*Purpose: Aggravated liver injury and enhanced intrahepatic inflammation was found in old livers post ischemia and reperfusion (IR). However, the function and underlying mechanism of macrophage innate immune activation are not well understood. Here, we investigated whether and how stimulator of interferon genes (Sting) signaling regulated macrophage proinflammatory activation and liver IR injury in old mice.

*Methods: Young (8-week-old) and aged (100-week-old) mice were subjected to hepatic IR in vivo. Macrophages isolated from IR-stressed livers and bone marrow derived macrophages (BMDMs) from the young and old mice were used for in vitro studies.

*Results: Compared to young mice, aged mice showed aggravated liver IR injury and increased intrahepatic inflammation. Enhanced nucleotide-binding domain and leucine-rich repeat containing protein 3 (NLRP3) activation was found in both aged livers and macrophages isolated from aged livers post IR. NLRP3 knockdown inhibited macrophage proinflammatory activation both in vitro and in vivo, leading to similar levels of intrahepatic inflammation and liver injury in the young and old mice. Moreover, enhanced activation of Sting/TBK1 signaling pathway was observed in macrophages isolated from aged livers post IR and aged BMDMs post activation. Interestingly, Sting suppression by its inhibitor or siRNA blocked the over activation of NLRP3 signaling and excessive secretion of proinflammatory cytokine/chemokine in BMDMs from old mice post mtDNA stimulation. More importantly, Sting knockdown in macrophages abrogated the detrimental role of aging in aggravating liver injury and intrahepatic inflammation in livers post IR. Finally, peripheral blood of the young and old recipients undergoing liver transplantation were collected and analyzed, showing that the old recipients had much higher levels of TNF-a, CXCL-10, IL-1β and IL-18 post transplantation.

*Conclusions: In conclusion, our study demonstrates for the first time that the Sting-NLRP3 axis is critical in promoting proinflammatory response of aged macrophages and may be a novel therapeutic target to reduce IR injury in aged livers.

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