The proportion of myeloid-derived suppressor cells in the spleen is related to the severity of the clinical course and tissue damage extent in a murine model of multiple sclerosis

Melero-Jerez, Carolina; Alonso-Gómez, Aitana; Moñivas, Esther; Lebrón-Galán, Rafael; Machín-Díaz, Isabel; Castro, Fernando de; Clemente, Diego

doi:10.1016/j.nbd.2020.104869

Cited by 36 publications

(64 citation statements)

References 90 publications

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“…In this study, we examined whether circulating PRR ligands produced constitutively by the gut microbiome regulate the splenic Ly6C high monocyte homeostasis and function during steady state. Our study focused on splenic Ly6C high monocytes as these immune cells play a regulatory role in the pathogenesis of many diseases such as EAE (Zhu et al, 2007;Melero-Jerez et al, 2020), ALS (Butovsky et al, 2012), stroke (Seifert and Offner, 2018;Pennypacker and Offner, 2015), atherosclerosis (Robbins et al, 2012;Swirski et al, 2016), ischemic myocardial injury (Leuschner et al, 2012;Swirski et al, 2009), lung ischemia-reperfusion injury (Hsiao et al, 2018), colitis (Griseri et al, 2012) and several tumor models (Cortez-Retamozo et al, 2012;Richards et al, 2013;Wu et al, 2018). We induced dysbiosis of the gut microbiome by administering a broad-spectrum antibiotic cocktail for a very short time period, compared with other studies (Kennedy et al, 2018), to identify the direct role of circulating PRR ligands on the maintenance of monocytes.…”

Section: Discussionmentioning

confidence: 99%

“…During the onset of EAE, splenic Ly6C high monocytes acquire an immunosuppressive function (Zhu et al, 2007), which they maintain within the central nervous system (CNS) as they express Nos2 and Arg1, hallmark genes of myeloid-derived suppressor cells (Zhu et al, 2007;Giladi et al, 2020). Their abundance has recently been related to a milder EAE course (Melero-Jerez et al, 2020). Splenic Ly6C high monocytes are also involved in the regulation of amyotrophic lateral sclerosis (ALS) because they acquire an M1 signature before disease onset and treatment with an anti-Ly6C monoclonal antibody leads to reduced monocyte recruitment to the spinal cord, diminished neuronal loss, and extended survival in mice (Butovsky et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

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Regulation of splenic monocyte homeostasis and function by gut microbial products

et al. 2021

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Summary Splenic Ly6C high monocytes are innate immune cells involved in the regulation of central nervous system-related diseases. Recent studies have reported the shaping of peripheral immune responses by the gut microbiome via mostly unexplored pathways. In this study, we report that a 4-day antibiotic treatment eliminates certain families of the Bacteroidetes, Firmicutes, Tenericutes, and Actinobacteria phyla in the gut and reduces the levels of multiple pattern recognition receptor (PRR) ligands in the serum. Reduction of PRR ligands was associated with reduced numbers and perturbed function of splenic Ly6C high monocytes, which acquired an immature phenotype producing decreased levels of inflammatory cytokines and exhibiting increased phagocytic and anti-microbial abilities. Addition of PRR ligands in antibiotic-treated mice restored the number and functions of splenic Ly6C high monocytes. Our data identify circulating PRR ligands as critical regulators of the splenic Ly6C high monocyte behavior and suggest possible intervention pathways to manipulate this crucial immune cell subset.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Regulation of splenic monocyte homeostasis and function by gut microbial products

et al. 2021

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“…Although the adoptive transfer was conducted with MOG-Th1 cells and the active immunization model is highly skewed toward a Th1 cell repertoire, we can’t ignore that many other immune cells contribute to EAE neuroinflammation. Peripheral myeloid cells, including macrophages, dendritic cells, and neutrophils, exhibit a prominent role during EAE, and are a major component of MS lesions ( Levesque et al, 2016 ; Giles et al, 2018 ; Tsai et al, 2019 ; Ifergan and Miller, 2020 ; Lu et al, 2020 ; Melero-Jerez et al, 2020 ; Owens et al, 2020 ; Tanwar et al, 2020 ; Wasser et al, 2020 ). Likewise, myeloid cells are both primary sources and targets of IL-20 subfamily cytokines ( Hsu et al, 2006 , 2011 ; Kragstrup et al, 2008 ; Wolk et al, 2008 , 2009a ; Wang et al, 2012 ; Rutz et al, 2014 ; Mayer et al, 2015 ; Bech et al, 2016 ; Kako et al, 2016 ; Gough et al, 2017 ; Senolt et al, 2017 ; Zhang et al, 2017 ; Dabitao et al, 2018 ; Niess et al, 2018 ; Weng et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Expression of IL-20 Receptor Subunit β Is Linked to EAE Neuropathology and CNS Neuroinflammation

Dayton

Yuan

Pacumio

et al. 2021

Front. Cell. Neurosci.

