Brain‐derived neurotrophic factor precursor (proBDNF) has been reported to strengthen the dysfunction of monocytes/macrophages in animal studies. However, it is still unknown the roles of proBDNF in the dysfunction of monocytes in the inflammatory diseases in humans. In the present study, we showed that proBDNF and pan neurotrophic receptor p75 were significantly upregulated in monocytes from healthy donors (HD) after lipopolysaccharide treatment. Exogenous proBDNF treatment upregulated CD40 and proinflammatory cytokines expression in monocytes including interleukin (IL)‐1β, IL‐6, and tumor necrosis factor (TNF)‐α. In Stanford type‐A acute aortic dissection (AAD) patients, proBDNF was upregulated in CD14 ⁺ CD163 ⁺ CX3CR1 ⁺ M2‐ but not CD14 ⁺ CD68 ⁺ CCR2 ⁺ M1‐like monocytes. In addition, sera from AAD patients activated gene expression of proinflammatory cytokines in cultured PBMCs from HD, which was attenuated by proBDNF monoclonal antibody (Ab‐proB) treatment. These findings suggested that upregulation of proBDNF in M2‐like monocytes may contribute to the proinflammatory response in the AAD.

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 ^hi CD38 ^hi ASCs in patients with SLE and in CD19 ⁺ CD44 ^hi CD138 ⁺ 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.