TREM2 Regulates the Removal of Apoptotic Cells and Inflammatory Processes during the Progression of NAFLD
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TREM2 Regulates the Removal of Apoptotic Cells and Inflammatory Processes during the Progression of NAFLD. / Liebold, Imke; Meyer, Simon; Heine, Markus; Kuhl, Anastasia; Witt, Jennifer; Eissing, Leah; Fischer, Alexander W; Koop, Anja Christina; Kluwe, Johannes; Wiesch, Julian Schulze Zur; Wehmeyer, Malte; Knippschild, Uwe; Scheja, Ludger; Heeren, Joerg; Bosurgi, Lidia; Worthmann, Anna.
In: CELLS-BASEL, Vol. 12, No. 3, 341, 17.01.2023.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - TREM2 Regulates the Removal of Apoptotic Cells and Inflammatory Processes during the Progression of NAFLD
AU - Liebold, Imke
AU - Meyer, Simon
AU - Heine, Markus
AU - Kuhl, Anastasia
AU - Witt, Jennifer
AU - Eissing, Leah
AU - Fischer, Alexander W
AU - Koop, Anja Christina
AU - Kluwe, Johannes
AU - Wiesch, Julian Schulze Zur
AU - Wehmeyer, Malte
AU - Knippschild, Uwe
AU - Scheja, Ludger
AU - Heeren, Joerg
AU - Bosurgi, Lidia
AU - Worthmann, Anna
PY - 2023/1/17
Y1 - 2023/1/17
N2 - 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.
AB - 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.
KW - Humans
KW - Mice
KW - Animals
KW - Non-alcoholic Fatty Liver Disease/metabolism
KW - Liver Cirrhosis/pathology
KW - Macrophages/metabolism
KW - Apoptosis
KW - Membrane Glycoproteins/genetics
KW - Receptors, Immunologic
U2 - 10.3390/cells12030341
DO - 10.3390/cells12030341
M3 - SCORING: Journal article
C2 - 36766683
VL - 12
JO - CELLS-BASEL
JF - CELLS-BASEL
SN - 2073-4409
IS - 3
M1 - 341
ER -