Potential Role of CHI3L1+ Astrocytes in Progression in MS

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.

(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.

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.