Mitochondrial DNA from hepatocytes as a ligand for TLR9: Drivers of nonalcoholic steatohepatitis?

Abstract

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide, affecting approximately one third of the Western world. It consists of a wide spectrum of liver disorders, ranging from fatty liver to nonalcoholic steatohepatitis (NASH), which consists of steatosis, ballooning injury and inflammation. Despite an alarming growth in the statistics surrounding NAFLD, there are as yet no effective therapies for its treatment. Innate immune signaling has been thought to play a significant role in initiating and augmenting hepatic inflammation, contributing to the transition from nonalcoholic fatty liver to NASH. An immune response is triggered by countless signals called damage-associated molecular patterns (DAMPs) elicited by lipid-laden and damaged hepatocytes, which are recognized by pattern recognition receptors (PRRs) on hepatic immune cells to initiate inflammatory signaling. In this editorial, in addition to summarizing innate immune signaling in NAFLD and discussing potential therapies that target innate immune pathways, we have described a recent study that demonstrated that mitochondrial DNA serves as a DAMP activating a hepatic PRR, TLR9, in mice and in the plasma of NASH patients. In addition to identifying a new ligand for TLR9 during NASH progression, the study shows that blocking TLR9 reverses NASH, paving the way for the development of future NASH therapy.

Keywords: Damage-associated molecular patterns; Hepatocytes; Inflammation; Innate immune signaling; Kupffer cells; Mitochondrial DNA; Nonalcoholic fatty liver disease; Nonalcoholic steatohepatitis; Products of microbial metabolism produced by pathogens; TLR9; Therapy.

Figure 1

Hepatocyte mitochondrial DNA serves as a damage-associated molecular pattern to activate TLR9 leading to nonalcoholic steatosis progression. Our current understanding of the pathophysiology of nonalcoholic steatosis (NASH) is that obesity and metabolic syndrome promote adipose tissue (AT) impairment to release free fatty acids (FFA) from the adipocytes into the portal circulation, which leads to accumulation of triglycerides in the hepatocytes. In addition to FFA, the adipocytes release increased levels of chemokines and cytokines, MCP-1 and IL-6, and reduced levels of beneficial adipokines such as adiponectin. In addition to the impaired AT, tissues such as the intestine contribute bacterial products such as endotoxin/LPS and other pathogen associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), which enter the liver, and activate their receptors on the Kupffer cells and other hepatic cell populations to produce cytokines such as IL-1β, TNFα and IL-6, which, in turn, promote injury and increased triglyceride accumulation in hepatocytes, inflammation and apoptosis in the hepatic immune cells and may activate fibrosis in the stellate cells, and thereby accelerate NASH progression. In addition to our current understanding, a recent study revealed that steatotic hepatocytes release mitochondrial DNA into the plasma, which once enclosed within microparticles, activates TLR9 in endosomes to undergo hyperactivation and produce inflammatory cytokines such as IL-1β, TNFα and IL-6, which, promote NASH progression by amplifying hepatic inflammation and injury. Additionally, an antagonist of TLR7/9, IRS 954, was effective in blocking TLR9 ligand binding and activation, and thereby attenuating NASH.

Figure 2

Role of innate immunity in nonalcoholic fatty liver disease progression. DAMPs and PAMPs bind to PRRs like TLRs and NLRs resulting in NAFLD progression. Binding of DAMPs and PAMPs to TLR4 and TLR9 receptors results in activation of MyD88 or TRIF signaling pathways, which activate NF-κβ and JNK signaling and induce production of cytokines like IL-1β and TNFα leading to lipid accumulation, cell injury and death in the liver. It has been demonstrated that binding of DAMPs and PAMPs to TLR2 can result in NAFLD/NASH through an undefined pathway. Binding of DAMPs and PAMPs to NLRs results in activation of NLRP3/ASC/Caspase1 through assembly of inflammasome complex, which induces production of cytokines IL-1 and IL-18 leading to hepatic inflammation and cell death.