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IL4I1 augments CNS remyelination and axonal protection by modulating T cell driven inflammation

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ABSTRACT

See pluchino and peruzzotti-jametti (doi:10.1093/aww266) for a scientific commentary on this article: .

Macrophages have a critical role in remyelination. Psachoulia et al. show that IL4I1, a macrophage-secreted enzyme, promotes CNS remyelination by modulating T cell driven inflammation after focal demyelination in mice. Injection of recombinant IL4I1 protein reverses disease progression in a mouse model of multiple sclerosis, resulting in recovery from hindlimb paralysis.

No MeSH data available.


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Il4i1 is upregulated in alternatively activated microglia and macrophages through IL-4 receptor signalling. qRT-PCR detection of Il4i1 in untreated, lipopolysaccharide (LPS)- and IL4-treated (A) microglia, (B) BV2 cells, and (C) RAW264.7 cell at 24 h after treatment (n = 3 per group). (D) qRT-PCR for Il4i1 expression in unlesioned wild-type (WT), lesioned wild-type and lesioned II4ra−/− spinal cord at 10 dpl (n = 3 per group). (E) In situ hybridization of Il4i1 in wild-type and II4ra−/− mice at 10 dpl. Spinal cord lesion is encircled. GM = grey matter, WM = white matter. Scale bar = 100 μm. Density of (F) oligodendrocyte precursor cells (PDGFRα+Olig2+) and (G) oligodendrocytes (CC1+Olig2+) from MACS purified primary oligodendrocyte precursor cell cultures at 3 days in vitro after treatment with vehicle (1XPBS) or recombinant IL4I1 for 24 h (n = 5 images per condition). All experimental results were replicated at least twice. **P < 0.01, ***P < 0.001, ****P < 0.0001; ANOVA followed by post hoc analysis.
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aww254-F2: Il4i1 is upregulated in alternatively activated microglia and macrophages through IL-4 receptor signalling. qRT-PCR detection of Il4i1 in untreated, lipopolysaccharide (LPS)- and IL4-treated (A) microglia, (B) BV2 cells, and (C) RAW264.7 cell at 24 h after treatment (n = 3 per group). (D) qRT-PCR for Il4i1 expression in unlesioned wild-type (WT), lesioned wild-type and lesioned II4ra−/− spinal cord at 10 dpl (n = 3 per group). (E) In situ hybridization of Il4i1 in wild-type and II4ra−/− mice at 10 dpl. Spinal cord lesion is encircled. GM = grey matter, WM = white matter. Scale bar = 100 μm. Density of (F) oligodendrocyte precursor cells (PDGFRα+Olig2+) and (G) oligodendrocytes (CC1+Olig2+) from MACS purified primary oligodendrocyte precursor cell cultures at 3 days in vitro after treatment with vehicle (1XPBS) or recombinant IL4I1 for 24 h (n = 5 images per condition). All experimental results were replicated at least twice. **P < 0.01, ***P < 0.001, ****P < 0.0001; ANOVA followed by post hoc analysis.

Mentions: To determine if Il4i1 is induced upon alternative activation in microglia and macrophages, IL4 was added to primary microglia cultures, BV2 cells (immortalized murine microglia cell line), and RAW264.7 cells (monocyte derived macrophage cell line) for AAM activation, followed by qRT-PCR analysis after 24 h for Il4i1 expression. Control cells were either left untreated, or treated with lipopolysaccharide for CAM activation. We found that lipopolysaccharide had no significant effect on Il4i1 expression in primary microglia or RAW264.7 cells, and appeared to slightly reduce Il4i1 expression in BV2 cells compared to untreated cells (Fig. 2A–C). By contrast, IL4 addition significantly induced Il4i1 expression in primary microglia, BV2 cells, and RAW264.7 cells (Fig. 2A–C). These findings suggest that microglia-derived as well as monocyte-derived AAM express Il4i1 on IL4 stimulation, and supports a recent study showing that Il4i1 is upregulated in AAM (Yue et al., 2015).Figure 2


