CD24 aggravates acute liver injury in autoimmune hepatitis by promoting IFN-γ production by CD4+ T cells

Abstract

The T-cell-mediated immune response is implicated in many clinical hepatic injuries, such as autoimmune hepatitis and acute virus hepatitis. CD24 is widely expressed by different immune cells and plays an important role in the pathogenesis of many autoimmune diseases. However, the role of CD24 in T-cell-mediated liver injury has not been elucidated until now. Here we showed that CD24 deficiency protects mice from concanavalin A (ConA)-induced fulminant liver injury by reducing serum interferon-γ (IFN-γ) levels. CD24 expression by hepatic T cells was markedly increased following ConA challenge. Moreover, decreased IFN-γ production by hepatic CD4+ T cells in CD24-deficient mice was detected, which was correlated with downregulated phosphorylation of STAT1 in hepatic tissue. In vitro experiments also supported the conclusion that CD24 deficiency impaired IFN-γ production by CD4+ T cells following ConA, CD3/CD28 and phorbol myristate acetate/ionomycin stimulation. Our study suggests that CD24 deficiency confers hepatoprotection by decreasing CD4+ T-cell-dependent IFN-γ production in vivo, which suggests that CD24 might be a potential target molecule for reducing clinical hepatitis.

Hepatoma‐derived growth factor participates in concanavalin A‐induced hepatitis

“…It has been demonstrated that TNF-α, 28 IL-1β, 29 IL-6, 30 COX-2, 31 and HDGF itself 19 were involved in neutrophils infiltration and migration, and these pro-inflammatory mediators also participates in ConAinduced hepatitis. [8][9][10][11] In this research, HDGF ablation or neutralization attenuated ConA-induced the upregulation of TNF-α, IL-1β, IL-6, and COX-2 in the mouse livers and hepatocytes, respectively. Moreover, rHDGF treatment could directly regulate pro-inflammatory signaling in cultured hepatocytes and neutrophils.…”

“…The animal model of ConA-induced hepatitis was performed as previously described. 9 Briefly, C57BL/6 mice (male; 6 week old) were used in this study. WT mice were purchased from BioLASCO Taiwan Co., Ltd., and HDGF-KO mice were acquired from Dr Franken group.…”

“…Evaluation of necrotic area in mouse livers according to H&E staining was performed. 9 TUNEL analysis was performed using the in situ Cell Death Detection Kit (Roche, Indianapolis, IN), according to the manufacturer's protocol.…”

“…6,7 Besides, the upregulation of pro-inflammatory mediators such as TNF-α, IL-1β, IL-6, and COX-2 also participates in ConA-induced hepatic inflammatory processes. [8][9][10][11] Hepatoma-derived growth factor (HDGF) is a secreted factor isolated from the conditioned medium of hepatoma cells 12 and later identified to be upregulated by contact inhibition in astrocytes. 13 In the liver diseases, HDGF upregulation participates in the progression of liver cancer [14][15][16] and hepatic fibrogenesis.…”

The CD24-Siglec G axis protects mice against cuprizone-induced oligodendrocyte loss: targeting danger signal for neuroprotection

“…Finally, it should be noted that CD24 is also known as a costimulatory molecule for the activation of T cells, 11 including autoreactive T cells, 12 and intrahepatic CD4 T cells. 13 Correspondingly, CD24Fc was also shown to inhibit autoimmune diseases. 14 Because CD24Fc phenocopies the genetic defect of the Cd24 gene in autoimmune diseases, 12,14 it likely works through a different mechanism as an antagonist.…”