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May 2021; 8 (3) ArticleOpen Access

Potential Role of CHI3L1+ Astrocytes in Progression in MS

Laura Cubas-Núñez, View ORCID ProfileSara Gil-Perotín, Jéssica Castillo-Villalba, Verónica López, Luis Solís Tarazona, Raquel Gasqué-Rubio, Sara Carratalá-Boscá, Carmen Alcalá-Vicente, View ORCID ProfileFrancisco Pérez-Miralles, Hans Lassmann, Bonaventura Casanova
First published March 3, 2021, DOI: https://doi.org/10.1212/NXI.0000000000000972
Laura Cubas-Núñez
From the Neuroimmunology Unit (L.C.-N., S.G.-P., J.C.-V., V.L., R.G., S.C., C.A., F.P.-M., B.C.), Polytechnic and University Hospital La Fe; Neurology Department (L.S.T.), University Hospital Dr Peset, Valencia, Spain; and Department of Neuroimmunology (H.L.), Center for Brain Research, Vienna, Austria.
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Sara Gil-Perotín
From the Neuroimmunology Unit (L.C.-N., S.G.-P., J.C.-V., V.L., R.G., S.C., C.A., F.P.-M., B.C.), Polytechnic and University Hospital La Fe; Neurology Department (L.S.T.), University Hospital Dr Peset, Valencia, Spain; and Department of Neuroimmunology (H.L.), Center for Brain Research, Vienna, Austria.
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Jéssica Castillo-Villalba
From the Neuroimmunology Unit (L.C.-N., S.G.-P., J.C.-V., V.L., R.G., S.C., C.A., F.P.-M., B.C.), Polytechnic and University Hospital La Fe; Neurology Department (L.S.T.), University Hospital Dr Peset, Valencia, Spain; and Department of Neuroimmunology (H.L.), Center for Brain Research, Vienna, Austria.
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Verónica López
From the Neuroimmunology Unit (L.C.-N., S.G.-P., J.C.-V., V.L., R.G., S.C., C.A., F.P.-M., B.C.), Polytechnic and University Hospital La Fe; Neurology Department (L.S.T.), University Hospital Dr Peset, Valencia, Spain; and Department of Neuroimmunology (H.L.), Center for Brain Research, Vienna, Austria.
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Luis Solís Tarazona
From the Neuroimmunology Unit (L.C.-N., S.G.-P., J.C.-V., V.L., R.G., S.C., C.A., F.P.-M., B.C.), Polytechnic and University Hospital La Fe; Neurology Department (L.S.T.), University Hospital Dr Peset, Valencia, Spain; and Department of Neuroimmunology (H.L.), Center for Brain Research, Vienna, Austria.
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Raquel Gasqué-Rubio
From the Neuroimmunology Unit (L.C.-N., S.G.-P., J.C.-V., V.L., R.G., S.C., C.A., F.P.-M., B.C.), Polytechnic and University Hospital La Fe; Neurology Department (L.S.T.), University Hospital Dr Peset, Valencia, Spain; and Department of Neuroimmunology (H.L.), Center for Brain Research, Vienna, Austria.
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Sara Carratalá-Boscá
From the Neuroimmunology Unit (L.C.-N., S.G.-P., J.C.-V., V.L., R.G., S.C., C.A., F.P.-M., B.C.), Polytechnic and University Hospital La Fe; Neurology Department (L.S.T.), University Hospital Dr Peset, Valencia, Spain; and Department of Neuroimmunology (H.L.), Center for Brain Research, Vienna, Austria.
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Carmen Alcalá-Vicente
From the Neuroimmunology Unit (L.C.-N., S.G.-P., J.C.-V., V.L., R.G., S.C., C.A., F.P.-M., B.C.), Polytechnic and University Hospital La Fe; Neurology Department (L.S.T.), University Hospital Dr Peset, Valencia, Spain; and Department of Neuroimmunology (H.L.), Center for Brain Research, Vienna, Austria.
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Francisco Pérez-Miralles
From the Neuroimmunology Unit (L.C.-N., S.G.-P., J.C.-V., V.L., R.G., S.C., C.A., F.P.-M., B.C.), Polytechnic and University Hospital La Fe; Neurology Department (L.S.T.), University Hospital Dr Peset, Valencia, Spain; and Department of Neuroimmunology (H.L.), Center for Brain Research, Vienna, Austria.
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  • ORCID record for Francisco Pérez-Miralles
Hans Lassmann
From the Neuroimmunology Unit (L.C.-N., S.G.-P., J.C.-V., V.L., R.G., S.C., C.A., F.P.-M., B.C.), Polytechnic and University Hospital La Fe; Neurology Department (L.S.T.), University Hospital Dr Peset, Valencia, Spain; and Department of Neuroimmunology (H.L.), Center for Brain Research, Vienna, Austria.
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Bonaventura Casanova
From the Neuroimmunology Unit (L.C.-N., S.G.-P., J.C.-V., V.L., R.G., S.C., C.A., F.P.-M., B.C.), Polytechnic and University Hospital La Fe; Neurology Department (L.S.T.), University Hospital Dr Peset, Valencia, Spain; and Department of Neuroimmunology (H.L.), Center for Brain Research, Vienna, Austria.
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Citation
Potential Role of CHI3L1+ Astrocytes in Progression in MS
Laura Cubas-Núñez, Sara Gil-Perotín, Jéssica Castillo-Villalba, Verónica López, Luis Solís Tarazona, Raquel Gasqué-Rubio, Sara Carratalá-Boscá, Carmen Alcalá-Vicente, Francisco Pérez-Miralles, Hans Lassmann, Bonaventura Casanova
Neurol Neuroimmunol Neuroinflamm May 2021, 8 (3) e972; DOI: 10.1212/NXI.0000000000000972

