Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Aug 21, 2016; 22(31): 6965-6971
Published online Aug 21, 2016. doi: 10.3748/wjg.v22.i31.6965
Mitochondrial DNA from hepatocytes as a ligand for TLR9: Drivers of nonalcoholic steatohepatitis?
Priya Handa, Akhila Vemulakonda, Kris V Kowdley, Misael Uribe, Nahum Méndez-Sánchez
Priya Handa, Akhila Vemulakonda, Kris V Kowdley, Senior Research Scientist, Organ Care Research and Liver Care Network, Swedish Medical Center, Seattle, WA 98104, United States
Misael Uribe, Nahum Mendez-Sanchez, Liver Research Unit, Medica Sur Clinic and Foundation, Mexico City 07510, Mexico
Author contributions: Handa P wrote the manuscript; Vemulakonda A, Kowdley KV and Méndez-Sánchez N contributed intellectual content to the revision of the manuscript; all authors contributed to the manuscript.
Conflict-of-interest statement: No potential conflicts of interest relevant to this article were reported.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Priya Handa, MS, PhD, Senior Research Scientist, Organ Care Research and Liver Care Network, 1124 Columbia Street, Suite 600, Swedish Medical Center, Seattle, WA 98104, United States. priya.handa@swedish.org
Telephone: +1-206-3862531 Fax: +1-206-2152126
Received: April 7, 2016
Peer-review started: April 7, 2016
First decision: May 12, 2016
Revised: June 2, 2016
Accepted: June 28, 2016
Article in press: June 28, 2016
Published online: August 21, 2016

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.