Author(s): Coelho, Inês ; Duarte, Nádia ; Barros, André ; Macedo, Maria Paula ; Penha-Gonçalves, Carlos
Date: 2021
Persistent ID: http://hdl.handle.net/10362/113692
Origin: Repositório Institucional da UNL
Subject(s): acetaminophen (paracetamol); carbon tetrachloride 4; endothelial cells; inflammation; macrophages; tissue repair and organ regeneration; triggering receptor expressed on myeloid cells 2; Immunology and Allergy; Immunology
This work was developed with the support of the research infrastructure Congento, project LISBOA-01-0145-FEDER022170, co-financed by Lisboa Regional Operational Programme (Lisboa 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (ERDF), and FCT – “Fundação para a Ciência e a Tecnologia” (Portugal). This work was partially supported by ONEIDA project (LISBOA-01-0145-FEDER016417) co-funded by FEEI – “Fundos Europeus Estruturais e de Investimento” from “Programa Operacional Regional Lisboa 2020” and by national funds from FCT through grants PTDC/ BIM-MET/2115/2014, PTDC/BIM-MET/4265/2014 and iNOVA4Health (UID/Multi/04462/2013). IC was supported by a FCT fellowship PD/BD/105997/2014
Macrophages are pivotal in mounting liver inflammatory and tissue repair responses upon hepatic injury, showing remarkable functional plasticity. The molecular mechanisms determining macrophage transition from inflammatory to restorative phenotypes in the damaged liver remain unclear. Using mouse models of acute (APAP) and chronic (CCl4) drug-induced hepatotoxic injury we show that the immune receptor Trem-2 controls phenotypic shifts of liver macrophages and impacts endothelial cell differentiation during tissue recovery. Trem-2 gene ablation led to a delayed re-population of Kupffer cells correlating with deterred resolution of hepatic damage following acute and chronic injury. During tissue recovery, we found that macrophages transitioning to Kupffer cells expressed high levels of Trem-2. Acquisition of the transition phenotype was associated with a 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), whose transcriptional program was compatible with endothelial de-differentiation. Accordingly, LDECs precursor potential is supported by the downregulation of surface endothelial cell markers and by striking in vitro morphological changes towards typical endothelial cells. In conclusion, we found that the dynamics of liver macrophages in response to liver injury are critically controlled by Trem-2 and this regulation is interlinked with the de-differentiation of endothelial cells and heightened liver pathology. We propose that Trem-2 promotes the transition from pro-inflammatory to tissue repair phase by driving the acquisition of restorative properties in phagocytic macrophages.
