Chi3l3 induces oligodendrogenesis in an experimental model of autoimmune neuroinflammation

Starossom, Sarah C.; Garcia, Juliana Campo; Woelfle, Tim; Romero-Suárez, Silvina; Olah, Marta; Watanabe, Fumihiro; Cao, Li; Yeste, Ada; Tukker, John J.; Quintana, Francisco J.; Imitola, Jaime; Witzel, Franziska; Schmitz, Dietmar; Morkel, Markus; Paul, Friedemann; Infante-Duarte, Carmen; Khoury, Samia J.

doi:10.1038/s41467-018-08140-7

Cited by 60 publications

(54 citation statements)

References 65 publications

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“…41 Although CHIT1 function in the CNS is not yet clear, a recent study shows that, like murine CHI3L3, human CHI3L1 and CHIT1 induce oligodendrogenesis in vitro. 42 First single-cell sequencing data emerged from a cancer context, where a branch of intratumoral macrophages was composed of 3 clusters with as top upregulated genes TREM2, APOE, CD68, and CHIT1. Despite this coregulation as part of the same branch, these genes were differentially expressed among the 3 clusters, with CHIT1 correlating the most with increasing intratumoral macrophage activation.…”

Section: Discussionmentioning

confidence: 99%

CHIT1 at Diagnosis Reflects Long‐Term Multiple Sclerosis Disease Activity

Oldoni

Smets

Mallants

et al. 2020

Annals of Neurology

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Objective Evidence for a role of microglia in the pathogenesis of multiple sclerosis (MS) is growing. We investigated association of microglial markers at time of diagnostic lumbar puncture (LP) with different aspects of disease activity (relapses, disability, magnetic resonance imaging parameters) up to 6 years later in a cohort of 143 patients. Methods In cerebrospinal fluid (CSF), we measured 3 macrophage and microglia‐related proteins, chitotriosidase (CHIT1), chitinase‐3–like protein 1 (CHI3L1 or YKL‐40), and soluble triggering receptor expressed on myeloid cells 2 (sTREM2), as well as a marker of neuronal damage, neurofilament light chain (NfL), using enzyme‐linked immunosorbent assay and electrochemiluminescence. We investigated the same microglia‐related markers in publicly available RNA expression data from postmortem brain tissue. Results CHIT1 levels at diagnostic LP correlated with 2 aspects of long‐term disease activity after correction for multiple testing. First, CHIT1 increased with reduced tissue integrity in lesions at a median 3 years later (p = 9.6E‐04). Second, CHIT1 reflected disease severity at a median 5 years later (p = 1.2E‐04). Together with known clinical covariates, CHIT1 levels explained 12% and 27% of variance in these 2 measures, respectively, and were able to distinguish slow and fast disability progression (area under the curve = 85%). CHIT1 was the best discriminator of chronic active versus chronic inactive lesions and the only marker correlated with NfL (r = 0.3, p = 0.0019). Associations with disease activity were, however, independent of NfL. Interpretation CHIT1 CSF levels measured during the diagnostic LP reflect microglial activation early on in MS and can be considered a valuable prognostic biomarker for future disease activity. ANN NEUROL 2020;87:633–645

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Section: Discussionmentioning

confidence: 99%

CHIT1 at Diagnosis Reflects Long‐Term Multiple Sclerosis Disease Activity

Oldoni

Smets

Mallants

et al. 2020

Annals of Neurology

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“…67 It is conceivable that in our EAE model, increased expression of Ptk2b triggered by MSC therapy, led to improvement of the PERG amplitude via modulation of neuronal activity at the PSD95 terminals in the inner plexiform layer. Furthermore, expression of Ptk2b seems to be a critical upstream regulator in Chi3l3-induced oligodendrogenesis, 68 which could have a positive effect on optic nerve myelination.…”

Section: Discussionmentioning

confidence: 99%

Systemic Mesenchymal Stem Cell Treatment Mitigates Structural and Functional Retinal Ganglion Cell Degeneration in a Mouse Model of Multiple Sclerosis

Gramlich

Brown

Godwin

et al. 2020

Trans. Vis. Sci. Tech.

