Indole derivative XCR-5a alleviates LPS-induced inflammation in vitro and in vivo

Abstract

Context

Few studies on anti-inflammatory drugs with indole groups have been published. This is the first study that demonstrates the anti-inflammatory effects of indole derivative XCR-5a in vitro and in vivo.

Objective

This study aimed to discover more anti-inflammatory drugs with indole groups and investigate their anti-inflammatory mechanisms.

Materials and methods

First, a series of indole derivatives was synthesized, then screened for XCR-5a, a compound with anti-inflammatory effects. Second, the in vitro production of IL-1β, IL-6, TNF-α, inducible nitric oxide synthase (iNOS), and cyclo-oxygenase-2 (COX-2) in lipopolysaccharide (LPS)-induced primary cells of mice pretreated with XCR-5a was determined using qPCR and ELISA. Finally, the effect of XCR-5a on LPS-induced NF-κB signaling activation was determined by Western blotting. An in vivo mouse sepsis model was established. In mouse lung tissue, the production of IL-1β, IL-6, and TNF-α was determined and H&E staining was performed.

Results

Our findings showed that XCR-5a could suppress the production of LPS-induced IL-1β, IL-6, and TNF-α, as well as mRNA expression of iNOS and COX-2. Pretreatment with XCR-5a inhibited the LPS-induced inflammatory response in septic mice in vivo by decreasing pro-inflammatory cytokines production in serum and reducing immune cell infiltration. Mechanistically, XCR-5a suppressed LPS-induced activation of the NF-κB signaling pathway.

Conclusions

XCR-5a has anti-inflammatory effects in vitro and in vivo. Therefore, XCR-5a could be a potential drug candidate for the treatment of inflammatory diseases.

Keywords:

• Indole derivatives
• NF-κB
• inflammation
• LPS
• macrophage

Disclosure statement

The authors declare that there are no financial conflicts of interest.

Jiajing Zhao, Xiaoli Li, Weilin Chen, and Weilie Xiao participated in the research design. Prasanta Roy synthesized XCR-5a. Jiajing Zhao, Haimei Tang, Xingyu Ma, Qianqian Di, and Jiazheng Quan conducted the experiments. Yonghong Guan, Xingyu Ma, and Weilie Xiao contributed analytic tools or new reagents. Jiajing Zhao, Weilin Chen, and Weilie Xiao performed data analysis. Weilin Chen and Jiajing Zhao contributed to the write-up of the manuscript.

Additional information

Funding

This work was supported by grants from the National Natural Science Foundation of China [No. U1801283, 31870908, 81860615], a joint project from Yunnan Science and Technology Office and Yunnan University [No. 2018FY001-001], Guangdong Provincial Science and Technology Program [No. 2019B030301009], SZU Top Ranking Project (No.86000000210) to Weilin Chen, and Project of Innovative Research Team of Yunnan Province [202005AE160005] to Weilie Xiao.