Stromal Cell Niches in the Inflamed Central Nervous System

Pikor, Natalia; Cupovic, Jovana; Onder, Lucas; Gommerman, Jennifer L.; Ludewig, Burkhard

doi:10.4049/jimmunol.1601566

Cited by 27 publications

(30 citation statements)

References 92 publications

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“…The meningeal pia mater, which contributes to form the tela choroidea [ 14 , 15 ], contains a thin sheet of flattened fibroblasts. These pial fibroblasts secrete vimentin [ 34 ]. As described in the CP, we also detected vimentin-positive cells in the tela choroidea in the roof of the dorsal part of the third ventricle, and most of the vimentin-positive cells expressed mRFP-HCA 1 ( Figure 4 a–d).…”

Section: Resultsmentioning

confidence: 99%

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The Lactate Receptor HCA1 Is Present in the Choroid Plexus, the Tela Choroidea, and the Neuroepithelial Lining of the Dorsal Part of the Third Ventricle

Hadzic

Nguyen

Hosoyamada

et al. 2020

IJMS

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The volume, composition, and movement of the cerebrospinal fluid (CSF) are important for brain physiology, pathology, and diagnostics. Nevertheless, few studies have focused on the main structure that produces CSF, the choroid plexus (CP). Due to the presence of monocarboxylate transporters (MCTs) in the CP, changes in blood and brain lactate levels are reflected in the CSF. A lactate receptor, the hydroxycarboxylic acid receptor 1 (HCA1), is present in the brain, but whether it is located in the CP or in other periventricular structures has not been studied. Here, we investigated the distribution of HCA1 in the cerebral ventricular system using monomeric red fluorescent protein (mRFP)-HCA1 reporter mice. The reporter signal was only detected in the dorsal part of the third ventricle, where strong mRFP-HCA1 labeling was present in cells of the CP, the tela choroidea, and the neuroepithelial ventricular lining. Co-labeling experiments identified these cells as fibroblasts (in the CP, the tela choroidea, and the ventricle lining) and ependymal cells (in the tela choroidea and the ventricle lining). Our data suggest that the HCA1-containing fibroblasts and ependymal cells have the ability to respond to alterations in CSF lactate in body–brain signaling, but also as a sign of neuropathology (e.g., stroke and Alzheimer’s disease biomarker).

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Section: Resultsmentioning

confidence: 99%

“…Vimentin is an intermediate filament (IF) protein expressed in fibroblasts [34]. Immunolabeling of mature fibroblast by an antibody against vimentin produced a strong labeling of cells in the CP.…”

Section: The Lactate Receptor Hca1 In the Choroid Plexus In The Roof mentioning

confidence: 99%

The Lactate Receptor HCA1 Is Present in the Choroid Plexus, the Tela Choroidea, and the Neuroepithelial Lining of the Dorsal Part of the Third Ventricle

Hadzic

Nguyen

Hosoyamada

et al. 2020

IJMS

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“…Chronic inflammation may trigger the maturation of immunostimulatory trabecular fibroblast-like cells in organized ectopic aggregates, commonly described as tertiary lymphoid tissues (56). Moreover, during CNS inflammation, these trabecular fibroblast-like cells could regulate immune cell entry into the SAS from the bloodstream and control the transition of inflammatory responses from regions proximal to CNS barriers into the parenchyma (57). Notably, chronic inflammatory conditions during MS and EAE induce the organization of a lymphoid-like tissue in which fibroblastic networks secrete extracellular matrix (ECM) components, chemokines and cytokines and upregulate ICAM-1 expression (58–62).…”

Section: Discussionmentioning

confidence: 99%

LFA-1 Controls Th1 and Th17 Motility Behavior in the Inflamed Central Nervous System