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The purpose of this study was to determine mesenchymal stem cell (MSC) therapy efficacy on rescuing the visual system in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS) and to provide new mechanistic insights. Methods: EAE was induced in female C57BL6 mice by immunization with myelin oligodendrocyte glycoprotein (MOG) 35-55 , complete Freund's adjuvant, and pertussis toxin. The findings were compared to sham-immunized mice. Half of the EAE mice received intraperitoneally delivered stem cells (EAE + MSC). Clinical progression was monitored according to a five-point EAE scoring scheme. Pattern electroretinogram (PERG) and retinal nerve fiber layer (RNFL) thickness were measured 32 days after induction. Retinas were harvested to determine retinal ganglion cell (RGC) density and prepared for RNAsequencing. Results: EAE animals that received MSC treatment seven days after EAE induction showed significantly lower motor-sensory impairment, improvement in the PERG amplitude, and preserved RNFL. Analysis of RNA-sequencing data demonstrated statistically significant differences in gene expression in the retina of MSC-treated EAE mice. Differentially expressed genes were enriched for pathways involved in endoplasmic reticulum stress, endothelial cell differentiation, HIF-1 signaling, and cholesterol transport in the MSC-treated EAE group. Conclusions: Systemic MSC treatment positively affects RGC function and survival in EAE mice. Better cholesterol handling by increased expression of Abca1, the cholesterol efflux regulatory protein, paired with the resolution of HIF-1 signaling activation might explain the improvements seen in PERG of EAE animals after MSC treatment. Translational Relevance: Using MSC therapy in a mouse model of MS, we discovered previously unappreciated biochemical pathways associated with RGC neuroprotection, which have the potential to be pharmacologically targeted as a new treatment regimen.

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“…A recent study reported that Ym1/2 promoted interleukin-17 (IL-17)–mediated neutrophilia and was involved in nematode killing and host damage in mice ( 16 ). It was also suggested that Ym1 induced oligodendrogenesis, and silencing Ym1 increased the severity of EAE ( 17 ). Furthermore, Ym1/2 promoted T H 2 (T helper 2) cytokine expression implicated to regulate allergic inflammation by inhibiting 12/15( S )-lipoxygenase in mice ( 18 ).…”

Section: Introductionmentioning

confidence: 99%

Natural polymorphism of Ym1 regulates pneumonitis through alternative activation of macrophages

et al. 2020

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We have positionally cloned the Ym1 gene, with a duplication and a promoter polymorphism, as a major regulator of inflammation. Mice with the RIIIS/J haplotype, with the absence of Ym1 expression, showed reduced susceptibility to mannan-enhanced collagen antibody–induced arthritis and to chronic arthritis induced by intranasal exposure of mannan. Depletion of lung macrophages alleviated arthritis, whereas intranasal supplement of Ym1 protein to Ym1-deficient mice reversed the disease, suggesting a key role of Ym1 for inflammatory activity by lung macrophages. Ym1-deficient mice with pneumonitis had less eosinophil infiltration, reduced production of type II cytokines and IgG1, and skewing of macrophages toward alternative activation due to enhanced STAT6 activation. Proteomics analysis connected Ym1 polymorphism with changed lipid metabolism. Induced PPAR-γ and lipid metabolism in Ym1-deficient macrophages contributed to cellular polarization. In conclusion, the natural polymorphism of Ym1 regulates alternative activation of macrophages associated with pulmonary inflammation.

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Chi3l3 induces oligodendrogenesis in an experimental model of autoimmune neuroinflammation

Cited by 60 publications

References 65 publications

CHIT1 at Diagnosis Reflects Long‐Term Multiple Sclerosis Disease Activity

CHIT1 at Diagnosis Reflects Long‐Term Multiple Sclerosis Disease Activity

Systemic Mesenchymal Stem Cell Treatment Mitigates Structural and Functional Retinal Ganglion Cell Degeneration in a Mouse Model of Multiple Sclerosis

Natural polymorphism of Ym1 regulates pneumonitis through alternative activation of macrophages

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