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

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.

ProBDNF and its receptors in immune-mediated inflammatory diseases: novel insights into the regulation of metabolism and mitochondria

“…In vitro intervention with mAb-proB inhibited the CpGB-stimulated B cell differentiation and production of IgG and IgM in PBMCs from healthy volunteers and patients with SLE. Therefore, the proBDNF/p75 NTR signaling pathway promoted the proliferation of ASCs, which plays a pathogenic role in SLE and may be a potential therapeutic biological target for SLE (9,113). Our recent research indicated that mAb-proB inhibited the overexpansion of CD3 + B220 + cells and altered transcription levels related to cholesterol metabolism, cell cycle, and cell apoptosis, which may contribute to the attenuation of conditions of MRL/lpr lupus mice (10).…”

“…In animal experiments, proBDNF/p75 NTR signaling was significantly upregulated in B cells of spontaneous and induced lupus mice. The intraperitoneal administration of mAb-proB can alleviate the condition of spontaneous and induced lupus mice, reduce the proportion of ASCs and production of auto-antibody and proinflammatory cytokines, as well as delay kidney damage ( 9 , 10 ). Intraperitoneally administering pristane to induce lupus in B cell-specific p75 NTR knockout (CD19 cre p75 f/f ) mice showed that the knockout of B cell p75 NTR signaling can also alleviate the progression of SLE.…”

“…ProBDNF can be expressed not only in the CNS and peripheral tissues, but also in immune cells such as monocytes/macrophages (28), T cells (29, 30), and B cells (9). In addition, proBDNF plays an important role in IMIDs.…”

“…Treatment of the extracellular domain of p75 NTR (p75 ECD ) can significantly relieve inflammatory pain in collagen-induced arthritis (CIA) model mice, which is a standard RA model. MAb-proB could also reduce the production of auto-antibodies and attenuate kidney injury in SLE by altering the mitochondrial respiratory chain complex transcription level and cholesterol metabolism ( 9 , 10 ).…”