Deubiquitinase USP3 in Macrophages Impaires the Inflammatory Responses in the Colitis Model

Abstract

Background: Dysregulated ubiquitination may contribute to the inflammation process in ulcerative colitis (UC). Genome-wide association studies indicate the association between ubiquitin-specific peptidases 3 (USP3) and UC. This study investigated the role of USP3 in macrophage activation in UC. Methods: The relative USP3 expression was assayed in the peripheral blood mononuclear cells (PBMCs) derived from UC patients and healthy volunteers or bone marrow-derived macrophages (BMDMs) stimulated with lipopolysaccharide (LPS). Myeloid cell-conditional USP3 transgenic (USP3-Tg) mice and wild type mice were treated with 3% dextran sulfate sodium for five successive days to induce colitis, and the relevant pro-inflammatory cytokines were detected in LPS or cytosine guanosine dinucleotide (CpG) stimulated BMDMs. Results: Down-regulated USP3 was observed in UC patients (p < 0.005) and LPS stimulated BMDMs (p < 0.05). USP3-Tg mice demonstrated alleviated colitis symptoms, including less weight loss (all p < 0.05 from day 2), better survival (p < 0.01), lower intestinal bleeding (all p < 0.05 from day 4), and longer large intestine length (p < 0.05). On the other hand, diminished nitric oxide synthase 2 (NOS2) (p < 0.05), interleukin (IL)-6 (p < 0.01), and tumor necrosis factor (TNF) expression (p < 0.05) were detected in USP3-Tg mice. Mechanically, USP3 directly bound with transforming growth factor β-activated kinase 1 (TAK1) to deubiquitinate TAK1 and inhibited downstream nuclear factor kappa-B (NF-κB) and mitogen-activated protein kinase signals. Conclusions: USP3 can function as deubiquitinase to promote the activation of TAK1 in macrophages to impair the inflammatory responses in colitis.