Deficiency of Socs3 leads to brain-targeted experimental autoimmune encephalomyelitis via enhanced neutrophil activation and ROS production

Yan, Zhaoqi; Yang, Wei; Parkitny, Luke; Gibson, Sara A.; Lee, Kevin M.; Collins, Forrest; Deshane, Jessy; Cheng, Wen; Weinmann, Amy S.; Wei, Hairong; Qin, Hongwei; Benveniste, Etty N.

doi:10.1172/jci.insight.126520

Cited by 42 publications

(43 citation statements)

References 102 publications

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“…Neutrophils can be direct inducers of neuron damage via enhanced secretion of neurotoxic elastases [58], ROS [59], and extracellular traps [23]. Understanding the range of effector functions that neutrophils can exert upon neurons is important because neutrophils invade CNS parenchyma in multiple contexts of neuroinflammation, including MS, Alzheimer's disease, and ischemic CNS damage [60].…”

Section: Discussionmentioning

confidence: 99%

Neutrophil-selective deletion of Cxcr2 protects against CNS neurodegeneration in a mouse model of multiple sclerosis

Khaw

Cunningham

Tierney

et al. 2020

J Neuroinflammation

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Background: Multiple sclerosis (MS) is a chronic debilitating immune-mediated disease of the central nervous system (CNS) driven by demyelination and gray matter neurodegeneration. We previously reported an experimental autoimmune encephalomyelitis (EAE) MS mouse model with elevated serum CXCL1 that developed severe and prolonged neuron damage. Our findings suggested that CXCR2 signaling may be important in neuronal damage, thus implicating neutrophils, which express CXCR2 in abundance, as a potential cell type involved. The goals of this study were to determine if CXCR2 signaling in neutrophils mediate neuronal damage and to identify potential mechanisms of damage. Methods: EAE was induced in wild-type control and neutrophil-specific Cxcr2 knockout (Cxcr2 cKO) mice by repeated high-dose injections of heat-killed Mycobacterium tuberculosis and MOG 35-55 peptide. Mice were examined daily for motor deficit. Serum CXCL1 level was determined at different time points throughout disease development. Neuronal morphology in Golgi-Cox stained lumbar spinal cord ventral horn was assessed using recently developed confocal reflection super-resolution technique. Immune cells from CNS and lymphoid organs were quantified by flow cytometry. CNS-derived neutrophils were co-cultured with neuronal crest cells and neuronal cell death was measured. Neutrophils isolated from lymphoid organs were examined for expression of reactive oxygen species (ROS) and ROS-related genes. Thioglycolate-activated neutrophils were isolated, treated with recombinant CXCL1, and measured for ROS production. Results: Cxcr2 cKO mice had less severe disease symptoms at peak and late phase when compared to control mice with similar levels of CNS-infiltrating neutrophils and other immune cells despite high levels of circulating CXCL1. Additionally, Cxcr2 cKO mice had significantly reduced CNS neuronal damage in the ventral horn of the spinal cord. Neutrophils isolated from control EAE mice induced vast neuronal cell death in vitro when compared with neutrophils isolated from Cxcr2 cKO EAE mice. Neutrophils isolated from control EAE mice, but not Cxcr2 cKO mice, exhibited elevated ROS generation, in addition to heightened Ncf1 and Il1b transcription. Furthermore, recombinant CXCL1 was sufficient to significantly increase neutrophils ROS production. Conclusions: CXCR2 signal in neutrophils is critical in triggering CNS neuronal damage via ROS generation, which leads to prolonged EAE disease. These findings emphasize that CXCR2 signaling in neutrophils may be a viable target for therapeutic intervention against CNS neuronal damage.

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Section: Discussionmentioning

confidence: 99%

Neutrophil-selective deletion of Cxcr2 protects against CNS neurodegeneration in a mouse model of multiple sclerosis

Khaw

Cunningham

Tierney

et al. 2020

J Neuroinflammation

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“…In agreement with this hypothesis deletion of SOCS3 in neutrophils was found to exacerbate EAE symptoms (Qin et al, ). Moreover, atypical EAE symptoms arising from conditional deletion of Socs3 in neutrophils were, in part, alleviated by G‐CSF neutralization or treatment with an ROS scavenger cocktail (Yan et al, ). The initiating signals within the brain that promote neutrophil trafficking to the CNS remain uncertain.…”

Section: Discussionmentioning

confidence: 99%

“…Neutrophils have garnered attention for their involvement in EAE (Pierson, Wagner, & Goverman, 2018), ability to facilitate demyelination (Bell et al, 1996;Ferrari et al, 2004;Liu et al, 2010) Ferrari et al, 2004Bell et al, 1996) and promote neurodegeneration (Zenaro et al, 2015). Indeed, neutrophil accumulation in the brain during experimental autoimmune encephalomyelitis (EAE) appears to underlie 'atypical' signs of disease characterized by clinical appearance of hunching, head tilt, ataxia, axial rotation and spinning (Yan, Yang, & Parkitny, 2019), which contrasts the traditional disease symptoms that are characterized by ascending paralysis. Mechanistically, neutrophil-mediated pathology and resulting atypical disease are thought to be dependent on G-CSF-stimulated STAT3 activation and reactive oxygen species (ROS) production.…”

