Abstract
We investigated the role of brain-derived neurotrophic factor (BDNF) and its signaling pathway in the proinflammatory cytokines production of macrophages. The effects of different concentrations of BDNF on proinflammatory cytokines expression and secretion in U937 cell-differentiated macrophages, and human monocyte-derived macrophages were analyzed using enzyme-linked immunosorbent assay and real-time polymerase chain reaction. The CRISPR-Cas9 system was used to knockout p75 neurotrophin receptor (p75NTR), one of the BDNF receptors. Next-generation sequencing (NGS) was conducted to search for BDNF-regulated microRNA. A very low concentration of BDNF (1 ng/mL) could suppress the secretion of interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and IL-6 in lipopolysaccharide (LPS)-stimulated macrophages but did not change their mRNA expression. BDNF suppressed IL-1β and IL-6 secretion in human monocyte-derived macrophages. In U937 cells, BDNF suppressed the phosphorylation of JNK and c-Jun. The p75NTR knockout strongly suppressed IL-1β, IL-6, and TNF-α secretion in macrophages and LPS-stimulated macrophages. BDNF regulated the expression of miR-3168 with Ras-related protein Rab-11A as its target. In conclusion, BDNF suppressed proinflammatory cytokines secretion in macrophages and inhibited the phosphorylation of JNK. Knockout of p75NTR suppressed proinflammatory cytokines expression and secretion. BDNF upregulated the expression of miR-3168. The inhibition of p75NTR could be a potential strategy to control inflammation.
Highlights
Brain-derived neurotrophic factor (BDNF) is well known for its role in the differentiation, maturation, and survival of neurons
We studied the effects of BDNF on tumor necrosis factor (TNF)-α, IL-1β, and IL-6 secretion in U937 cell-differentiated macrophages and human monocyte-derived macrophages
The mRNA expression of IL-1β, TNF-α, and IL-6 was increased in differentiated macrophages or LPS-stimulated macrophages compared with U937 cells
Summary
Brain-derived neurotrophic factor (BDNF) is well known for its role in the differentiation, maturation, and survival of neurons. Elevated serum levels of BDNF were found in some autoimmune diseases, such as Sjögren’s syndrome, systemic lupus erythematosus, and rheumatoid arthritis, and altered serum levels of BDNF was associated with disease activity or medication used in patients with these diseases [5,6,7,8]. As these reports suggest that BDNF might be directly participating in the inflammatory response, human immune cells could produce BDNF [9]. BDNF was suggested to play a role in the pathogenesis of rheumatoid arthritis [10]
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