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    Figure 1 NfL and CHI3L1 Levels in the CSF of Patients With MS, NMO, and ADEM Relative to Disease Activity

    (A) NfL levels in the CSF increased significantly in patients with MS in the context of disease activity alone. In remission, the levels of NfL in the patients with ADEM differed significantly to those in the patients with MS and NMO. (B) Increased CHI3L1 levels in the CSF of patients with MS, NMO, and ADEM during disease activity, and they were higher in the NMO and ADEM samples than in those from patients with MS. The levels of CSF CHI3L1 in ADEM were significantly higher than in the remission phase. (C) There was significantly more CHI3L1 in progressive MS (PMS) irrespective of disease activity. (D) There was a trend toward more CHI3L1 in patients with PMS than in patients with NMO and ADEM in remission. (E) NfL levels in the CSF were associated with radiologic activity, with a trend toward an association with CHI3L1. (F) The average number of Gd+ lesions in MS and the distribution of these lesions in patients with high levels of NfL and CHI3L1 (oNfL/oCHI3l1) or high NfL and low CHI3L1 (oNfL). Median levels of NfL and CHI3L1 in RMS outside relapse are represented as a red line for reference. A p value of <0.05 was considered statistically significant (*p < 0.05; **p < 0.01; ***p < 0.001). ADEM = acute disseminated encephalomyelitis; CHI3L1 = chitinase 3–like 1; Gd+ = gadolinium-enhanced lesion; NfL = neurofilament light protein; NMO = neuromyelitis optica; oCHI3L1 = outlier CHI3L1; oNfL = outlier NfL; RMS = relapsing MS.

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    Figure 2 Distribution of CHI3L1 Expression in the Brain of Controls, Patients With AMS, and Patients With RRMS

    Light microscope micrographs of AMS and RRMS specimens (A–I). NAWM (A–C). CHI3L1 expression was not found in the NAWM of controls (A), whereas diffuse expression was detected in patients with AMS (B) and RRMS (C). Cortex (D–F). Similarly, no CHI3L1 expression was detected in control specimens (D), whereas it was weakly expressed in the cortex of patients with AMS (E) but not patients with RRMS (F). Active lesion (G–I). A typical early active white matter lesion in a patient with AMS with profuse perivenular infiltrates of CD68+ cells (H) and demyelination, as shown by Klüver-Barrera staining (G). CHI3L1 expression (I) was intense within the lesion, expressed in the center by round cells that correspond to microglia, and at the periphery or active border by larger ramified cells corresponding to astrocytes (arrows in I). CHI3L1, chitinase 3–like 1; AMS = acute MS; NAWM = normal-appearing white matter; RRMS, relapsing-remitting MS.

