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Published on: April 2, 2014
Fn14 exacerbates acute lung injury by activating the NLRP3 inflammasome in mice
Xin-Xin Guan1, Hui-Hui Yang1, Wen-Jing Zhong1
1Department of Physiology, School of Basic Medicine Science, Central South University, Changsha, 410078, Hunan, China.
Background:
Uncontrolled inflammation is an important factor in the occurrence and development of acute lung injury (ALI). Fibroblast growth factor-inducible 14 (Fn14), a plasma membrane-anchored receptor, takes part in the pathological process of a variety of acute and chronic inflammatory diseases. However, the role of Fn14 in ALI has not yet been elucidated. This study aimed to investigate whether the activation of Fn14 exacerbated lipopolysaccharide (LPS)-induced ALI in mice.
Methods:
In vivo, ALI was induced by intratracheal LPS-challenge combined with/without Fn14 receptor blocker aurintricarboxylic acid (ATA) treatment in C57BL/6J mice. Following LPS administration, the survival rate, lung tissue injury, inflammatory cell infiltration, inflammatory factor secretion, oxidative stress, and NLRP3 inflammasome activation were assessed. In vitro, primary murine macrophages were used to evaluate the underlying mechanism by which Fn14 activated the NLRP3 inflammasome. Lentivirus was used to silence Fn14 to observe its effect on the activation of NLRP3 inflammasome in macrophages.
Results:
In this study, we found that Fn14 expression was significantly increased in the lungs of LPS-induced ALI mice. The inhibition of Fn14 with ATA downregulated the protein expression of Fn14 in the lungs and improved the survival rate of mice receiving a lethal dose of LPS. ATA also attenuated lung tissue damage by decreasing the infiltration of macrophages and neutrophils, reducing inflammation, and suppressing oxidative stress. Importantly, we found that ATA strongly inhibited the activation of NLRP3 inflammasome in the lungs of ALI mice. Furthermore, in vitro, TWEAK, a natural ligand of Fn14, amplified the activation of NLRP3 inflammasome in the primary murine macrophage. By contrast, inhibition of Fn14 with shRNA decreased the expression of Fn14, NLRP3, Caspase-1 p10, and Caspase-1 p20, and the production of IL-1β and IL-18. Furthermore, the activation of Fn14 promoted the production of reactive oxygen species and inhibited the activation of Nrf2-HO-1 in activated macrophages.
Conclusions:
Our study first reports that the activation of Fn14 aggravates ALI by amplifying the activation of NLRP3 inflammasome. Therefore, blocking Fn14 may be a potential way to treat ALI.
Insights
Blocking Fibroblast growth factor-inducible 14 (Fn14) activation can treat acute lung injury (ALI). Fn14 exacerbates LPS-induced ALI by amplifying NLRP3 inflammasome activation, making Fn14 a potential therapeutic target for ALI.
Area of Science:
- Immunology
- Pulmonology
- Molecular Biology
Background:
- Uncontrolled inflammation is a key factor in acute lung injury (ALI).
- Fibroblast growth factor-inducible 14 (Fn14) is implicated in inflammatory diseases, but its role in ALI is unclear.
Purpose of the Study:
- To investigate if Fn14 activation exacerbates lipopolysaccharide (LPS)-induced ALI in mice.
- To explore the underlying mechanisms of Fn14's role in ALI.
Main Methods:
- In vivo: LPS-induced ALI model in mice, treated with Fn14 blocker (ATA). Assessed survival, lung injury, inflammation, oxidative stress, and NLRP3 inflammasome activation.
- In vitro: Primary murine macrophages used to study Fn14's effect on NLRP3 inflammasome activation. Lentivirus-mediated Fn14 silencing was employed.
Main Results:
- Fn14 expression increased in LPS-induced ALI lungs. ATA treatment improved survival, reduced lung injury, inflammation, and oxidative stress.
- ATA inhibited NLRP3 inflammasome activation in vivo. In vitro, Fn14 activation amplified NLRP3 inflammasome activation, while Fn14 inhibition decreased it.
- Fn14 activation promoted reactive oxygen species production and inhibited Nrf2-HO-1 activation in macrophages.
Conclusions:
- Fn14 activation aggravates ALI by amplifying NLRP3 inflammasome activation.
- Blocking Fn14 represents a potential therapeutic strategy for treating ALI.
