IL-1β enables CNS access to CCR2
            <sup>hi</sup>
            monocytes and the generation of pathogenic cells through GM-CSF released by CNS endothelial cells

Paré, Alexandre; Mailhot, Benoit; Lévesque, Sébastien A.; Juźwik, Camille A.; Doss, Prenitha Mercy Ignatius Arokia; Lécuyer, Marc-André; Prat, Alexandre; Rangachari, Manu; Fournier, Alyson E.; Lacroix, Steve

doi:10.1073/pnas.1714948115

Cited by 82 publications

(73 citation statements)

References 41 publications

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“…Of interest, our results show that double-deficient mice in NCF1 and NOS2 exhibited an increase pro-IL-1β expression in neutrophils and a rapid development of enhanced EAE. Moreover, we did not find a similar increase in monocyte-limited pro-IL-1β expression in double-deficient mice, and our results are different from the published data that the periphery monocyte was the key to drive EAE by releasing IL-1β [42].…”

Section: Discussioncontrasting

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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Section: Discussioncontrasting

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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“…The significant inflammatory role of GM-CSF in autoimmune disorders such as multiple sclerosis (MS) and rheumatoid arthritis (RA) has recently been shown 3,31 . Even though the mechanistic basis of the GM-CSF inflammatory role has not been fully elucidated, its biological and clinical implications are clear [32][33][34][35][36] .…”

Section: Discussionmentioning

confidence: 99%

Evaluation of the effect of GM-CSF blocking on the phenotype and function of human monocytes

Lotfi

Zhang

Esmaeil

et al. 2020

Sci Rep

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Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a multipotent cytokine that prompts the proliferation of bone marrow-derived macrophages and granulocytes. In addition to its effects as a growth factor, GM-CSF plays an important role in chronic inflammatory autoimmune diseases such as multiple sclerosis and rheumatoid arthritis. Reports have identified monocytes as the primary target of GM-CSF; however, its effect on monocyte activation has been under-estimated. Here, using flow cytometry and ELISA we show that GM-CSF induces an inflammatory profile in human monocytes, which includes an upregulated expression of HLA-DR and CD86 molecules and increased production of TNF-α and IL-1β. Conversely, blockage of endogenous GM-CSF with antibody treatment not only inhibited the inflammatory profile of these cells, but also induced an immunomodulatory one, as shown by increased IL-10 production by monocytes. Further analysis with qPCR, flow cytometry and ELISA experiments revealed that GM-CSF blockage in monocytes stimulated production of the chemokine CXCL-11, which suppressed T cell proliferation. Blockade of CXCL-11 abrogated anti-GM-CSF treatment and induced inflammatory monocytes. Our findings show that anti-GM-CSF treatment induces modulatory monocytes that act in a CXCL-11-dependent manner, a mechanism that can be used in the development of novel approaches to treat chronic inflammatory autoimmune diseases.

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“…Cortical neurons from wildtype (WT) C57Bl/6 mice were prepared as previously described (Juzwik et al ., 2018; Pare et al ., 2018). Cortical neurons were seeded in 48-wells at 80 000 cells/well and aged 4 DIV prior to addition of PBMC-CM.…”

Section: Methodsmentioning

confidence: 99%

MicroRNA-223 protects neurons from degeneration in Experimental Autoimmune Encephalomyelitis

Morquette

Juźwik

Drake

et al. 2018

Preprint

Self Cite

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Multiple sclerosis (MS) is an autoimmune disease characterized by demyelination and neurodegeneration in the brain, spinal cord and optic nerve. Neuronal degeneration and death underlie progressive forms of MS and cognitive dysfunction. Neuronal damage is triggered by numerous harmful factors in the brain that engage diverse signalling cascades in neurons thus therapeutic approaches to protect neurons will need to focus on agents that can target broad biological processes. To target the broad spectrum of signaling events that mediate neurodegeneration in MS we have focused on non-coding small microRNAs (miRNAs). microRNAs are epigenetic regulators of protein expression, targeting messenger RNAs (mRNAs) and inhibiting their translation. Dysregulation of miRNAs has been described in many neurodegenerative diseases including MS. In this study we identified two miRNAs, miR-223-3p and miR-27a-3p, that were upregulated in neurons in the experimental autoimmune encephalomyelitis (EAE) mouse model of CNS inflammation and in active MS lesions. Overexpression of miR-27a-3p or miR-223-3p protected dissociated cortical neurons from degeneration in response to peripheral blood mononuclear cell conditioned media (PBMC-CM). Introduction of miR-223-3p in vivo in mouse retinal ganglion cells (RGCs) protected RGC axons from degeneration in the EAE model. By in silico analysis we found that mRNAs in the glutamate receptor (GluR) pathway are enriched in miR-27a-3p and miR-223-3p targets. Antagonism of the GluR pathway protected neurons from PBMC-CM-dependent degeneration. Our results suggest that miR-223-3p and miR-27a-3p are upregulated in response to inflammation to mediate a compensatory neuroprotective gene expression program that desensitizes neurons to glutamate by downregulating mRNAs involved in GluR signalling.

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IL-1β enables CNS access to CCR2 ^hi monocytes and the generation of pathogenic cells through GM-CSF released by CNS endothelial cells

Cited by 82 publications

References 41 publications

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

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

Evaluation of the effect of GM-CSF blocking on the phenotype and function of human monocytes

MicroRNA-223 protects neurons from degeneration in Experimental Autoimmune Encephalomyelitis

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IL-1β enables CNS access to CCR2 hi monocytes and the generation of pathogenic cells through GM-CSF released by CNS endothelial cells

Cited by 82 publications

References 41 publications

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

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

Evaluation of the effect of GM-CSF blocking on the phenotype and function of human monocytes

MicroRNA-223 protects neurons from degeneration in Experimental Autoimmune Encephalomyelitis

Contact Info

Product

Resources

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IL-1β enables CNS access to CCR2 ^hi monocytes and the generation of pathogenic cells through GM-CSF released by CNS endothelial cells