Dataset Information

Up-regulation of proBDNF/p75^NTR signaling in antibody-secreting cells drives systemic lupus erythematosus.

ABSTRACT: Inappropriate expansion of antibody-secreting cells (ASCs) is typical of systemic lupus erythematosus (SLE), but the regulatory signaling of pathogenic ASCs is unclear. The present study shows that brain-derived neurotrophic factor precursor (proBDNF) and its high-affinity pan-75 neurotrophin receptor (p75^NTR) are highly expressed in CD19⁺CD27^hiCD38^hi ASCs in patients with SLE and in CD19⁺CD44^hiCD138⁺ ASCs in lupus-like mice. The increased proBDNF⁺ ASCs were positively correlated with clinical symptoms and higher titers of autoantibodies in SLE. Administration of monoclonal antibodies against proBDNF or specific knockout of p75^NTR in CD19⁺ B cells exerted a therapeutic effect on lupus mice by limiting the proportion of ASCs, reducing the production of autoantibodies and attenuating kidney injury. Blocking the biological function of proBDNF or p75^NTR also inhibits ASC differentiation and antibody production in vitro. Together, these findings suggest that proBDNF-p75^NTR signaling plays a critical pathogenic role in SLE through promoting ASC dysfunction.

SUBMITTER: Shen WY

PROVIDER: S-EPMC8769540 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Up-regulation of proBDNF/p75NTR signaling in antibody-secreting cells drives systemic lupus erythematosus.

Shen Wei-Yun WY Luo Cong C Hurtado Plinio Reinaldo PR Liu Xiao-Jing XJ Luo Ru-Yi RY Li Hui H Hu Zhao-Lan ZL Xu Jun-Mei JM Coulson Elizabeth J EJ Zhao Ming M Zhou Xin-Fu XF Dai Ru-Ping RP

Science advances 20220119 3

Inappropriate expansion of antibody-secreting cells (ASCs) is typical of systemic lupus erythematosus (SLE), but the regulatory signaling of pathogenic ASCs is unclear. The present study shows that brain-derived neurotrophic factor precursor (proBDNF) and its high-affinity pan-75 neurotrophin receptor (p75NTR) are highly expressed in CD19+CD27hiCD38hi ASCs in patients with SLE and in CD19+CD44hiCD138+ ASCs in lupus-like ...[more]

PMID: 35044824

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Project description:Bupivacaine (BPV) can cause severe central nervous system toxicity when absorbed into the blood circulation system. Rapid intravenous administration of lipid emulsion (LE) could be used to treat local anaesthetic toxicity. This study aimed to investigate the mechanism by which the BDNF-TrkB/proBDNF-p75NTR pathway regulation by LE rescues BPV induced neurotoxicity in hippocampal neurons in rats. Seven- to nine-day-old primary cultured hippocampal neurons were randomly divided into 6 groups: the blank control group (Ctrl), the bupivacaine group (BPV), the lipid emulsion group (LE), the bupivacaine + lipid emulsion group (BPV + LE), the bupivacaine + lipid emulsion + tyrosine kinase receptor B (TrkB) inhibitor group (BPV + LE + K252a), the bupivacaine + lipid emulsion + p75 neurotrophic factor receptor (p75NTR) inhibitor group (BPV + LE + TAT-Pep5). All hippocampal neurons were incubated for 24 h, and their growth state was observed by light microscopy. The relative TrkB and p75NTR mRNA levels were detected by real-time PCR. The protein expression levels of brain-derived neurotrophic factor (BDNF), proBDNF, TrkB, p75NTR and cleaved caspase-3 were detected by western blotting. The results showed that primary hippocampal neuron activity was reduced by BPV. As administration of LE elevated hippocampal neuronal activity, morphology was also somewhat improved. The protein expression and mRNA levels of TrkB and p75NTR were decreased when BPV induced hippocampal neuronal toxicity, while the expression of BDNF was increased. At the same time, BPV increased the original generation of cleaved caspase-3 protein content by hippocampal neurons, while the content of cleaved caspase-3 protein in hippocampal neurons cotreated with LE and BPV was decreased. Thus, this study has revealed LE may reduce apoptosis and promote survival of hippocampal neurons by regulating the BDNF-TrkB pathway and the proBDNF-p75NTR pathway to rescue BPV induced central neurotoxicity in rats.

Dataset Information

Up-regulation of proBDNF/p75^NTR signaling in antibody-secreting cells drives systemic lupus erythematosus.

Publications

Up-regulation of proBDNF/p75<sup>NTR</sup> signaling in antibody-secreting cells drives systemic lupus erythematosus.

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