Protective roles for myeloid cells in neuroinflammation

Owens, Trevor; Benmamar‐Badel, Anouk; Włodarczyk, Agnieszka; Marczynska, Joanna; Mørch, Marlene; Dubik, Magdalena; Arengoth, Dina S.; Asgari, Nasrin; Webster, Gill; Khorooshi, Reza

doi:10.1111/sji.12963

Cited by 19 publications

(14 citation statements)

References 51 publications

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“…Taken together, simultaneous stimulation of TLR9 and NOD2 receptors appears to induce selective infiltration to the lesion site and reduce lesion formation. Although the mechanistic basis for this selectivity remains unknown, other innate ligands such as poly-I:C (ligand for TLR3) have been shown to recruit myeloid cells into the CNS and attenuate EAE, and ligands for TLR7 and TLR9 have also been shown to reduce EAE disease severity ( Hayashi et al, 2012 ; Longhini et al, 2014 ; Owens et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Innate Signaling in the CNS Prevents Demyelination in a Focal EAE Model

et al. 2021

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The pathological hallmark of multiple sclerosis (MS) is the formation of multifocal demyelinating lesions in the central nervous system (CNS). Stimulation of innate receptors has been shown to suppress experimental autoimmune encephalomyelitis (EAE), an MS-like disease in mice. Specifically, targeting Toll-like receptor 9 (TLR9) and NOD-like receptor 2 (NOD2) significantly reduced disease severity. In the present work we have developed a novel focal EAE model to further study the effect of innate signaling on demyelinating pathology. Focal lesions were induced by stereotactic needle insertion into the corpus callosum (CC) of mice previously immunized for EAE. This resulted in focal pathology characterized by infiltration and demyelination in the CC. We find that intrathecal delivery of MIS416, a TLR9 and NOD2 bispecific innate ligand, into the cerebrospinal fluid reduced focal lesions in the CC. This was associated with upregulation of type I and II interferons, interleukin-10, arginase-1, CCL-2 and CXCL-10. Analysis of draining cervical lymph nodes showed upregulation of type II interferons and interleukin 10. Moreover, intrathecal MIS416 altered the composition of early CNS infiltrates, increasing proportions of myeloid and NK cells and reducing T cells at the lesion site. This study contributes to an increased understanding of how innate immune responses can play a protective role, which in turn may lead to additional therapeutic strategies for the prevention and treatment of demyelinating pathologies.

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Section: Discussionmentioning

confidence: 99%

Innate Signaling in the CNS Prevents Demyelination in a Focal EAE Model

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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“…The broad range of functions of the UPS is particularly well exemplified in immune cells of myeloid origin whereby it regulates key features of both innate and adaptive immunity including signal transduction, protein homeostasis, and MHC class I antigen presentation. Myeloid cells are critical components of the immune system and include monocytes, macrophages, (DC), and granulocytes whose main function resides in patrolling the body for potential invaders [45,46]. Recognition of microbial products by myeloid cells occurs through the binding of pathogen-associated molecular patterns (PAMP) to their pattern recognition receptor (PRR).…”

Section: The Ups Is a Major Regulator Of Cell Signalling In Response To Pathogensmentioning

confidence: 99%

“…Recognition of microbial products by myeloid cells occurs through the binding of pathogen-associated molecular patterns (PAMP) to their pattern recognition receptor (PRR). Depending on their cellular localization and ligand specificity, PRR are traditionally subdivided into Toll-like receptors (TLR), retinoic acid-induced gene-I (RIG-I)-like receptors (RLR), nucleotide-binding oligomerization domain (NOD)-like receptors, and cytosolic DNA or RNA sensors inducing the cyclic-GMP-AMP synthase (cGAS) and protein kinase R (PKR), respectively [46]. The sensing of PAMP by PRR initiates a series of signalling cascades which ultimately leads to the activation of major transcription factors driving inflammation, namely, the nuclear factor-κB (NF-κB) as well as the interferon regulatory factors (IRF) 3 and 7 [47,48].…”

Section: The Ups Is a Major Regulator Of Cell Signalling In Response To Pathogensmentioning

confidence: 99%

The Ubiquitin–Proteasome System in Immune Cells

et al. 2021

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The ubiquitin–proteasome system (UPS) is the major intracellular and non-lysosomal protein degradation system. Thanks to its unique capacity of eliminating old, damaged, misfolded, and/or regulatory proteins in a highly specific manner, the UPS is virtually involved in almost all aspects of eukaryotic life. The critical importance of the UPS is particularly visible in immune cells which undergo a rapid and profound functional remodelling upon pathogen recognition. Innate and/or adaptive immune activation is indeed characterized by a number of substantial changes impacting various cellular processes including protein homeostasis, signal transduction, cell proliferation, and antigen processing which are all tightly regulated by the UPS. In this review, we summarize and discuss recent progress in our understanding of the molecular mechanisms by which the UPS contributes to the generation of an adequate immune response. In this regard, we also discuss the consequences of UPS dysfunction and its role in the pathogenesis of recently described immune disorders including cancer and auto-inflammatory diseases.

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Protective roles for myeloid cells in neuroinflammation

Cited by 19 publications

References 51 publications

Innate Signaling in the CNS Prevents Demyelination in a Focal EAE Model

Innate Signaling in the CNS Prevents Demyelination in a Focal EAE Model

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

The Ubiquitin–Proteasome System in Immune Cells

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