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

Core tip: Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease. It has been shown that innate immune activation contributes to the progression of NAFLD by inducing hepatic inflammation. A new study recently demonstrated that hepatocyte mitochondrial DNA acts as a damage -induced molecular pattern activating hepatic TLR9 to initiate and amplify inflammatory signaling leading to nonalcoholic steatohepatitis (NASH). Inhibiting TLR9 by using a synthetic antagonist, IRS 954, reversed steatohepatitis; as did a whole body ablation of TLR9 or a myeloid-specific knockout of TLR9. This editorial summarizes the findings of the new study and describes potential novel therapeutic targets that may hold promise for NASH treatment.