Mitochondrial DNA from hepatocytes as a ligand for TLR9: Drivers of nonalcoholic steatohepatitis?
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.
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.
Priya
P
Handa
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.
Akhila
A
Vemulakonda
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.
Kris V
KV
Kowdley
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
M
Uribe
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.
Nahum
N
Méndez-Sánchez
D000818:Animals; D004272:DNA, Mitochondrial / Q000502:physiology*; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D007113:Immunity, Innate; D008024:Ligands; D051379:Mice; D065626:Non-alcoholic Fatty Liver Disease / Q000209:etiology*; D051217:Toll-Like Receptor 9 / Q000502:physiology*
D004272:DNA, Mitochondrial; D008024:Ligands; D051217:Toll-Like Receptor 9
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