Insights into Macrophage/Monocyte-Endothelial Cell Crosstalk in the Liver: A Role for Trem-2

Abstract

Liver disease accounts for millions of deaths worldwide annually being a major cause of global morbidity. Hepatotoxic insults elicit a multilayered response involving tissue damage, inflammation, scar formation, and tissue regeneration. Liver cell populations act coordinately to maintain tissue homeostasis and providing a barrier to external aggressors. However, upon hepatic damage, this tight regulation is disrupted, leading to liver pathology which spans from simple steatosis to cirrhosis. Inflammation is a hallmark of liver pathology, where macrophages and endothelial cells are pivotal players in promoting and sustaining disease progression. Understanding the drivers and mediators of these interactions will provide valuable information on what may contribute to liver resilience against disease. Here, we summarize the current knowledge on the role of macrophages and liver sinusoidal endothelial cells (LSEC) in homeostasis and liver pathology. Moreover, we discuss the expanding body of evidence on cell-to-cell communication between these two cell compartments and present triggering receptor expressed on myeloid cells-2 (Trem-2) as a plausible mediator of this cellular interlink. This review consolidates relevant knowledge that might be useful to guide the pursue of successful therapeutic targets and pharmacological strategies for controlling liver pathogenesis.

Hepatic TREM2+ macrophages express matrix metalloproteinases to control fibrotic scar formation

“…The conditioned medium obtained from TREM2 + macrophages enhances transcriptional expression of collagen marker genes in hepatic stellate cells (HSCs) 20 . Therefore, TREM2 + macrophages have been suggested as SAMacs that regulate hepatic fibrogenesis 22 . However, the mechanisms of how TREM2 + macrophages control fibrotic scar formation in the liver is largely unclear.…”

“…20 Therefore, TREM2 + macrophages have been suggested as SAMacs that regulate hepatic fibrogenesis. 22 However, the mechanisms of how TREM2 + macrophages control fibrotic scar formation in the liver is largely unclear. Here, we examined the gene profiles of heterogeneous hepatic macrophage populations and found that TREM2 + macrophages predominantly expressed MMPs to control hepatic scar formation with phenotypes of SAMac in fibrotic injured livers.…”

TREM2 expression promotes liver and peritoneal M2 macrophage polarization in mice infected with Schistosoma japonicum

“…However, we also observed that some TREM2+ cells were not co‐localized with F4/80+ cells, which may be due the fact that TREM2 is expressed not only in F4/80+ cells like macrophages, but also in other F4/80‐ cells such as dendritic cells, hepatic stellate cells and adipocytes. 30 , 32 Additionally, the variety of F4/80+ cells may contribute to the discrepancy, as F4/80 + CD86+ cells represent M1 polarized macrophages which express low levels of TREM2, while F4/80 + CD206+ cells represent M2 polarized macrophages which may express higher levels of TREM2. However, further studies are needed to confirm whether macrophages with low TREM2 expression are indeed M1 macrophages.…”

Self-Renewal of Macrophages: Tumor-Released Factors and Signaling Pathways

“…Another mechanism that could control the proliferation of macrophages involves the triggering receptor expressed on myeloid cells 2 (TREM2). TREM2 is a single-pass transmembrane receptor of the immunoglobulin superfamily that binds phospholipids as well as anionic molecules, including bacterial products, DNA, and lipoproteins [ 112 , 113 ].…”

“…Although most of the information about TREM2 are from microglia in central nervous system [ 115 ], TREM2 is expressed in TAMs and seems to play an immunosuppressive role in cancer [ 55 , 110 ]. An increase in TREM2 + macrophages has been observed in HCC [ 113 ] and in pancreatic ductal adenocarcinoma [ 116 ]. Martina M. et al [ 110 ] also demonstrated that Trem2 –/– mice exhibited resistance to tumor growth due to an alteration in macrophage subsets and an increase of intra-tumoral CD8 + T cells.…”