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MSC transplantation ameliorates depression in lupus by suppressing Th1 cell–shaped synaptic stripping
Xiaojuan Han, Dandan Wang, Liang Chen, Hua Song, Xiulan Zheng, Xin Zhang, Shengnan Zhao, Jun Liang, Tianshu Xu, Zhibin Hu, Lingyun Sun
Xiaojuan Han, Dandan Wang, Liang Chen, Hua Song, Xiulan Zheng, Xin Zhang, Shengnan Zhao, Jun Liang, Tianshu Xu, Zhibin Hu, Lingyun Sun
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Research Article Inflammation Neuroscience

MSC transplantation ameliorates depression in lupus by suppressing Th1 cell–shaped synaptic stripping

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Abstract

Systemic lupus erythematosus (SLE), an autoimmune disease, can cause psychiatric disorders, particularly depression, via immune activation. Human umbilical cord mesenchymal stromal cell (hUCMSC) transplantation (MSCT) has been shown to ameliorate immune dysfunction in SLE by inducing immune tolerance. However, whether MSCT can relieve the depressive symptoms in SLE remains incompletely understood. Here, we demonstrate that MSCT relieved early-onset depression-like behavior in both genetically lupus-prone (MRL/lpr) and pristane-induced lupus mice by rescuing impaired hippocampal synaptic connectivity. Transplanted hUCMSCs targeted Th1 cell–derived IFN-γ to inhibit neuronal JAK/STAT1 signaling and downstream CCL8 expression, reducing phagocytic microglia apposition to alleviate synaptic engulfment and neurological dysfunction in young (8-week-old) lupus mice. Systemic delivery of exogenous IFN-γ blunted MSCT-mediated alleviation of synaptic loss and depressive behavior in lupus mice, suggesting that the IFN-γ/CCL8 axis may be an effective therapeutic target and that MSCT is a potential therapy for lupus-related depression. In summary, transplanted hUCMSCs can target systemic immunity to ameliorate psychiatric disorders by rescuing synaptic loss, highlighting the active role of neurons as intermediaries between systemic immunity and microglia in this process.

Authors

Xiaojuan Han, Dandan Wang, Liang Chen, Hua Song, Xiulan Zheng, Xin Zhang, Shengnan Zhao, Jun Liang, Tianshu Xu, Zhibin Hu, Lingyun Sun

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Figure 4

IFN-γ/JAK/STAT1 signaling contributes to MSCT-mediated improvements in neuronal function in recipient MRL/lpr mice.

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IFN-γ/JAK/STAT1 signaling contributes to MSCT-mediated improvements in n...
(A) The expression of IFN response genes was significantly altered by MSCT in the hippocampi of MRL/lpr mice (n = 3 mice/group). (B and C) qPCR analysis of Ifng and Ifitm3 expression in the spleens and hippocampi of the indicated mice (n = 5 mice/group). (D–F) Representative flow cytometric analysis of splenic CD4+IFN-γ+ (Th1) cells in the mice. The percentages (E) and numbers (F) of Th1 cells are shown in the right 2 panels (n = 5 mice/group). (G and H) Representative images of brain sections coimmunostained for p-STAT1 together with a neuronal marker (NeuN+) and quantification of positive cells in the CA1 region of the indicated groups (n = 5 mice/group). Scale bar: 20 μm. (I–K) IFN-γ (10 ng/mL) was used to treat hippocampal neurons. (I) p-JAK1, p-JAK2, and p-STAT1 levels were measured by Western blotting 30 minutes after treatment. (J) The expression of CCL8 was measured by ELISA 24 hours after treatment. (K) Ccl8 expression was assessed by RT-PCR 6 hours after treatment with IFN-γ and fludarabine. (L–O) Pharmacological inhibition of JAK1/2 or STAT1 in MRL/lpr mice. Ruxolitinib (Rux, p.o.) or fludarabine (Flu, i.p.) was given to MRL/lpr mice from 5 to 8 weeks of age. Immunostaining (L) and quantification (M) of p-STAT1+NeuN+ cells in the hippocampal sections were performed 3 weeks after pharmacological inhibitor treatment (n = 5 mice/group). Scale bar: 20 μm. The TST (N) and FST (O) were performed at the end of the experiment (n = 7–8 mice/group). The data are presented as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001, determined using 1-way ANOVA followed by Tukey’s post hoc test (B, C, E, F, H, K, M and N) or Dunnett’s multiple comparisons test (O), or 2-tailed unpaired t test (J). Ctrl, control; TST, tail suspension test; FST, forced swim test. See also Supplemental Figure 9.

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