Trem-2 promotes emergence of restorative macrophages and endothelial cells during recovery from hepatic tissue damage

Abstract

Macrophages are pivotal in mounting liver inflammatory and tissue repair reactions upon hepatic injury showing remarkable functional plasticity. Nevertheless, the molecular mechanisms determining macrophage transition from inflammatory to restorative phenotypes in the damaged liver remain unclear. Using mouse models of acute (APAP) or chronic (CCl4) drug-induced hepatotoxic injury we show that the immune receptor Trem-2 controls phenotypic shifts in liver macrophages and impacts endothelial cell differentiation during tissue recovery.Trem-2 gene ablation led to delayed re-population of Kupffer cells correlating with deterred resolution of hepatic damage following acute and chronic injury. We found that during tissue recovery macrophages in transition to the Kupffer cell compartment expressed high levels of Trem-2. Acquisition of the transition phenotype was associated with an unique transcriptomic profile denoting strong responsiveness to oxidative stress and downmodulation of the pro-inflammatory phenotype, which was not observed in absence of Trem-2.During tissue recovery lack of Trem-2 favored accumulation of a liver-damage associated endothelial cell population (LDECs) engaged in a transcriptional program compatible with endothelial de-differentiation. Accordingly, LDECs precursor potential is supported by the downregulation of surface endothelial cell markers and striking in vitro morphological changes towards typical endothelial cells.In conclusion, we found that the dynamics of liver macrophages in response to liver injury is critically controlled by Trem-2 and is interlinked with the de-differentiation of endothelial cells and heightened liver pathology. We propose that Trem-2 promotes the transition from the pro-inflammatory to the tissue repair phase by driving the acquisition of restorative properties of phagocytic macrophages.

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

“…In line with Perugorria et al [ 89 ], we have recently shown that in acute and chronic mouse models of liver disease, Trem-2 is particularly upregulated in a specific macrophage population, named “transition macrophages” [ 99 ]. Transcriptomic analyses showed that absence of Trem-2 impacts the switching from recruited to transition macrophages, with the latter showing muted transcriptional response to oxidative stress and an inability to shut down the inflammatory profile.…”

“…Interestingly, an endothelial liver damage endothelial cell (LDECs) population showing a distinct transcriptional profile was identified. The accumulation of LDECs significantly correlated to the degree of liver damage and to impaired replenishment of KC compartment [ 99 ] ( Figure 2 ). These results fit the notion that a crosstalk between macrophages and endothelial cells is part of the liver regeneration process after liver injury.…”

Trem-2 modulation of gut microbiota is blunted during hepatotoxic injury and uncoupled from liver repair responses

“…Despite microbiota composition homogenization in the co-housed mice, APAP treatment (D3) recapitulated the hepatic tissue repair phenotype that we have previously described 17 . Namely, wild-type showed complete recover from hepatic tissue damage at D3 after injury, while Trem-2 KO mice revealed persistent liver damage, as quantified by liver necrosis scoring (Figure 3C).…”

“…Finding that Trem-2 modulated the gut microbiota composition in untreated mice prompted us to determine whether this trait was involved in the impaired tissue repair responses observed in Trem-2 KO mice 17 . We performed co-housing experiments followed by administration of APAP.…”

“…Interestingly, these results were also recapitulated in models of multiple sclerosis and aging 15, 16 . In the liver, we recently found that expression of Trem-2 promotes macrophage restorative activities during recovery from acute and chronic liver damage 17 . Additionally, a recent study showed that antibiotic treatment followed by CCl4-induced acute liver injury, abolished the increase in hepatic enzymes levels observed in Trem-2 KO mice, while intestinal permeability was not affected 18 .…”