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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 5

Blockage of IFN-γ signaling rescues depression phenotypes in MRL/lpr mice.

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Blockage of IFN-γ signaling rescues depression phenotypes in MRL/lpr mic...
(A) Experimental protocol for model establishment and analysis. (B) qPCR analysis of Ifitm3 expression in the hippocampi of the indicated mice (n = 4 mice/group). (C and D) 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 = 4 mice/group). Scale bar: 20 μm. (E and F) Quantification of IBA-1+CD68+ phagocytes (E) and CD68 staining intensity (F) in the hippocampi of the indicated groups (n = 5 mice/group). (G and H) Representative 3D reconstruction and quantification of engulfed PSD-95+ puncta (green) in CD68+ lysosomes (red) in the CA1 region of the indicated groups (n = 15–17 cells/group from 5 mice). Scale bar: 2 μm. (I and J) Immunostaining and quantification of presynaptic (SYP, red) and postsynaptic (PSD-95, green) proteins in hippocampal sections from the indicated mice (n = 5 mice/group, with an average of 3–4 slices per mouse). Scale bar: 10 μm. (K–M) The depression-like behavior of the indicated mice was assessed. The SPT (K), TST (L), and FST (M) were performed 3 weeks after antibody treatment (n = 8 mice/group). (N) Quantification of Golgi-stained dendritic spines of dentate gyrus granule neurons in MSCT (or MSCT plus IFN-γ–treated) MRL/lpr mice (n = 5 mice/group). (O and P) Depression-like behavior of the indicated mice was assessed via the TST (O) and the FST (P) (n = 8–10 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, D, H and J), or 2-tailed unpaired t test (E, F and K–P). IOD, integrated optical density; SPT, sucrose preference test; TST, tail suspension test; FST, forced swim test. See also Supplemental Figure 10.

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