TREM2 Regulates the Removal of Apoptotic Cells and Inflammatory Processes during the Progression of NAFLD.
Imke LieboldSimon MeyerMarkus HeineAnastasia KuhlJennifer WittLeah EissingAlexander W FischerAnja Christina KoopJohannes KluweJulian Schulze Zur WieschMalte WehmeyerUwe KnippschildLudger SchejaJoerg HeerenLidia BosurgiAnna WorthmannPublished in: Cells (2023)
Nonalcoholic fatty liver disease (NAFLD) is the most common liver pathology worldwide. In mice and humans, NAFLD progression is characterized by the appearance of TREM2-expressing macrophages in the liver. However, their mechanistic contributions to disease progression have not been completely elucidated. Here, we show that TREM2 + macrophages prevent the generation of a pro-inflammatory response elicited by LPS-laden lipoproteins in vitro . Further, Trem2 expression regulates bone-marrow-derived macrophages (BMDMs) and Kupffer cell capacity to phagocyte apoptotic cells in vitro , which is dependent on CD14 activation. In line with this, loss of Trem2 resulted in an increased pro-inflammatory response, which ultimately aggravated liver fibrosis in murine models of NAFLD. Similarly, in a human NAFLD cohort, plasma levels of TREM2 were increased and hepatic TREM2 expression was correlated with higher levels of liver triglycerides and the acquisition of a fibrotic gene signature. Altogether, our results suggest that TREM2 + macrophages have a protective function during the progression of NAFLD, as they are involved in the processing of pro-inflammatory lipoproteins and phagocytosis of apoptotic cells and, thereby, are critical contributors for the re-establishment of liver homeostasis.
Keyphrases
- inflammatory response
- induced apoptosis
- cell cycle arrest
- cell death
- anti inflammatory
- liver fibrosis
- poor prognosis
- endothelial cells
- type diabetes
- oxidative stress
- mesenchymal stem cells
- lps induced
- stem cells
- signaling pathway
- gene expression
- transcription factor
- induced pluripotent stem cells
- bone marrow
- cell proliferation
- pi k akt
- idiopathic pulmonary fibrosis