Abstract
Chemokines are important regulators of the immune system, inducing specific cellular responses by binding to receptors on immune cells. In SLE patients, decreased expression of CCL2 on mesenchymal stem cells (MSC) prevents inhibition of B-cell proliferation, causing the characteristic autoimmune phenotype. Nevertheless, the intrinsic role of CCL2 on B-cell autoimmunity is unknown. In this study using Ccl2 KO mice, we found that CCL2 deficiency enhanced BCR signaling by upregulating the phosphorylation of the MST1-mTORC1-STAT1 axis, which led to reduced marginal zone (MZ) B cells and increased germinal center (GC) B cells. The abnormal differentiation of MZ and GC B cells were rescued by in vivo inhibition of mTORC1. Additionally, the inhibition of MST1-mTORC1-STAT1 with specific inhibitors in vitro also rescued the BCR signaling upon antigenic stimulation. The deficiency of CCL2 also enhanced the early activation of B cells including B-cell spreading, clustering and signalosome recruitment by upregulating the DOCK8-WASP-actin axis. Our study has revealed the intrinsic role and underlying molecular mechanism of CCL2 in BCR signaling, B-cell differentiation, and humoral response.
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Funding
This study was supported by grants from the National Key R&D Program of China (1316203 to HM), China Postdoctoral Science Foundation (2020M682419), National Natural Science Foundation of China (82001656, 31970839, and 31900654), and HUST Academic Frontier Youth Team (2018QYTD10).
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LY draft the paper. CL designed the study, reviewed, and revised the initial paper. LY, DY, and AC performed the TRIFm experiments. LY, PJ, JL, and XD performed the confocal experiments. LY, NL, YJ, DK, QC, and YH carried out the western blotting. LY, NL, JT, JC, LL, HG, ZL, and QC carried out the flow cytometry assay. LY analyzed the date and generated figures. HM, YC, and LQ, HM, YH, and QG assisted with the paper. All authors approved the final paper as submitted and agreed to be accountable for all aspects of the work.
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All animal experiments were approved by the Medical Ethics Committee of Tongji Medical College, Huazhong University of Science and Technology.
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Yang, L., Li, N., Yang, D. et al. CCL2 regulation of MST1-mTOR-STAT1 signaling axis controls BCR signaling and B-cell differentiation. Cell Death Differ 28, 2616–2633 (2021). https://doi.org/10.1038/s41418-021-00775-2
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DOI: https://doi.org/10.1038/s41418-021-00775-2
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