The inhibition of NLRP3 signaling attenuates liver injury in an alpha-galactosylceramide-induced hepatitis model

作者：Kanbe Ayumu; Ito Hiroyasu^*; Omori Yukari; Hara Akira; Seishima Mitsuru

来源：Biochemical and Biophysical Research Communications, 2017, 490(2): 364-370.

DOI：10.1016/j.bbrc.2017.06.049

• Immune-mediated liver injury
• Inflammasomes
• NLRP3
• Alpha-galactosylceramide

Inflammasomes are involved in innate immune responses. Several NOD-Like receptors (NLRs) participate in the formation of inflammasomes. NACHT, LRR and PYD domains-containing protein 3 (NALP3) belongs to the NLR family and recognizes adenosine triphosphate (ATP), crystals, and Reactive Oxygen Species (ROS). This study examined the effect of inflammasomes on alpha-galactosylceramide (GalCer)-induced liver injury using NALP3-knockout (KO) mice. GalCer administration induced inflammasome activation and IL-1 beta-maturation. In NALP3-KO mice treated with GalCer, serum ALT levels were significantly reduced compared with those in GalCer-treated WT mice. Histological examination revealed decreased necrosis in NALP3-KO mice compared with WT mice, consistent with ALT levels. Expression of proinflammatory cytokines (such as IL-6, and TNF-alpha) and chemokines was also significantly suppressed in NALP3-KO mice. Moreover, flow cytometry analysis revealed fewer infiltrating immune cells in the livers of GalCer-treated NALP3-KO mice. Inportantly, the frequency of MDSCs (CD11b(+)Gr-1(int) cells), which suppress the immune response, was significantly increased in GalCer-treated NALP3-KO mice. In conclusion, NALP3 inhibition attenuated liver injury in GalCer-induced hepatitis. The inhibition of NALP3 signaling coused be a therapeutic target in immune-mediated liver injury.

• 出版日期2017-8-19