Diversity of innate immune cell subsets across spatial and temporal scales in an EAE mouse model

Caravagna, Céline; Jaouën, Alexandre; Desplat‐Jégo, Sophie; Fenrich, Keith K.; Bergot, Elise; Luche, Hervé; Grenot, Pierre; Rougon, Geneviève; Malissen, Marie; Debarbieux, Franck

doi:10.1038/s41598-018-22872-y

Cited by 66 publications

(61 citation statements)

References 46 publications

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“…To test this, we examined the lumbar spinal cord ventral horn because it is the residential address of lower motor neurons and interneurons, both indispensable for normal functioning of hindlimbs [46,47]. Further, neutrophils are more abundant in the ventral spinal cord than in lateral areas [48]. Neutrophil-specific Cxcr2 ablation markedly improved spinal cord neuron morphology, as measured by neuron soma size and dendritic density, at late-phase EAE.…”

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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“…Finally, my team recently reported that neutrophils invade the spinal cord before monocyte-derived macrophages in EAE mice (Caravagna et al, 2018). But if it is correct, as Tsutsui et al (2018) conclude, that decreased production of CXCL2 by macrophages in TRPM2-KO mice re-duces neutrophil infiltration, neutrophils would have to enter the spinal cord after monocyte-derived macrophages.…”

Section: Review Of Tsutsui Et Almentioning

confidence: 98%

Intricate Interplay between Innate Immune Cells and TRMP2 in a Mouse Model of Multiple Sclerosis

Caravagna

2019

J. Neurosci.

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“…Nevertheless, hematopoieticderived myeloid cells including neutrophils, monocytes, and DCs are likely to be important mediators of Dectin-1 function in EAE. Neutrophils in particular may be involved, given their abundance 40 , protective functions 41 , and localization at sites of demyelination and axonal damage in the SC parenchyma during EAE 63, 64, 65 66, 67 . While the role of neutrophils in MS remains elusive, multiple studies suggest involvement of neutrophils, or granulocytic myeloid-derived suppressor cells (G-MDSCs), in both MS and EAE 41,68,69,70,71,72,73,74,75,76 .…”

Section: Studies On Clrs In Eae and Related Models Have Mostly Focusementioning

confidence: 99%

Dectin-1 limits central nervous system autoimmunity through a non-canonical pathway

Deerhake

Danzaki

Inoue

et al. 2020

Preprint

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Pathologic roles for innate immunity in neurologic disorders are well-described, but protective aspects of the immune response are less understood. Dectin-1, a C-type lectin receptor (CLR), is largely known to induce inflammation. However, we found that Dectin-1 is protective in experimental autoimmune encephalomyelitis (EAE), while its canonical signaling mediator, Card9, promotes the disease. Notably, Dectin-1 does not respond to heat-killed Mycobacteria, an adjuvant to induce EAE. Myeloid cells mediate the protective function of Dectin-1 in EAE and upregulate gene expression of neuroprotective molecules, including Oncostatin M (Osm) through a non-canonical Card9-independent pathway, mediated by NFAT. Furthermore, we found that the Osm receptor (OsmR) functions specifically in astrocytes to reduce EAE severity. Our study revealed a new mechanism of protective myeloid-astrocyte crosstalk regulated by a non-canonical Dectin-1 pathway and identifies novel therapeutic targets for CNS autoimmunity.development. We found that non-canonical Card9-independent Dectin-1 signaling involving NFAT drives expression of Oncostatin M (Osm), an IL-6 family cytokine with neuroprotective functions 16,17,18 , and signaling through the Osm receptor (OsmR) on astrocytes reduces disease progression and promotes recovery in EAE. Furthermore, we identified a Card9-independent Dectin-1-mediated transcriptional program driving expression of Osm and other neuroprotective genes. Our findings provoke a re-consideration of Dectin-1 signaling and functions by identifying a new mechanism of protective myeloid-astrocyte communication in CNS autoimmunity. RESULTS Elevated gene expression of the C-type lectin receptor, Dectin-1 (CLEC7A) in MS lesionsWe evaluated gene expression of CLRs in multiple datasets profiling MS brain lesions 18 .Among genes encoding CLRs with known immune functions, CLEC7A (Dectin-1) and CLEC4A (DCIR), closely linked on chromosome 12, were notable for their elevated expression in MS brain specimens in two independent datasets ( Supplementary Fig. 1a-c) 19, 20, 21 , suggesting possible involvement of Dectin-1 and DCIR in MS. In EAE, DCIR has been reported to be protective 22,23 but the function of Dectin-1 in CNS autoimmunity remained unknown. Dectin-1 is a protective C-type lectin receptor in EAENext, we sought to test the function of Dectin-1 in CNS autoimmunity using EAE induced with the MOG35−55 autoantigen peptide. We initially hypothesized that Dectin-1 may exacerbate EAE severity by promoting IL-1β expression and Th17 differentiation, given its known role in antifungal immunity 3, 4 and the pathogenicity of Th17 cells in EAE development 24 . Instead, we found that Dectin-1-deficient (Clec7a -/-) mice developed more severe disease than WT mice (Fig. 1a). A mild EAE induction with a reduced amount of adjuvant also showed the protective effect of Dectin-1 (Fig. 1b). Next, we tested whether administering a Dectin-1 agonist was sufficient to limit EAE severity. To test this, we used hot alkali-depleted zymosan (d-zymosa...

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Diversity of innate immune cell subsets across spatial and temporal scales in an EAE mouse model

Cited by 66 publications

References 46 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

Intricate Interplay between Innate Immune Cells and TRMP2 in a Mouse Model of Multiple Sclerosis

Dectin-1 limits central nervous system autoimmunity through a non-canonical pathway

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