Section: Discussionmentioning

confidence: 99%

TAK1 inhibition in mouse astrocyte cultures ameliorates cytokine‐induced chemokine production and neutrophil migration

Soto-Diaz

Juda

Blackmore

et al. 2019

Journal of Neurochemistry

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Systemic inflammation can exacerbate symptoms of many neurological diseases. This effect may be facilitated by glial cells of the central nervous system (CNS) that alter their transcriptional responses and up‐regulate cytokine and chemokine expression which can, in turn trigger immune surveillance. In this study, we sought to determine the effects of pro‐inflammatory cytokine stimulation (TNF, IL‐1α, IL‐1β) on astrocyte and microglia chemokine secretion. Primary cultures of astrocytes or microglia were stimulated with the recombinant cytokines and the levels of secreted chemokines were semi‐quantitatively determined using a chemokine‐specific proteome profiler array and densitometry. Pharmacological inhibitors were used to determine the effects of p38 MAPK, JNK, ERK1/2, NFkB, and transforming growth factor beta‐associated kinase 1 (TAK1) in controlling chemokine production. Finally, neutrophil migration assays were performed to demonstrate functionality. Our data show that stimulated astrocytes secrete at least eight chemokines as a response to cytokine stimulation. These include those involved in neutrophil chemo‐attraction and proved capable of promoting neutrophil migration in vitro. In contrast, microglia up‐regulated few chemokines in response to cytokine stimulation and did not promote neutrophil migration. However, microglia readily secreted chemokines following stimulation with the toll‐like receptor agonists. Finally, we show that both the production of chemokines and neutrophil migration resulting from cytokine stimulation of astrocytes was dependent on TAK1 signaling. Collectively, this study adds to the understanding of how astrocytes and microglia respond to stimuli and their role in promoting neutrophil migration to the CNS during inflammatory conditions.

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“…The oxidative mechanisms underlaying transcription of the gene encoding the IL-1β precursor pro-IL-1β, pro-IL-1β processing, and IL-1β cellular export are not understood well yet. IL-1β transcription can be induced by pertussis toxin at the time of immunization, and increased recruitment of pro-IL-1β-producing neutrophils from the bone marrow to draining lymph nodes and the spleen was required for EAE induction [33][34][35]. Interestingly, the peak number of blood-derived neutrophils infiltrated into the brain of C57/BL6 mice was on day 4 post injection of pertussis toxin alone [33].…”

Section: Discussionmentioning

confidence: 99%

Independent and inter-dependent immunoregulatory effects of NCF1 and NOS2 in experimental autoimmune encephalomyelitis

Zhong

Yau

Holmdahl

2020

J Neuroinflammation

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Background: Increasing evidence has suggested that a single nucleotide polymorphism in the Ncf1 gene is associated with experimental autoimmune encephalomyelitis (EAE). However, the mechanisms of NCF1-induced immunoregulatory effects remain poorly understood. In this study, we focus on NCF1 deficiency-mediated effects on EAE in NOS2 dependent and independent ways. Methods: To determine the effects of NCF1 and NOS2 during EAE development, we have established recombinant mouse strains deficient at NCF1 and/or NOS2 in a crossbreeding system. Different strains allow us to examine the entire course of the disease in the Nos2-null mice bearing a Ncf1 gene that encodes a mutated NCF1, deficient in triggering oxidative burst, after immunization with recombinant myelin oligodendrocyte glycoprotein (MOG) 79-96 peptides. The peptide-induced innate and adaptive immune responses were analyzed by flow cytometry.Results: NCF1-deficient mice developed a reduced susceptibility to EAE, whereas NCF1-NOS2 double-deficient mice developed an enhanced EAE, as compared with NOS2-deficient mice. Flow cytometry analyses show that double deficiencies resulted in an increase of neutrophils in the spleen, accompanied with higher release of interleukin-1β in neutrophils prior to EAE onset. The additional deficiency in NCF1 had no added effect on either interleukin-17 or interferon-γ secretion of T cells during the priming phase.Conclusions: These studies show that NCF1 and NOS2 interact to regulate peptide-induced EAE.

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Deficiency of Socs3 leads to brain-targeted experimental autoimmune encephalomyelitis via enhanced neutrophil activation and ROS production

Cited by 42 publications

References 102 publications

Neutrophil-selective deletion of Cxcr2 protects against CNS neurodegeneration in a mouse model of multiple sclerosis

Neutrophil-selective deletion of Cxcr2 protects against CNS neurodegeneration in a mouse model of multiple sclerosis

TAK1 inhibition in mouse astrocyte cultures ameliorates cytokine‐induced chemokine production and neutrophil migration

Independent and inter-dependent immunoregulatory effects of NCF1 and NOS2 in experimental autoimmune encephalomyelitis

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