Induced CNS expression of CXCL1 augments neurologic disease in a murine model of multiple sclerosis via enhanced neutrophil recruitment

Grist, Jonathan J.; Marro, Brett S.; Skinner, Dominic D; Syage, Amber R.; Worne, Colleen L.; Doty, Daniel J.; Fujinami, Robert S.; Lane, Thomas E.

doi:10.1002/eji.201747442

Cited by 34 publications

(44 citation statements)

References 65 publications

(97 reference statements)

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“…Conversely, inducible overproduction of CXCL1 by astrocytes reduced EAE clinical disease, although it was unclear whether increased levels of CXCL1 directly affected oligodendrocyte biology or modulated immune cell recruitment into the CNS (65). We have recently shown that induced expression of CXCL1 resulted in increased demyelination mediated by neutrophils in both JHMV and EAE models of neurologic disease (18,19). In addition, previous work from our laboratories employing antibody-mediated targeting of CXCR2 shows that blocking signaling in JHMV-infected mice increases the severity of demyelination, arguing for a protective role for CXCR2 in a model of virus-induced demyelination, as previously discussed (37).…”

Section: Discussionmentioning

confidence: 99%

“…CXCR2 is a receptor for ELR-positive CXC chemokines, e.g., CXCL1 and CXCL2, and is expressed on polymorphonuclear neutrophils (PMN) as well as glia (12)(13)(14)(15)(16). CXCR2 signaling on neutrophils promotes demyelination in models of experimental autoimmune encephalomyelitis (EAE), cuprizone-induced demyelination, as well as virus-induced demyelination (8,(17)(18)(19). However, CXCR2 has additional roles that extend beyond influencing neutrophil activity, as it is expressed on immature oligodendrocyte progenitor cells (OPCs) as well as mature myelinating oligodendrocytes (20).…”

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confidence: 99%

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Disrupted CXCR2 Signaling in Oligodendroglia Lineage Cells Enhances Myelin Repair in a Viral Model of Multiple Sclerosis

Marro

Skinner

Cheng

et al. 2019

J Virol

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CXCR2 is a chemokine receptor expressed on oligodendroglia that has been implicated in the pathogenesis of neuroinflammatory demyelinating diseases as well as enhancement of the migration, proliferation, and myelin production by oligodendroglia. Using an inducible proteolipid protein (Plp) promoter-driven Cre-loxP recombination system, we were able to assess how timed ablation of Cxcr2 in oligodendroglia affected disease following intracranial infection with the neurotropic JHM strain of mouse hepatitis virus (JHMV). Generation of Plp-Cre-ER(T)::Cxcr2 flox/flox transgenic mice (termed Cxcr2-CKO mice) allows for Cxcr2 to be silenced in oligodendrocytes in adult mice following treatment with tamoxifen. Ablation of oligodendroglia Cxcr2 did not influence clinical severity in response to intracranial infection with JHMV. Infiltration of activated T cells or myeloid cells into the central nervous system (CNS) was not affected, nor was the ability to control viral infection. In addition, the severity of demyelination was similar between tamoxifen-treated mice and vehicletreated controls. Notably, deletion of Cxcr2 resulted in increased remyelination, as assessed by g-ratio (the ratio of the inner axonal diameter to the total outer fiber diameter) calculation, compared to that in vehicle-treated control mice. Collectively, our findings argue that CXCR2 signaling in oligodendroglia is dispensable with regard to contributing to neuroinflammation, but its deletion enhances remyelination in a preclinical model of the human demyelinating disease multiple sclerosis (MS). IMPORTANCE Signaling through the chemokine receptor CXCR2 in oligodendroglia is important for developmental myelination in rodents, while chemical inhibition or nonspecific genetic deletion of CXCR2 appears to augment myelin repair in animal models of the human demyelinating disease multiple sclerosis (MS). To better understand the biology of CXCR2 signaling on oligodendroglia, we generated transgenic mice in which Cxcr2 is selectively ablated in oligodendroglia upon treatment with tamoxifen. Using a viral model of neuroinflammation and demyelination, we demonstrate that genetic silencing of CXCR2 on oligodendroglia did not affect clinical disease, neuroinflammation, or demyelination, yet there was increased remyelination. These findings support and extend previous findings suggesting that targeting CXCR2 may offer a therapeutic avenue for enhancing remyelination in patients with demyelinating diseases.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Disrupted CXCR2 Signaling in Oligodendroglia Lineage Cells Enhances Myelin Repair in a Viral Model of Multiple Sclerosis

