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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.


Related in: MedlinePlus

IL4I1 reverses clinical severity and preserves axons in mice with EAE. (A) Clinical scores of PBS-treated (n = 8) and IL4I1-treated (n = 10) mice for 28 days after EAE induction. Flow cytometry analysis of (B) spinal cord and (C) spleen from untreated and IL4I1 treated mice at 35 days after EAE induction showing the percentage and total number of gated T-bet+CD4+, Rorγt+CD4+ and Gata3+CD4+ cells (samples from n = 2 mice were combined for each group and analysed). (D) Immunostaining of SMI-32 (green), NF200 (red) and DAPI (blue) in spinal cord of untreated and IL4I1 treated mice with EAE at 35 days after EAE induction. Axonal dystrophy is detected by SMI-32+NF200+ co-labelling. (E) SMI-32 signal intensity normalized to NF200 in untreated, and IL4I1-treated mice showing reduced axonal dystrophy in IL4I1 treated mice (n = 3 per group). Scale bar = 100 μm. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001; one-way Wilcoxon Rank-Sum Test (EAE), two-tailed Student’s t-test (SMI-32 analysis).
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aww254-F7: IL4I1 reverses clinical severity and preserves axons in mice with EAE. (A) Clinical scores of PBS-treated (n = 8) and IL4I1-treated (n = 10) mice for 28 days after EAE induction. Flow cytometry analysis of (B) spinal cord and (C) spleen from untreated and IL4I1 treated mice at 35 days after EAE induction showing the percentage and total number of gated T-bet+CD4+, Rorγt+CD4+ and Gata3+CD4+ cells (samples from n = 2 mice were combined for each group and analysed). (D) Immunostaining of SMI-32 (green), NF200 (red) and DAPI (blue) in spinal cord of untreated and IL4I1 treated mice with EAE at 35 days after EAE induction. Axonal dystrophy is detected by SMI-32+NF200+ co-labelling. (E) SMI-32 signal intensity normalized to NF200 in untreated, and IL4I1-treated mice showing reduced axonal dystrophy in IL4I1 treated mice (n = 3 per group). Scale bar = 100 μm. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001; one-way Wilcoxon Rank-Sum Test (EAE), two-tailed Student’s t-test (SMI-32 analysis).

Mentions: To determine if IL4I1 can therapeutically modulate T cell activity in vivo, we examined the effect of recombinant IL4I1 administration in mice with EAE. EAE is an autoimmune-mediated inflammatory condition in the CNS that is characterized by demyelination and axonal injury (Kornek et al., 2000; Nikić et al., 2011). For the therapeutic study, mice that developed EAE were assigned either into IL4I1 treated, or PBS (vehicle) treated group (n = 8–10 per group). In a separate experiment, mice were assigned into IL4I1 treated, or untreated control group (n = 10 per group). For treatment, 100 μl of IL4I1 (1 μg/ml blood volume), or PBS was injected intravenously into mice with EAE—first dose at clinical score 2.0–2.5, when hindlimb weakness became apparent, and a second dose 4 days later. The mice were then monitored daily for disease severity until at least 28 days post EAE induction. We found that the untreated, and PBS-treated groups displayed the typical profile of disease progression, in which complete hindlimb paralysis (clinical score 3.0–3.5) appeared by 16–18 days post EAE induction, and persisted until the end of the experiment (Supplementary Video 1). We found that mice with IL4I1 treatment also displayed hindlimb paralysis, reaching the clinical score of 3.0. However, the clinical deficit was transient, as all of the mice subsequently recovered from paralysis (Fig. 7A and Supplementary Video 2). This result indicates that IL4I1 treatment reversed the course of the disease, leading to the reduction in disease severity.Figure 7


IL4I1 augments CNS remyelination and axonal protection by modulating T cell driven inflammation
IL4I1 reverses clinical severity and preserves axons in mice with EAE. (A) Clinical scores of PBS-treated (n = 8) and IL4I1-treated (n = 10) mice for 28 days after EAE induction. Flow cytometry analysis of (B) spinal cord and (C) spleen from untreated and IL4I1 treated mice at 35 days after EAE induction showing the percentage and total number of gated T-bet+CD4+, Rorγt+CD4+ and Gata3+CD4+ cells (samples from n = 2 mice were combined for each group and analysed). (D) Immunostaining of SMI-32 (green), NF200 (red) and DAPI (blue) in spinal cord of untreated and IL4I1 treated mice with EAE at 35 days after EAE induction. Axonal dystrophy is detected by SMI-32+NF200+ co-labelling. (E) SMI-32 signal intensity normalized to NF200 in untreated, and IL4I1-treated mice showing reduced axonal dystrophy in IL4I1 treated mice (n = 3 per group). Scale bar = 100 μm. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001; one-way Wilcoxon Rank-Sum Test (EAE), two-tailed Student’s t-test (SMI-32 analysis).
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aww254-F7: IL4I1 reverses clinical severity and preserves axons in mice with EAE. (A) Clinical scores of PBS-treated (n = 8) and IL4I1-treated (n = 10) mice for 28 days after EAE induction. Flow cytometry analysis of (B) spinal cord and (C) spleen from untreated and IL4I1 treated mice at 35 days after EAE induction showing the percentage and total number of gated T-bet+CD4+, Rorγt+CD4+ and Gata3+CD4+ cells (samples from n = 2 mice were combined for each group and analysed). (D) Immunostaining of SMI-32 (green), NF200 (red) and DAPI (blue) in spinal cord of untreated and IL4I1 treated mice with EAE at 35 days after EAE induction. Axonal dystrophy is detected by SMI-32+NF200+ co-labelling. (E) SMI-32 signal intensity normalized to NF200 in untreated, and IL4I1-treated mice showing reduced axonal dystrophy in IL4I1 treated mice (n = 3 per group). Scale bar = 100 μm. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001; one-way Wilcoxon Rank-Sum Test (EAE), two-tailed Student’s t-test (SMI-32 analysis).
Mentions: To determine if IL4I1 can therapeutically modulate T cell activity in vivo, we examined the effect of recombinant IL4I1 administration in mice with EAE. EAE is an autoimmune-mediated inflammatory condition in the CNS that is characterized by demyelination and axonal injury (Kornek et al., 2000; Nikić et al., 2011). For the therapeutic study, mice that developed EAE were assigned either into IL4I1 treated, or PBS (vehicle) treated group (n = 8–10 per group). In a separate experiment, mice were assigned into IL4I1 treated, or untreated control group (n = 10 per group). For treatment, 100 μl of IL4I1 (1 μg/ml blood volume), or PBS was injected intravenously into mice with EAE—first dose at clinical score 2.0–2.5, when hindlimb weakness became apparent, and a second dose 4 days later. The mice were then monitored daily for disease severity until at least 28 days post EAE induction. We found that the untreated, and PBS-treated groups displayed the typical profile of disease progression, in which complete hindlimb paralysis (clinical score 3.0–3.5) appeared by 16–18 days post EAE induction, and persisted until the end of the experiment (Supplementary Video 1). We found that mice with IL4I1 treatment also displayed hindlimb paralysis, reaching the clinical score of 3.0. However, the clinical deficit was transient, as all of the mice subsequently recovered from paralysis (Fig. 7A and Supplementary Video 2). This result indicates that IL4I1 treatment reversed the course of the disease, leading to the reduction in disease severity.Figure 7

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