Distinct functionality of neutrophils in multiple sclerosis and neuromyelitis optica

Hertwig, Laura; Pache, Florence; Romero-Suárez, Silvina; Stürner, Klarissa Hanja; Borisow, Nadja; Behrens, Janina; Bellmann‐Strobl, Judith; Seeger, Bibiane; Asselborn, Natascha; Ruprecht, Klemens; Millward, Jason M.; Infante-Duarte, Carmen; Paul, Friedemann

doi:10.1177/1352458515586084

Cited by 59 publications

(57 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Regarding the effects of peripheral infection on exacerbation of neurological diseases, the ELR group of CXC chemokines is of particular interest since these chemokines are particularly important in facilitating neutrophil trafficking. Notably, multiple lines of evidence suggest that neutrophil trafficking to the CNS exacerbates neurodegenerative diseases such as multiple sclerosis (Blackmore et al, 2017;Hemond, Glanz, Bakshi, Chitnis, & Healy, 2019;Hertwig et al, 2016), Alzheimer's disease (Zenaro et al, 2015), and Amyotrophic lateral sclerosis (Trias et al, 2018).…”

Section: Introductionmentioning

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

View full text Add to dashboard Cite

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.

show abstract

Section: Introductionmentioning

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

View full text Add to dashboard Cite

show abstract

“…The purpose of this study was to characterize the histopathology of inflammatory foci in our cuprizone‐EAE model. Specifically, we sought to determine the composition of inflammatory infiltrates, which can include T lymphocytes and macrophages (Lucchinetti et al, ), as well as activated astrocytes and microglia and neutrophil granulocytes (Hertwig et al, ). We found that fluorescently labeled microglia and monocytes are both present in inflammatory lesions, with gene expression studies implicating the involvement of the chemokines C–X–C motif ligand 10 (CXCL10), C–C motif ligand 2 (CCL2), and C–C motif ligand 3 (CCL3) in inflammatory lesion formation.…”

Section: Introductionmentioning

confidence: 99%

Combination of cuprizone and experimental autoimmune encephalomyelitis to study inflammatory brain lesion formation and progression

Rüther

Scheld

Dreymueller

et al. 2017

Glia

View full text Add to dashboard Cite

Brain-intrinsic degenerative cascades are a proposed factor driving inflammatory lesion formation in multiple sclerosis (MS) patients. We recently described a model combining noninflammatory cytodegeneration (via cuprizone) with the classic active experimental autoimmune encephalomyelitis (Cup/EAE model), which exhibits inflammatory forebrain lesions. Here, we describe the histopathological characteristics and progression of these Cup/EAE lesions. We show that inflammatory lesions develop at various topographical sites in the forebrain, including white matter tracts and cortical and subcortical grey matter areas. The lesions are characterized by focal demyelination, discontinuation of the perivascular glia limitans, focal axonal damage, and neutrophil granulocyte extravasation. Transgenic mice with enhanced green fluorescent protein-expressing microglia and red fluorescent protein-expressing monocytes reveal that both myeloid cell populations contribute to forebrain inflammatory infiltrates. EAE-triggered inflammatory cerebellar lesions were augmented in mice pre-intoxicated with cuprizone. Gene expression studies suggest roles of the chemokines Cxcl10, Ccl2, and Ccl3 in inflammatory lesion formation. Finally, follow-up experiments in Cup/EAE mice with chronic disease revealed that forebrain, but not spinal cord, lesions undergo spontaneous reorganization and repair. This study underpins the significance of brain-intrinsic degenerative cascades for immune cell recruitment and, in consequence, MS lesion formation.

show abstract

“…The evidence for the involvement of granulocytes in the pathogenesis of MS has been scarce so far, while some early studies indicate a role of neutrophils in NMOSD pathogenesis. (7,8) In this study, we provide the first evidence for the existence of LDGs in MS and NMOSD and thus add another puzzle piece to the role of the innate immune system in the pathogenesis of these diseases.…”

Section: Introductionmentioning

confidence: 72%

“…This study demonstrates the presence of LDGs in MS and NMOSD. In contrast to MS, in NMO classical granulocytes are thought to play a pivotal role as they can be found in tissue biopsies (7) and alterations in neutrophil function have been described (8). We recently described CD11b+ leucocytes in the PBMCs of MS patients that were characterized by increased activation of NAD(P)H oxidase (NOX).…”

Section: Discussionmentioning

confidence: 99%

Low-Density Granulocytes are a novel immunopathological feature in both Multiple Sclerosis and Neuromyelitis optica spectrum disorder

Ostendorf

Mothes

Köppen

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

Objective: To investigate whether low-density granulocytes (LDGs) are a immunophenotypic feature of patients with multiple sclerosis (MS) and/or neuromyelitis optica spectrum disorder (NMOSD).Methods: Blood samples were collected from 26 patients with NMOSD and 20 patients with MS, as well as from 18 patients with Systemic Lupus Erythematosus (SLE) and 23 Healthy Donors (HD). We isolated peripheral blood mononuclear cells (PBMCs) with density gradient separation and stained the cells with antibodies against CD14, CD15, CD16, and CD45, and analysed the cells by flow cytometry or imaging flow cytometry. We defined LDGs as CD14 -CD15 high and calculated their share in total PBMC leukocytes (CD45 + ) as well as the share of CD16 hi LDGs. Clinical data on disease course, medication, and antibody status were obtained.Results: LDGs were significantly more common in MS and NMOSD than in HDs, comparable to SLE samples (median values HD 0.2%, MS 0.9%, NMOSD 2.1%, SLE 4.3%). 0/23 of the HDs, but 17/20 NMOSD and 11/17 MS samples as well as 13/15 SLE samples had at least 0.7 % LDGs. NMOSD patients without continuous immunosuppressive treatment had significantly more LDGs compared to their treated counterparts. LDG nuclear morphology ranged from segmented to rounded, suggesting a heterogeneity within the group. Conclusion:LDGs are a feature of the immunophenotype in some patients with MS and NMOSD.

show abstract

Distinct functionality of neutrophils in multiple sclerosis and neuromyelitis optica

Abstract: Although NMO and MS neutrophils display an activated phenotype in comparison with HC, NMO neutrophils show a compromised functionality when compared with MS patients. These results suggest a distinct functional profile of neutrophils in MS and NMO.

Cited by 59 publications

References 30 publications

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

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

Combination of cuprizone and experimental autoimmune encephalomyelitis to study inflammatory brain lesion formation and progression

Low-Density Granulocytes are a novel immunopathological feature in both Multiple Sclerosis and Neuromyelitis optica spectrum disorder

Contact Info

Product

Resources

About