*Purpose: Liver ischemia reperfusion injury (IRI) remains a clinical problem associated with both surgical and non-surgical settings. Innate immune-dominated inflammation drives the pathogenesis of liver injuries. Although the activation of liver inflammation by IR have been studied extensively, few has been focused on the inflammation resolution in the disease process.

*Methods: In a murine liver partial warm ischemia model, we characterized the inflammation resolution during IR at histological, cellular and molecular levels. The role of Kupffer cells (KCs) was determined by clodronate-liposome (CL)-mediated depletion, and their functional mechanisms were explored by the inhibition of KC efferocytosis via TIM-4 blocking Abs, during the recovery stage of liver IRI (three doses at 24h, day 3 and day5 post reperfusion).

*Results: The restoration of liver homeostasis from a 90 min ischemia lasts for 7 days, as defined by: (i) repair of hepatocellular damage, (ii) clearance of infiltrating neutrophils, (iii) downregulation of inflammatory and fibrosis genes, and (iv) recovery of KCs and disappearance of infiltrating macrophages. KC depletion by CLs drastically interfered with all these restoration processes, leading to persistent liver inflammation and fibrosis gene upregulation. As macrophage (MФ) efferocytosis plays key roles in tissue repair and immune regulation, we studied KCs and infiltrating MФs in their abilities of efferocytosis. KCs were much more efficient in engulfing apoptotic cells. KCs, but not infiltrating MФs, expressed TIM-4, and TIM-4-signaling was critical for KC effereocytosis in vitro. In vivo TIM-4 blockade by its antagonist antibodies significantly delayed the repair of liver damages, leading to higher fibrosis gene expressions. Furthermore, confocal microscopy of liver macrophages revealed efferocytotic (>2 DAPI positive nucleuses) F4/80 positive cells isolated from ischemic livers at day 3 and 5, but not 6h or sham, post reperfusion. TIM4-4 blockade significantly decreased the numbers of those efferocytotic cells.

*Conclusions: The study documents key roles of KCs in liver inflammation resolution after IR. The repair of IR-induced hepatocellular damages is dependent on TIM-4-mediated KC efferocytosis.

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