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USP18 negatively regulates and inhibits lipopolysaccharides-induced sepsis by targeting TAK1 activity.

Sepsis is an inflammatory disease with exacerbated inflammation at early stage. Inflammatory cytokines play critical roles in the pathophysiology of sepsis. Ubiquitin specific peptidase 18 (USP18), a deubiquitinating enzyme, has been shown to modulate transforming growth factor-β-activated kinase 1 (TAK1) activity. However, it is not clear about the precise role of USP18 in sepsis. Here we investigated the potential effect of USP18 on inflammation in sepsis. We generated mice with USP18 or/and TAK1 deficiency in macrophages (USP18 MKO mice, TAK1 MKO mice and USP18 MKO TAK1 MKO mice) and established lipopolysaccharides (LPS)-induced septic mice model. Bone marrow derived macrophages were isolated from wild type (WT), USP18 MKO or TAK1 MKO mice and treated with LPS or CpG, the expressions of cytokines including IL-6, IL-10, IL-1β, and TNF-α were measured. The activation of NF-κB, ERK, p38 signaling pathways and ubiquitination of TAK1 were detected. We induced sepsis in WT, USP18 MKO, TAK1 MKO or USP18 MKO TAK1 MKO mice and evaluated the survival rate, lung pathology and inflammation cytokine level in serum. Macrophages deficient in USP18 produced significantly increased IL-6, IL-1β and TNF-α post LPS or CpG stimulation. Macrophages deficient in USP18 had promoted activation of NF-κB, p38 and ERK, and increased ubiquitination of TAK1. Mice with TAK1 deficiency in macrophages had increased survival rates, decreased immune cell infiltration in lung, and decreased pro-inflammatory cytokines in serum. In contrast, mice with USP18 deficiency in macrophages had decreased survival rates, increased cell infiltration in lung and increased pro-inflammatory cytokines in serum. USP18 alleviated LPS-induced sepsis by inhibiting TAK1 activity.