*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 reaction remains an open question. As macrophages are the dominant innate immune cells in livers and they recognize apoptotic cells mainly by phosphatidylserine (PS)-binding Tyro3-Axl-Mer (TAM) receptor tyrosine kinases (RTKs), we analyze roles of TAM RTKs 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 or single deficient mice in their response to liver IRI (Tyro3 is not expressed in livers). 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 declined, while the MerTK level increased at the resolution of liver IRI (day 3-7 post reperfusion). Compared with WT controls, myeloid Axl/MerTK double or single 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. Interestingly, liver recovery from IRI was significantly delayed only in Axl/MerTK double and MerTK single KO, but not Axl single KO mice, as documented by histological and molecular analysis of IR livers at day 7 post reperfusion. In vitro, although there were no differences in the response to simple TLR stimulation between WT and Axl/MerTK deficient macrophages (KCs and bone marrow-derived 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 RTK deficient macrophages were defective in their abilities of efferocytosis. Furthermore, The regulatory effect of TAM RTKs on inflammatory activation was specific for DAMP- (context of tissue damages), but not PAMP-initiated response, as no differences were found in the zymosan-induced peritoneal inflammatory activation. MerTK only regulated the resolution of zymosan-induced peritonitis

*Conclusions: TAM RTKs play critical roles in both the activation and resolution of liver IRI. Both Axl and MerTK regulate the activation, but only MerTK regulates the resolution of liver inflammatory response in IRI. TAM RTKs dampen liver macrophage activation via efferocytosis.

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