Myeloid-derived suppressor cells expressing a self-antigen ameliorate experimental autoimmune encephalomyelitis

Casacuberta-Serra, Sílvia; Costa, Carme; Eixarch, Herena; Mansilla, María José; López‐Estévez, Sergio; Martorell, L.; Parés, Marta; Montalbán, Xavier; Espejo, Carmen; Barquinero, Jordi

doi:10.1016/j.expneurol.2016.09.012

Cited by 22 publications

(15 citation statements)

References 41 publications

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“…Interestingly, EGFR downstream signalling inhibition is a promising strategy in diverse tumour types by inducing MHC-II in APCs and breaking down tolerance [42]. Our data reinforces the idea of targeting EGFR activity as an interesting target to modulate MHC-II expression, either to potentiate it, as in the case of cancer, or to reduce it, as in the case of MS or other autoimmune diseases in which tolerance induction is one of the golden aims in cell-therapy-based strategies [43].…”

Section: Discussionsupporting

confidence: 80%

Tissue plasminogen activator worsens experimental autoimmune encephalomyelitis by complementary actions on lymphoid and myeloid cell responses

Hélie

Toledano

Miralles

et al. 2020

Preprint

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Background Tissue plasminogen activator (tPA) is a serine protease involved in fibrinolysis. It is released by endothelial cells, but also expressed by neurons and glial cells in the central nervous system (CNS). Interestingly, this enzyme also contributes to pathological processes in the CNS such as neuroinflammation by activating microglia and increasing blood-brain-barrier permeability. Nevertheless, its role in the control of adaptive and innate immune response remains poorly understood. Methods tPA effects on myeloid and lymphoid cell response were studied in vivo in the mouse model of multiple sclerosis experimental autoimmune encephalomyelitis and in vitro in splenocytes. Results tPA−/− animals exhibited less severe experimental autoimmune encephalomyelitis than their wild type counterparts. This was accompanied by a reduction in both lymphoid and myeloid cell populations in the spinal cord parenchyma. In parallel, tPA increased T cell activation and proliferation, as well as cytokine production by a protease-dependent mechanism and via plasmin generation. In addition, tPA raised the expression of MHC-II and the co-stimulatory molecule CD80 and CD86 at the surface of dendritic cells and macrophages by an effect dependent of the proteolytic activity of tPA and of the activation of epidermal growth factor receptor. Conclusions Our study provides new insights into the mechanisms responsible for the harmful functions of tPA in multiple sclerosis and its animal models: tPA promotes the proliferation and activation of both lymphoid and myeloid populations by distinct, though complementary, mechanisms.

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Section: Discussionsupporting

confidence: 80%

Tissue plasminogen activator worsens experimental autoimmune encephalomyelitis by complementary actions on lymphoid and myeloid cell responses

Hélie

Toledano

Miralles

et al. 2020

Preprint

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“…MDSCs can block hematoprogenitor cell differentiation and play a critical role in suppressing immune responses. Previous research has demonstrated that MDSCs are important immunosuppres- sive mediators in cancer and inflammatory disorders (29)(30)(31)(32)(33)(34), including endotoxin shock, experimental autoimmune encephalomyelitis, graft-vs.-host disease, rheumatoid arthritis and diabetes. Recently, Foks et al (26) showed MDSCs reduced AS via suppression of pro-inflammatory immune responses in LDLr-deficient mice.…”

Section: Discussionmentioning

confidence: 99%

The inhibitor of autophagy SBI‑0206965 aggravates atherosclerosis through decreasing myeloid‑derived suppressor cells

et al. 2019

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Atherosclerosis (AS) is currently the leading cause of mortality worldwide, with the development of new strategies to prevent the formation and rupture of atherosclerotic plaques being a paramount area of research. Amounting evidence suggests autophagy has an important role in the pathogenesis of AS and may be a potential therapeutic target. In this study, the effect of SBI-0206965(6965), a novel inhibitor of autophagy, was tested on the development of AS in apolipoprotein E deficient (ApoE-/-) mice. Systemic application of 6965 was found to aggravate AS, with increased plaque size and decreased plaque stability in comparison with the control. Of note, it was observed that 6965 decreased the proportion of myeloid-derived suppressor cells (MDSCs). Further investigation demonstrated MDSCs markedly alleviated AS in ApoE-/mice; while 6965 reduced the viability and promoted apoptosis of MDSCs in vitro. This is the first study describing an association between autophagy and MDSCs in AS models, providing a novel mechanism to potentially target in the management of this condition.

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“…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 . Here, further studies using a conditional deletion approach will be essential to determine which myeloid cells mediate protective functions of Dectin-1 in EAE.…”

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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Myeloid-derived suppressor cells expressing a self-antigen ameliorate experimental autoimmune encephalomyelitis

Cited by 22 publications

References 41 publications

Tissue plasminogen activator worsens experimental autoimmune encephalomyelitis by complementary actions on lymphoid and myeloid cell responses

Tissue plasminogen activator worsens experimental autoimmune encephalomyelitis by complementary actions on lymphoid and myeloid cell responses

The inhibitor of autophagy SBI‑0206965 aggravates atherosclerosis through decreasing myeloid‑derived suppressor cells

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

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