Marro

Skinner

Cheng

et al. 2019

J Virol

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“…EAE was initiated using a myosin oligodendrocyte protein (MOG)/Bordetella pertussis toxin (PT) method [15]. Briefly, mice were subcutaneously injected with 0.2 μmol of MOG peptide (MEVGWYRSPFSRVVHLYRNGK, synthesized at the University of Utah HSC Core) in complete Freund's adjuvant (CFA, Sigma, 2 mg/mL).…”

Section: Induction and Scoring Of Eaementioning

confidence: 99%

“…Spinal cords were isolated at defined time points and fixed overnight with 4% paraformaldehyde at 4°C. Sections were subsequently cryoprotected in 30% sucrose for 5-7 days, separated into 12 coronal sections and embedded in optimum cutting temperature (OCT) formulation (VWR, Radnor, PA, USA) [15,[19][20][21]. Coronal sections (8-μm thick) were cut, and sections were stained with luxol fast blue (LFB) in combination with hematoxylin and eosin (H&E).…”

Section: Histologymentioning

confidence: 99%

T cell-selective deletion of Oct1 protects animals from autoimmune neuroinflammation while maintaining neurotropic pathogen response

Kim

Dickey

Stone

et al. 2019

J Neuroinflammation

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Background Treatments for autoimmune diseases aim to dampen autoreactivity while preserving normal immune function. In CD4 + T cells, the transcription factor Oct1/Pou2f1 is a dispensable transcription factor for T cell development and response to primary infection, but promotes expression of target genes, including Il2 and Ifng , under conditions of antigen reencounter. As a result, they are more strongly expressed upon secondary stimulation. Such repeated antigen encounters occur in memory recall responses, in autoimmunity where self-antigen can be recognized multiple times, and in chronic infection where foreign antigen is persistent. Based on these previous findings, we hypothesized that Oct1 loss would protect animals from autoimmunity but maintain normal responses to pathogens in the CNS. Objective We used a conditional mouse Oct1 ( Pou2f1 ) allele and a CD4-Cre driver to determine the effect of T cell-specific Oct1 loss on autoimmune- and viral-induced neuroinflammation using an autoantigen-driven EAE model of autoimmunity and a JHMV model of viral infection. Results Oct1 conditional deletion mitigated clinical scores and reduced infiltrating T cells and cytokine production in the EAE model. Consistently, Oct1-deficient CD4 + T cells stimulated in vitro showed increased expression of markers associated with T cell anergy, particularly in the absence of co-stimulatory signals. In contrast, anti-viral T cell effector functions are intact in the absence of Oct1, with no changes in neuroinflammation, infiltrating T cells or cytokine production. Conclusion Our findings uncover a significant difference between the effect of Oct1 loss on autoimmune and anti-pathogen responses, which potentially could be exploited for therapeutic benefit. Electronic supplementary material The online version of this article (10.1186/s12974-019-1523-3) contains supplementary material, which is available to authorized users.

