Systemic blockade of proBDNF inhibited the expansion and altered the transcriptomic expression in CD3+B220+cells in MRL/lpr lupus mice

Author:

Zha An-Hui,Luo Cong,Shen Wei-Yun,Fu DiORCID,Dai Ru-Ping

Abstract

ObjectivesThe overexpansion of CD3+B220+cells is the hallmark and main pathological mechanism of clinical manifestations of spontaneously developed MRL/lpr mice, which are primarily used as a mouse model of SLE. Our recent report demonstrated that blocking brain-derived neurotrophic factor precursor (proBDNF) suppressed the antibody-secreting cell differentiation and proliferation and inhibited the progression of SLE; however, the effect of proBDNF blockade on these CD3+B220+cells in MRL/lpr mice is unclear.MethodsTo explore the effect of proBDNF on CD3+B220+cells, MRL/lpr mice at 12 weeks old were intraperitoneally injected with monoclonal anti-proBDNF antibody (McAb-proB) or control IgG continuously for 8 weeks. The manifestations in mice were observed, and peripheral blood and splenocytes were collected and analysed via flow cytometry at 20 weeks old. In addition, splenic CD3+B220+cells were subjected to RNA sequencing (RNA-seq) analysis to identify transcriptomic alterations.ResultsCD3+B220+cells in peripheral blood (p=0.0101) and spleen (p<0.0001) were expanded in MRL/lpr mice. Meanwhile, inhibition of proBDNF signalling reduced the percentage of CD3+B220+cells in peripheral blood (p=0.0036) and spleen (p=0.0280), alleviated lymphadenopathy, reduced urine protein level (p<0.0001) and increased the body weight (p=0.0493). RNA-seq revealed 501 upregulated and 206 downregulated genes in splenic CD3+B220+cells in McAb-proB-treated MRL/lpr mice compared with IgG-treated mice. The differentially expressed genes were found to be involved in apoptosis, tumour necrosis factor signalling, and T cell differentiation and proliferation.ConclusionSystemic blockade of proBDNF inhibited the overexpansion of CD3+B220+cells and altered their signals related to cell cycle, cell apoptosis and the immune response, which may contribute to the attenuation of disease symptoms in murine lupus.

Funder

Hunan Provincial Natural Science of Foundation

National Natural Science Foundation of China

Fundamental Research Funds for the Central Universities of Central South University

Publisher

BMJ

Subject

Rheumatology,General Medicine

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