Enterogenous bacterial glycolipids are required for the generation of natural killer T cells mediated liver injury.

Yingfeng Wei,Wei Wu,Chong Lu,Benhua Zeng,Rufeng Xue,Zhi Chen,Jianing Chen,Guangying Cui,Hong Wei,Toshimitsu Uede,Li Bai,Kazuya Iwabuchi,Jiezuan Yang,Luc Van Kaer,Lanjuan Li,Hongyan Diao

doi:10.1038/srep36365

Abstract

Glycolipids are potent activator of natural killer T (NKT) cells. The relationship between NKT cells and intestinal bacterial glycolipids in liver disorders remained unclear. We found that, in sharp contrast to specific pathogen-free (SPF) mice, germ-free (GF) mice are resistant to Concanavalin A (ConA)-induced liver injury. ConA treatment failed to trigger the activation of hepatic NKT cells in GF mice. These defects correlated with the sharply reduced levels of CD1d-presented glycolipid antigens in ConA-treated GF mice compared with SPF counterparts. Nevertheless, CD1d expression was similar between these two kinds of mice. The absence of intestinal bacteria did not affect the incidence of αGalCer-induced liver injury in GF mice. Importantly, we found the intestinal bacteria contain glycolipids which can be presented by CD1d and recognized by NKT cells. Furthermore, supplement of killed intestinal bacteria was able to restore ConA-mediated NKT cell activation and liver injury in GF mice. Our results suggest that glycolipid antigens derived from intestinal commensal bacteria are important hepatic NKT cell agonist and these antigens are required for the activation of NKT cells during ConA-induced liver injury. These finding provide a mechanistic explanation for the capacity of intestinal microflora to control liver inflammation.

Highlights

Mechanism and they secrete various cytokines that recruit and activate other innate immune cells to exacerbate inflammatory responses in the liver[6]
Gut microbiota have been implicated in many liver disorders, and Natural killer T (NKT) cells play a critical role in the progression of many liver diseases
This study showed that, in contrast to specific pathogen-free (SPF) mice, GF mice are protected from ConA-induced liver injury and that hepatic NKT cells from GF mice are resistant to activation following ConA treatment

Summary

Introduction

Mechanism and they secrete various cytokines that recruit and activate other innate immune cells to exacerbate inflammatory responses in the liver[6]. Administration of α-galactosylceramide (αGalCer), a typical glycolipid antigens derived from marine sponges, leads to rapid activation of hepatic NKT cells and causes significant liver injury in mice[7]. This indicated that NKT-recognized glycolipids could induce NKT-mediated liver injury in vivo; whether the enterogenous glycolipid antigens could serve as the activator of NKT cell in the liver injury process remains elusive. Result revealed that enterogenous bacterial glycolipids are important NKT cell activator and are required for activation of hepatic NKT cells during liver injury These finding provide a mechanistic explanation for the capacity of intestinal microflora to control liver inflammation

Methods

Results

Conclusion