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“…Production of IL-17 and CXCL1 has previously been shown to enhance recruitment of neutrophils to inflamed tissues and enhance their activity in certain disease contexts [45-50]. Neutrophil recruitment to the central nervous system however, has been shown to be detrimental in many cases [50-52]. With the increased mRNA levels of both IL-17 and CXCL1 seen in the brain after IL-10R blockade, we wanted to assess whether more neutrophils were recruited to the inflamed brain in this context.…”

Section: Resultsmentioning

confidence: 99%

IL-10 and ICOS differentially regulate T cell responses in the brain during chronicToxoplasma gondiiinfection

OʼBrien

Batista

Still

et al. 2018

Preprint

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25Control of chronic CNS infection with the parasite Toxoplasma gondii requires an ongoing T cell 26 response in the brain. Immunosuppressive cytokines are also important for preventing lethal 27 immunopathology during chronic infection. To explore the loss of suppressive cytokine exclusively 28 during the chronic phase of infection we blocked IL-10 receptor (IL-10R). Blockade was associated with 29 widespread changes in the inflammatory response, including increased antigen presenting cell (APC) 30 activation, expansion of CD4+ T cells, and increased neutrophil recruitment to the brain, consistent with 31 previous reports. We then sought to identify regulatory mechanisms contributing to IL-10 production, 32 focusing on ICOS (inducible T cell costimulator), a molecule that promotes IL-10 production in many 33 systems. Unexpectedly, ICOS-ligand (ICOSL) blockade led to a local expansion of effector T cells in the 34 inflamed brain without affecting IL-10 production or APC activation. Instead, we found that ICOSL 35 blockade led to changes in T cells associated with their proliferation and survival. Specifically, we 36 observed increased expression of IL-2 associated signaling molecules, including CD25, STAT5 37 phosphorylation, Ki67, and Bcl-2 in T cells in the brain. Interestingly, increases in CD25 and Bcl-2 were 38 not observed following IL-10R blockade. Also unlike IL-10R blockade, ICOSL blockade led to an 39 expansion of both CD8+ and CD4+ T cells in the brain, with no expansion of peripheral T cell 40 populations or neutrophil recruitment to the brain Overall, these results suggest that IL-10 and ICOS 41 differentially regulate T cell responses in the brain during chronic T. gondii infection. 42 45 themselves. The importance of a balanced immune response is apparent in models of infection, where 46 inflammation is required for pathogen control and survival, yet amplified immune responses observed 47 after depletion of regulatory T cells or immunosuppressive cytokines often leads to exacerbated tissue 48 pathology and increased mortality [3-8]. One such immunosuppressive cytokine, IL-10, has been broadly 49 studied in the context of both tissue homeostasis and during infection, and has been shown to play a key 50 role in suppressing many aspects of an immune response. Production of IL-10 during immune responses 51 to infection has been attributed to a wide variety of cell types, including T cells, dendritic cells, 52 macrophages, NK cells, and B cells [9]. IL-10 also acts on a wide range of cell types, with one of its main 53 roles being the downregulation of MHC and costimulatory molecules in antigen presenting cells (APCs), 54 thereby preventing their full activation capacity and limiting T cell responses [10-12]. IL-10 also has 55 direct effects on T cells, limiting IFNγ and IL-2 production, as well as T cell proliferation in vitro [13, 56 14]. 57Infection with the eukaryotic parasite Toxoplasma gondii leads to widespread activation of the 58 immune system and systemic inflammation that is required for h...

show abstract

Induced CNS expression of CXCL1 augments neurologic disease in a murine model of multiple sclerosis via enhanced neutrophil recruitment

Cited by 34 publications

References 65 publications

Disrupted CXCR2 Signaling in Oligodendroglia Lineage Cells Enhances Myelin Repair in a Viral Model of Multiple Sclerosis

Disrupted CXCR2 Signaling in Oligodendroglia Lineage Cells Enhances Myelin Repair in a Viral Model of Multiple Sclerosis

T cell-selective deletion of Oct1 protects animals from autoimmune neuroinflammation while maintaining neurotropic pathogen response

IL-10 and ICOS differentially regulate T cell responses in the brain during chronicToxoplasma gondiiinfection

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