Spotlight on liver macrophages for halting injury and progression in nonalcoholic fatty liver disease

Laursen, Tea Lund; Mellemkjær, Anders; Møller, Holger Jon; Grønbæk, Henning; Kazankov, Konstantin

doi:10.1080/14728222.2022.2132145

Cited by 6 publications

(1 citation statement)

References 75 publications

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“…Fatty liver disease is increasing in incidence and is predicted to become the main etiology leading to liver transplantation for both men and women [1]. Non-alcoholic fatty liver disease (NAFLD) is the most common cause of liver disease worldwide and affects approximately 25% of the population [2]. In the United States, the prevalence of non-alcoholic steatohepatitis (NASH) is estimated to be between 1.5% to 6.45% and it is commonly associated with dyslipidemia, obesity, metabolic disease, and type 2 diabetes [3] [4].…”

Section: Introductionmentioning

confidence: 99%

Patients with fibrosis from non-alcoholic steatohepatitis have heterogeneous intrahepatic macrophages and therapeutic targets

Saldarriaga

Krishnan

Wanninger

et al. 2023

Preprint

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Background and Aims. In clinical trials for reducing fibrosis in NASH patients, therapeutics that target macrophages have had variable results. We evaluated intrahepatic macrophages in patients with non-alcoholic steatohepatitis to determine if fibrosis influenced phenotypes and expression of CCR2 and Galectin-3. Approach & Results. We used nCounter to analyze liver biopsies from well-matched patients with minimal (n=12) or advanced (n=12) fibrosis to determine which macrophage-related genes would be significantly different. Known therapy targets (e.g., CCR2 and Galectin-3) were significantly increased in patients with cirrhosis. However, several genes (e.g., CD68, CD16, and CD14) did not show significant differences, and CD163, a marker of pro-fibrotic macrophages was significantly decreased with cirrhosis. Next, we analyzed patients with minimal (n=6) or advanced fibrosis (n=5) using approaches that preserved hepatic architecture by multiplex-staining with anti-CD68, Mac387, CD163, CD14, and CD16. Spectral data were analyzed using deep learning/artificial intelligence to determine percentages and spatial relationships. This approach showed patients with advanced fibrosis had increased CD68+, CD16+, Mac387+, CD163+, and CD16+CD163+ populations. Interaction of CD68+ and Mac387+ populations was significantly increased in patients with cirrhosis and enrichment of these same phenotypes in individuals with minimal fibrosis correlated with poor outcomes. Evaluation of a final set of patients (n=4) also showed heterogenous expression of CD163, CCR2, Galectin-3, and Mac387, and significant differences were not dependent on fibrosis stage or NAFLD activity. Conclusions. Approaches that leave hepatic architecture intact, like multispectral imaging, may be paramount to developing effective treatments for NASH. In addition, understanding individual differences in patients may be required for optimal responses to macrophage-targeting therapies.

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