CD205-TLR9-IL-12 axis contributes to CpG-induced oversensitive liver injury in HBsAg transgenic mice by promoting the interaction of NKT cells with Kupffer cells

Abstract

Gut-derived bacterial products contribute to liver inflammation and injury during chronic hepatitis B virus infection; however, the underlying mechanisms remain obscure. In this study, hepatitis B surface antigen transgenic (HBs-Tg) mice and their wild-type (WT) control C57BL/6 mice were injected with CpG-oligodeoxynucleotides (ODNs) to mimic the translocation of gut microbial products into the systemic circulation. We found that, compared with the WT mice, the HBs-Tg mice were oversensitive to CpG-ODN-induced liver injury, which was dependent on natural killer T (NKT) cells. CpG-ODN injection enhanced the expression of Fas ligand (FasL) on NKT cells. In addition, hepatocytes from the HBs-Tg mice expressed higher levels of Fas than did those from the WT mice, which was further augmented by CpG-ODN. Interaction of Fas and FasL was involved in the cytotoxicity of NKT cells against hepatocytes in the HBs-Tg mice. Moreover, Kupffer cells in the HBs-Tg mice expressed higher levels of CD205 and produced greater amounts of interleukin (IL)-12 than did those in the WT mice. Finally, the depletion of Kupffer cells, neutralization of IL-12 or specific silencing of CD205 on Kupffer cells significantly inhibited CpG-ODN-induced liver injury and NKT activation in the HBs-Tg mice. Our data suggest that CD205-expressing Kupffer cells respond to CpG-ODNs and subsequently release IL-12 to promote NKT cell activation. Activated NKT cells induce liver damage through the Fas signaling pathway in HBs-Tg mice.

Identification of pro-inflammatory CD205+ macrophages in livers of hepatitis B virus transgenic mice and patients with chronic hepatitis B

“…Our recent study showed that a population of CD205 + macrophages accumulated in the liver of hepatitis B surface antigen transgenic (HBs-Tg) mice. These CD205 + macrophages contributed to HBs-Tg mice having greater amounts of IL-12 and severer liver injury than B6 mice20. In the present study, we characterised CD205 + macrophages in the liver of HBs-Tg mice and found that CD205 + macrophages had a more pro-inflammatory phenotype and function than CD205 − macrophages.…”

“…We previously reported that the levels of macrophage-derived cytokines IL-12 and TNF-α were higher in the serum of HBs-Tg mice than those in B6 mice after treatment with CpG-ODNs20, which suggests that hepatic macrophages in HBs-Tg mice are more sensitive to bacterial DNA. To confirm this in the present study, we isolated hepatic macrophages from HBs-Tg and B6 mice and assessed the function of the cytokines produced after stimulation with CpG-ODNs or commensal Escherichia coli (E. coli ) DNA.…”

Hepatic mitochondrial DNA/Toll‐like receptor 9/MicroRNA‐223 forms a negative feedback loop to limit neutrophil overactivation and acetaminophen hepatotoxicity in mice

“…For example, investigators have demonstrated that during APAP‐induced liver injury, necrotic hepatocytes release mtDNA, which acts as an agonist for Toll‐like receptor 9 (TLR9) to induce neutrophil infiltration and liver inflammation that may further exacerbate hepatocellular damage . In addition, the pathological role of TLR9 activation in inducing neutrophil infiltration and liver injury has also been reported in other liver injury models, including liver ischemia/reperfusion, chronic‐plus‐binge ethanol feeding, nonalcoholic fatty liver disease, and hepatitis B surface antigen transgenic mice . However, how the inflammation is terminated in APAP‐induced hepatotoxicity remains largely unknown.…”

“…(7)(8)(9) In addition, the pathological role of TLR9 activation in inducing neutrophil infiltration and liver injury has also been reported in other liver injury models, including liver ischemia/reperfusion, (10)(11)(12) chronic-plus-binge ethanol feeding, (13) nonalcoholic fatty liver disease, (14) and hepatitis B surface antigen transgenic mice. (15) However, how the inflammation is terminated in APAP-induced hepatotoxicity remains largely unknown.…”

The Biological Function of Kupffer Cells in Liver Disease

“…These data CD205-expressing KCs respond to CpG-ODNs and subsequently release IL-12 to promote NKT cell activation. Activated NKT cells induce liver damage through the Fas-signaling pathway in HBs-Tg mice [98].…”