TIPE3 protects mice from lipopolysaccharide-induced acute lung injury

Acute lung injury (ALI) is a severe inflammatory disease with high morbidity and mortality in patients and lung transplant recipients. Tumor necrosis factor-α-induced protein 8-like 3 (TIPE3) is one of the members of the TIPE family. While TIPE2 has been demonstrated to be protective against lipopolysaccharide (LPS)-induced ALI, the role of TIPE3 in ALI is currently unidentified. To examine the role of TIPE3 in ALI, we pretreated C57BL/6 mice with control or TIPE3-lentivirus in LPS-induced ALI models. The C57BL/6 mice were randomly divided into four groups: control group; ALI-induced group; ALI-induced group with control lentivirus; and ALI-induced group with TIPE3-lentivirus. Additionally, RAW 264.7 cells were used to validate the role and molecular mechanism of TIPE3 signaling in vitro. An increased expression of TIPE3 reduced lung histopathological damage in ALI-affected mice. ALI-affected mice treated with TIPE3-lentivirus exhibited reduced lung microvascular permeability, myeloperoxidase (MPO) activity, neutrophil buildup, and inflammation response. Additionally, over-expression of TIPE3 significantly inhibited NF-κB activation and promoted the activation of Liver X receptors alpha (LXRα). In LPS-treated RAW264.7 cells, enforced TIPE3 expression produced anti-inflammatory effects, whereas the LXR inhibitor geranylgeranyl pyrophosphate (GGPP) reversed these effects. TIPE3 protected against LPS-induced ALI by regulating the LXRα/NF-κB signaling pathway. These results suggest that TIPE3 might provide a novel insight into the prevention of ALI. •LPS induced lung injury and inflammatory response and decreased the expression of TIPE3.•Overexpression of TIPE3 alleviates the lung injury induced by LPS.•The enforced expression of TIPE3 reduces inflammatory response induced by LPS.•Overexpression of TIPE3 activates the LXRα signaling pathway both in vitro and in vivo.•LXRα inhibitor attenuates the inhibitory effect of TIPE3 on the inflammatory responses.