Infiltrating monocyte-derived macrophages and resident Kupffer cells display different ontogeny and functions in acute liver injury

Ehud Zigmond, Shany Samia-Grinberg, Metsada Pasmanik-Chor, Eli Brazowski, Oren Shibolet, Zamir Halpern, Chen Varol*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

The liver has a remarkable capacity to regenerate after injury; yet, the role of macrophages (MF) in this process remains controversial mainly due to difficulties in distinguishing between different MF subsets. In this study, we used a murine model of acute liver injury induced by overdose of N-acetyl-p-aminophenol (APAP) and defined three distinct MF subsets that populate the liver following injury. Accordingly, resident Kupffer cells (KC) were significantly reduced upon APAP challenge and started recovering by self-renewal at resolution phase without contribution of circulating Ly6C hi monocytes. The latter were recruited in a CCR2- and M-CSF-mediated pathway at the necroinflammatory phase and differentiated into ephemeral Ly6Clo MF subset at resolution phase. Moreover, their inducible ablation resulted in impaired recovery. Microarray-based molecular profiling uncovered high similarity between steady-state KC and those recovered at the resolution phase. In contrast, KC and monocyte-derived MF displayed distinct prorestorative genetic signature at the resolution phase. Finally, we show that infiltrating monocytes acquire a prorestorative polarization manifested by unique expression of proangiogenesis mediators and genes involved with inhibition of neutrophil activity and recruitment and promotion of their clearance. Collectively, our results present a novel phenotypic, ontogenic, and molecular definition of liver-MF compartment following acute injury.

Original languageEnglish
Pages (from-to)344-353
Number of pages10
JournalJournal of Immunology
Volume193
Issue number1
DOIs
StatePublished - 1 Jul 2014

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