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    Figure 3 CHI3L1-Expressing Cells in MS and Their Relationship to the Immune Response in MS Lesions

    (A) Quantification of CHI3L1 expression, measured by the OD of staining in different areas of all MS and control specimens. (B) Density of CHI3L1+ cells in each area and type of lesion. (C) Density of CD68+ cells in the distinct types of lesions. (D) There was a positive correlation between CHI3L1 and CD68 expressing cells in all the regions analyzed. (E) There was a positive correlation between perivascular infiltrates and CD68+ cells but not with CHI3L1-expressing cells (not shown). CHI3L1 density: AL cortex vs IL cortex (p = 0.053), AL WM vs IL WM (p = 0.083), and SEL edge vs SEL core (p = 0.053). *CD68 density: AL cortex vs IL cortex (p = 0.000), AL WM vs IL WM (p = 0.083), and SEL edge vs SEL core (p = 0.053). AL = active lesion; AMS = acute MS; CHI3L1 = chitinase 3–like 1; IL = inactive lesion; OD = optical density; PMS = progressive MS. SEL = slow-expanding lesion; WM = white matter.

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    Figure 4 Distribution of CHI3L1 Expression in the Brain of PMS Cases

    Light microscopy micrographs of active and inactive lesions in patients with PMS. Active lesions in the WM (left column), cortex (medium column), and SEL (right column) (A–L). All active lesions displayed extensive demyelination, evident as a loss of reactivity to PLP (A–C), intense inflammatory infiltrates of CD68+ cells (D–F), and an accumulation of APP in transected axons and spheroids as a sign of neurodegeneration (G–I). A detail of the spatial relationship between CHI3L1+ astrocytes and APP+ spheroids is shown as a subset in H; APP: red, GFAP: white, CHI3L1: green, DAPI: blue. CHI3L1 expression was less diffuse and more restricted to the expanding border of the lesions (arrows), and most cells were morphologically identified as astrocytes (see details in J–L). Scale bar: 100 µm (A–L), 20 µm (details J–L); 10 µm (detail in H). APP = amyloid precursor protein; CHI3L1 = chitinase 3–like 1; GFAP = glial fibrillary acidic protein; PLP = myelin proteolipid protein; PMS = progressive MS; SEL = slow-expanding lesion; WM = white matter.

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    Figure 5 CHI3L1 Expression in NMO and ADEM

    Light microscopy micrographs of a case of NMO and of ADEM. NMO (A–H). Active lesions in NMO were devoid of GFAP (A) and AQP4 (B), reflecting astrocyte damage. Loss of PLP reactivity at the active border of the lesion is related to active demyelination (C). The active edge showed CD68+ (D) and CHI3L1 (E) infiltrates. All CHI3L1+ astrocytes had a disrupted morphology as a result of a process referred to as clasmatodendrosis (detail in E). At the inactive center of the lesion, residual demyelination could be observed in the absence of inflammatory cells (F–G), and CHI3L1+ extracellular debris was seen (asterisk in H). Scale bar: 250 μm (A, B); 100 μm (C–J); 10 μm (detail in E and K). ADEM = acute disseminated encephalomyelitis; AQP4 = aquaporin type 4; CHI3L1 = chitinase 3–like 1; GFAP = glial fibrillary acid protein; NMO = neuromyelitis optica; PLP = myelin proteolipid protein.

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  • links.lww.com/NXI/A427
  • links.lww.com/NXI/A428
  • links.lww.com/NXI/A422
  • links.lww.com/NXI/A423
  • links.lww.com/NXI/A429
  • links.lww.com/NXI/A424
  • links.lww.com/NXI/A425
  • links.lww.com/NXI/A426

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