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Considerable clinical evidence supports that increased blood–brain barrier (BBB) permeability is linked to immune extravasation of CNS parenchyma during neuroinflammation. Although BBB permeability and immune extravasation are known to be provoked by vascular endothelial growth factor-A (i.e., VEGF-A) and C-X-C motif chemokine ligand 12 (CXCL12), respectively, the mechanisms that link both processes are still elusive. The interleukin-20 (i.e., IL-20) cytokine signaling pathway was previously implicated in VEGF-mediated angiogenesis and is known to induce cellular response by way of signaling through IL-20 receptor subunit β (i.e., IL-20RB). Dysregulated IL-20 signaling is implicated in many inflammatory pathologies, but it’s contribution to neuroinflammation has yet to be reported. We hypothesize that the IL-20 cytokine, and the IL cytokine subfamily more broadly, play a key role in CNS neuroinflammation by signaling through IL-20RB, induce VEGF activity, and enhance both BBB-permeability and CXCL12-mediated immune extravasation. To address this hypothesis, we actively immunized IL-20RB–/– mice and wild-type mice to induce experimental autoimmune encephalomyelitis (EAE) and found that IL-20RB–/– mice showed amelioration of disease progression compared to wild-type mice. Similarly, we passively immunized IL-20RB–/– mice and wild-type mice with myelin-reactive Th1 cells from either IL-20RB–/– and wild-type genotype. Host IL-20RB–/– mice showed lesser disease progression than wild-type mice, regardless of the myelin-reactive Th1 cells genotype. Using multianalyte bead-based immunoassay and ELISA, we found distinctive changes in levels of pro-inflammatory cytokines between IL-20RB–/– mice and wild-type mice at peak of EAE. We also found detectable levels of all cytokines of the IL-20 subfamily within CNS tissues and specific alteration to IL-20 subfamily cytokines IL-19, IL-20, and IL-24, expression levels. Immunolabeling of CNS region-specific microvessels confirmed IL-20RB protein at the spinal cord microvasculature and upregulation during EAE. Microvessels isolated from macaques CNS tissues also expressed IL-20RB. Moreover, we identified the expression of all IL-20 receptor subunits: IL-22 receptor subunit α-1 (IL-22RA1), IL-20RB, and IL-20 receptor subunit α (IL-20RA) in human CNS microvessels. Notably, human cerebral microvasculature endothelial cells (HCMEC/D3) treated with IL-1β showed augmented expression of the IL-20 receptor. Lastly, IL-20-treated HCMEC/D3 showed alterations on CXCL12 apicobasal polarity consistent with a neuroinflammatory status. This evidence suggests that IL-20 subfamily cytokines may signal at the BBB via IL-20RB, triggering neuroinflammation.

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“…A1 positive myeloid cells have been found to be upregulated during the progression of EAE [59][60][61] and their presence was shown to be inversely correlated with the severity of disease with greater expression at the earlier stage [61,80]. These A1 expressing cells, especially the myeloid-derived suppressor cells are hypothesized to inhibit T-cell activation and therefore, may dampen the autoimmune-mediated demyelination in EAE [81,82]. A report by Xu et al provided data showing a less severe EAE phenotype in mice treated with the arginase inhibitor, amino-6-boronohexanoic acid (ABH) [57].…”

Section: Plos Onementioning

confidence: 99%

Deletion of arginase 2 attenuates neuroinflammation in an experimental model of optic neuritis

et al. 2021

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Vision impairment due to optic neuritis (ON) is one of the major clinical presentations in Multiple Sclerosis (MS) and is characterized by inflammation and degeneration of the optic nerve and retina. Currently available treatments are only partially effective and have a limited impact on the neuroinflammatory pathology of the disease. A recent study from our laboratory highlighted the beneficial effect of arginase 2 (A2) deletion in suppressing retinal neurodegeneration and inflammation in an experimental model of MS. Utilizing the same model, the present study investigated the impact of A2 deficiency on MS-induced optic neuritis. Experimental autoimmune encephalomyelitis (EAE) was induced in wild-type (WT) and A2 knockout (A2-/-) mice. EAE-induced cellular infiltration, as well as activation of microglia and macrophages, were reduced in A2-/- optic nerves. Axonal degeneration and demyelination seen in EAE optic nerves were observed to be reduced with A2 deletion. Further, the lack of A2 significantly ameliorated astrogliosis induced by EAE. In conclusion, our findings demonstrate a critical involvement of arginase 2 in mediating neuroinflammation in optic neuritis and suggest the potential of A2 blockade as a targeted therapy for MS-induced optic neuritis.

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The proportion of myeloid-derived suppressor cells in the spleen is related to the severity of the clinical course and tissue damage extent in a murine model of multiple sclerosis

Cited by 36 publications

References 90 publications

Regulation of splenic monocyte homeostasis and function by gut microbial products

Regulation of splenic monocyte homeostasis and function by gut microbial products

Expression of IL-20 Receptor Subunit β Is Linked to EAE Neuropathology and CNS Neuroinflammation

Deletion of arginase 2 attenuates neuroinflammation in an experimental model of optic neuritis

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