IL4I1 augments CNS remyelination and axonal protection by modulating T cell driven inflammation
Il4i1 is upregulated in alternatively activated microglia and macrophages through IL-4 receptor signalling. qRT-PCR detection of Il4i1 in untreated, lipopolysaccharide (LPS)- and IL4-treated (A) microglia, (B) BV2 cells, and (C) RAW264.7 cell at 24 h after treatment (n = 3 per group). (D) qRT-PCR for Il4i1 expression in unlesioned wild-type (WT), lesioned wild-type and lesioned II4ra−/− spinal cord at 10 dpl (n = 3 per group). (E) In situ hybridization of Il4i1 in wild-type and II4ra−/− mice at 10 dpl. Spinal cord lesion is encircled. GM = grey matter, WM = white matter. Scale bar = 100 μm. Density of (F) oligodendrocyte precursor cells (PDGFRα+Olig2+) and (G) oligodendrocytes (CC1+Olig2+) from MACS purified primary oligodendrocyte precursor cell cultures at 3 days in vitro after treatment with vehicle (1XPBS) or recombinant IL4I1 for 24 h (n = 5 images per condition). All experimental results were replicated at least twice. **P < 0.01, ***P < 0.001, ****P < 0.0001; ANOVA followed by post hoc analysis.
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aww254-F2: Il4i1 is upregulated in alternatively activated microglia and macrophages through IL-4 receptor signalling. qRT-PCR detection of Il4i1 in untreated, lipopolysaccharide (LPS)- and IL4-treated (A) microglia, (B) BV2 cells, and (C) RAW264.7 cell at 24 h after treatment (n = 3 per group). (D) qRT-PCR for Il4i1 expression in unlesioned wild-type (WT), lesioned wild-type and lesioned II4ra−/− spinal cord at 10 dpl (n = 3 per group). (E) In situ hybridization of Il4i1 in wild-type and II4ra−/− mice at 10 dpl. Spinal cord lesion is encircled. GM = grey matter, WM = white matter. Scale bar = 100 μm. Density of (F) oligodendrocyte precursor cells (PDGFRα+Olig2+) and (G) oligodendrocytes (CC1+Olig2+) from MACS purified primary oligodendrocyte precursor cell cultures at 3 days in vitro after treatment with vehicle (1XPBS) or recombinant IL4I1 for 24 h (n = 5 images per condition). All experimental results were replicated at least twice. **P < 0.01, ***P < 0.001, ****P < 0.0001; ANOVA followed by post hoc analysis.
Mentions: To determine if Il4i1 is induced upon alternative activation in microglia and macrophages, IL4 was added to primary microglia cultures, BV2 cells (immortalized murine microglia cell line), and RAW264.7 cells (monocyte derived macrophage cell line) for AAM activation, followed by qRT-PCR analysis after 24 h for Il4i1 expression. Control cells were either left untreated, or treated with lipopolysaccharide for CAM activation. We found that lipopolysaccharide had no significant effect on Il4i1 expression in primary microglia or RAW264.7 cells, and appeared to slightly reduce Il4i1 expression in BV2 cells compared to untreated cells (Fig. 2A–C). By contrast, IL4 addition significantly induced Il4i1 expression in primary microglia, BV2 cells, and RAW264.7 cells (Fig. 2A–C). These findings suggest that microglia-derived as well as monocyte-derived AAM express Il4i1 on IL4 stimulation, and supports a recent study showing that Il4i1 is upregulated in AAM (Yue et al., 2015).Figure 2

View Article: PubMed Central - PubMed

ABSTRACT

See pluchino and peruzzotti-jametti (doi:10.1093/aww266) for a scientific commentary on this article: .

Macrophages have a critical role in remyelination. Psachoulia et al. show that IL4I1, a macrophage-secreted enzyme, promotes CNS remyelination by modulating T cell driven inflammation after focal demyelination in mice. Injection of recombinant IL4I1 protein reverses disease progression in a mouse model of multiple sclerosis, resulting in recovery from hindlimb paralysis.

No MeSH data available.


Related in: MedlinePlus