et al. 2019

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Leukocyte trafficking is a key event during autoimmune and inflammatory responses. The subarachnoid space (SAS) and cerebrospinal fluid are major routes for the migration of encephalitogenic T cells into the central nervous system (CNS) during experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis, and are sites of T cell activation before the invasion of CNS parenchyma. In particular, autoreactive Th1 and Th17 cell trafficking and reactivation in the CNS are required for the pathogenesis of EAE. However, the molecular mechanisms controlling T cell dynamics during EAE are unclear. We used two-photon laser microscopy to show that autoreactive Th1 and Th17 cells display distinct motility behavior within the SAS in the spinal cords of mice immunized with the myelin oligodendrocyte glycoprotein peptide MOG35−55. Th1 cells showed a strong directional bias at the disease peak, moving in a straight line and covering long distances, whereas Th17 cells exhibited more constrained motility. The dynamics of both Th1 and Th17 cells were strongly affected by blocking the integrin LFA-1, which interfered with the deformability and biomechanics of Th1 but not Th17 cells. The intrathecal injection of a blocking anti-LFA-1 antibody at the onset of disease significantly inhibited EAE progression and also strongly reduced neuro-inflammation in the immunized mice. Our results show that LFA-1 plays a pivotal role in T cell motility during EAE and suggest that interfering with the molecular mechanisms controlling T cell motility can help to reduce the pathogenic potential of autoreactive lymphocytes.

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“…Recently, a crucial role for CNS stromal cells in the recruitment of antiviral CD8 + T cells was demonstrated in a mouse model of neurotropic virus infection [ 13 ]. These findings led to the concept of fibroblastic stromal niches in the CNS, which are capable of sustaining protective immune cells [ 53 ]. Our findings add another facet to the role of the CNS stroma in supporting immune cell accumulation, as we also find that stromal cells are able to produce critical factors for the longevity and persistence of immune cells in a chronic autoimmune setting.…”

Section: Discussionmentioning

confidence: 99%

The chronically inflamed central nervous system provides niches for long-lived plasma cells

Pollok

Mothes

Ulbricht

et al. 2017

acta neuropathol commun

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Although oligoclonal bands in the cerebrospinal fluid have been a hallmark of multiple sclerosis diagnosis for over three decades, the role of antibody-secreting cells in multiple sclerosis remains unclear. T and B cells are critical for multiple sclerosis pathogenesis, but increasing evidence suggests that plasma cells also contribute, through secretion of autoantibodies. Long-lived plasma cells are known to drive various chronic inflammatory conditions as e.g. systemic lupus erythematosus, however, to what extent they are present in autoimmune central nervous system inflammation has not yet been investigated. In brain biopsies from multiple sclerosis patients and other neurological diseases, we could detect non-proliferating plasma cells (CD138 + Ki67 − ) in the parenchyma. Based on this finding, we hypothesized that long-lived plasma cells can persist in the central nervous system (CNS). In order to test this hypothesis, we adapted the multiple sclerosis mouse model experimental autoimmune encephalomyelitis to generate a B cell memory response. Plasma cells were found in the meninges and the parenchyma of the inflamed spinal cord, surrounded by tissue areas resembling survival niches for these cells, characterized by an up-regulation of chemokines (CXCL12), adhesion molecules (VCAM-1) and survival factors (APRIL and BAFF). In order to determine the lifetime of plasma cells in the chronically inflamed CNS, we labeled the DNA of proliferating cells with 5-ethynyl-2′-deoxyuridine (EdU). Up to five weeks later, we could detect EdU + long-lived plasma cells in the murine CNS. To our knowledge, this is the first study describing non-proliferating plasma cells directly in the target tissue of a chronic inflammation in humans, as well as the first evidence demonstrating the ability of plasma cells to persist in the CNS, and the ability of the chronically inflamed CNS tissue to promote this persistence. Hence, our results suggest that the CNS provides survival niches for long-lived plasma cells, similar to the niches found in other organs. Targeting these cells in the CNS offers new perspectives for treatment of chronic autoimmune neuroinflammatory diseases, especially in patients who do not respond to conventional therapies.

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Stromal Cell Niches in the Inflamed Central Nervous System

Cited by 27 publications

References 92 publications

The Lactate Receptor HCA1 Is Present in the Choroid Plexus, the Tela Choroidea, and the Neuroepithelial Lining of the Dorsal Part of the Third Ventricle

The Lactate Receptor HCA1 Is Present in the Choroid Plexus, the Tela Choroidea, and the Neuroepithelial Lining of the Dorsal Part of the Third Ventricle

LFA-1 Controls Th1 and Th17 Motility Behavior in the Inflamed Central Nervous System

The chronically inflamed central nervous system provides niches for long-lived plasma cells

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