*Purpose: Although the inflammatory response in liver ischemia reperfusion injury has been studied extensively, how the context of tissue injury (presence of necrotic/apoptotic cells) regulates the DAMP-initiated innate immune activation remains an open question. As macrophages are the dominant innate immune cells in livers and they recognize apoptotic (dead) cells mainly by phosphatidylserine (PS)-binding Tyro3-Axl-Mer (TAM) receptors, we analyze roles of TAM receptors in liver ischemia/reperfusion injury at both the inflammation activation and resolution stages.

*Methods: In a murine liver partial ischemia model (90m), we compared WT and myeloid-specific Axl/MerTK double deficient mice in their response to liver IRI. Liver inflammation activation and resolution were evaluated at the peak of liver injury (6-24h) or during the course of tissue repair (3-7 days), respectively.

*Results: IR downregulated MerTK, but induced Axl, expression in IR livers at the peak of injury (6-24h). The Axl level was decreased, while the MerTK level increased at the resolution of liver IRI (day 3-7 post reperfusion). Tyro3 expression was minimal in livers over the course of IRI. Compared with WT controls, myeloid Axl/MerTK double deficient mice developed significantly more severe liver IRI with enhanced pro-inflammatory activation, as evidenced by elevated sALT levels, worse damaged liver architecture (H/E staining) with higher Suzuki scores, and upregulated pro- but downregulated anti-inflammatory gene expressions in IR livers. Furthermore, liver recovery from IRI was significantly delayed in these deficient mice that significant amounts of hepatocellular damages persisted at day 7 post reperfusion when liver IRI was fully recovered in WT controls. This was associated with higher levels of pro-inflammatory and pro-fibrotic (a-SMA, Col1A1), but lower levels of immune regulatory/reparative (TGF-b, Arg, MRC1) gene expressions. In vitro, although there were no differences in the response to simple TLR stimulation between WT and Axl/MerTK deficient macrophages (KCs and peritoneal macrophages), the presence of apoptotic cells during inflammatory activation downregulated TNF-a and upregulated IL-10 productions in WT, but not Axl/MerTK deficient, macrophages. Indeed, these TAM receptor deficient macrophages were defective in their abilities of efferocytosis.

*Conclusions: TAM receptors regulate macrophage inflammatory activation in the context of tissue injury. Axl and MerTK inhibit pro-inflammatory activation and facilitate the inflammation resolution in liver IRI.

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