TNF superfamily receptor OX40 triggers invariant NKT cell pyroptosis and liver injury
Peixiang Lan, … , Xiang Xiao, Xian Chang Li
Peixiang Lan, … , Xiang Xiao, Xian Chang Li
Published April 24, 2017
Citation Information: J Clin Invest. 2017;127(6):2222-2234. https://doi.org/10.1172/JCI91075.
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Research Article Immunology Inflammation

TNF superfamily receptor OX40 triggers invariant NKT cell pyroptosis and liver injury

Abstract

Tissue-resident immune cells play a key role in local and systemic immune responses. The liver, in particular, hosts a large number of invariant natural killer T (iNKT) cells, which are involved in diverse immune responses. However, the mechanisms that regulate survival and homeostasis of liver iNKT cells are poorly defined. Here we have found that liver iNKT cells constitutively express the costimulatory TNF superfamily receptor OX40 and that OX40 stimulation results in massive pyroptotic death of iNKT cells, characterized by the release of potent proinflammatory cytokines that induce liver injury. This OX40/NKT pyroptosis pathway also plays a key role in concanavalin A–induced murine hepatitis. Mechanistically, we demonstrated that liver iNKT cells express high levels of caspase 1 and that OX40 stimulation activates caspase 1 via TNF receptor–associated factor 6–mediated recruitment of the paracaspase MALT1. We also found that activation of caspase 1 in iNKT cells results in processing of pro–IL-1β to mature IL-1β as well as cleavage of the pyroptotic protein gasdermin D, which generates a membrane pore–forming fragment to produce pyroptotic cell death. Thus, our study has identified OX40 as a death receptor for iNKT cells and uncovered a molecular mechanism of pyroptotic cell death. These findings may have important clinical implications in the development of OX40-directed therapies.

Authors

Peixiang Lan, Yihui Fan, Yue Zhao, Xiaohua Lou, Howard P. Monsour, Xiaolong Zhang, Yongwon Choi, Yaling Dou, Naoto Ishii, Rafik M. Ghobrial, Xiang Xiao, Xian Chang Li

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Figure 7

The OX40/NKT pathway is required in ConA-induced hepatitis.

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The OX40/NKT pathway is required in ConA-induced hepatitis. (A) The WT B...
(A) The WT B6 mice were injected with ConA at 1 mg/kg, i.p., or PBS as a control, and OX40L expression was examined by immunofluorescence staining 1 week later (from 9 fields of view per condition). Cell nuclei were stained with DAPI (blue) for identification and merged with OX40L (green). Scale bars: 100 μm. (B and C) ELISA analysis of serum ALT and AST in WT B6 mice injected with ConA, or with ConA and anti-OX40L antibody. The data shown are mean ± SD of 6 animals in each group. (D and E) ELISA analysis of serum IL-1β and IL-18 levels in WT B6 mice injected with ConA, or with ConA and anti-OX40L antibody. The data shown are mean ± SD of 6 animals in each group. (F) WT B6 mice were injected with ConA, and groups of mice were also treated with control IgG or anti-OX40L antibody; iNKT cells in the liver of treated mice were determined by FACS 1 week later. The FACS plot shows representative data of one of 6 animals. (G and H) The summary graphs represent relative percentage and absolute number of iNKT cells in WT B6 mice treated with PBS, ConA, or ConA and anti-OX40L mAb. Data shown are mean ± SD of 6 animals. (I) Ox40-KO mice were injected with ConA or PBS, and iNKT cells in the liver of treated mice were determined by FACS 1 week later. The FACS plot shows representative data of one of 6 animals in each group. (J and K) ELISA analysis of serum ALT and AST in Ox40-KO mice injected with ConA or PBS as a control. The data shown are mean ± SD of 6 animals in each group. P values were calculated by 1-way ANOVA (B, C, D, E, G, and H) and unpaired 2-tailed Student’s t test between control and ConA treatment (J and K), *P < 0.05.