lethality at the early phase of EAE. Altogether, these results suggest that SOCS2 plays a dual role in the immune response during EAE. It is necessary for damage during the acute phase damage but plays a beneficial role in the recovery stage of the disease.

scholarly journals CCR8+FOXp3+ Treg cells as master drivers of immune regulation

2017 ◽  
Vol 114 (23) ◽  
pp. 6086-6091 ◽  
Author(s):  
Yiftah Barsheshet ◽  
Gizi Wildbaum ◽  
Eran Levy ◽  
Alon Vitenshtein ◽  
Chika Akinseye ◽  
...  
Keyword(s):  
Human Peripheral Blood ◽  
Granzyme B ◽  
Critical Role ◽  
Treg Cells ◽  
Clinical Implications ◽  
Regulatory Cells ◽  
Autoimmune Encephalomyelitis ◽  
Experimental Autoimmune

The current study identifies CCR8+ regulatory T cells (Treg cells) as drivers of immunosuppression. We show that in human peripheral blood cells, more than 30% of Treg up-regulate CCR8 following activation in the presence of CCL1. This interaction induces STAT3-dependent up-regulation of FOXp3, CD39, IL-10, and granzyme B, resulting in enhanced suppressive activity of these cells. Of the four human CCR8 ligands, CCL1 is unique in potentiating Treg cells. The relevance of these observations has been extended using an experimental model of multiple sclerosis [experimental autoimmune encephalomyelitis, (EAE)] and a stabilized version of mouse CCL1 (CCL1–Ig). First, we identified a self-feeding mechanism by which CCL1 produced by Treg cells at an autoimmune site up-regulates the expression of its own receptor, CCR8, on these cells. Administration of CCL1–Ig during EAE enhanced the in vivo proliferation of these CCR8+ regulatory cells while inducing the expression of CD39, granzyme B, and IL-10, resulting in the efficacious suppression of ongoing EAE. The critical role of the CCL1–CCR8 axis in Treg cells was further dissected through adoptive transfer studies using CCR8−/− mice. Collectively, we demonstrate the pivotal role of CCR8+ Treg cells in restraining immunity and highlight the potential clinical implications of this discovery.

Critical role of preproenkephalin in experimental autoimmune encephalomyelitis

2006 ◽  
Vol 179 (1-2) ◽  
pp. 18-25 ◽  
Author(s):  
Catherine Weir ◽  
Andrea McNeill ◽  
Sarah Hook ◽  
Marina Harvie ◽  
Anne Camille La Flamme ◽  
...  
Keyword(s):  
Experimental Autoimmune Encephalomyelitis ◽  
Critical Role ◽  
Autoimmune Encephalomyelitis ◽  
Experimental Autoimmune
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