Date: Monday, June 13, 2016
Session Time: 6:00pm-7:00pm
Presentation Time: 6:00pm-7:00pm
Location: Halls C&D
Background & Aims
Although mechanisms of liver immune activation against ischemia reperfusion injury (IRI) have been studied extensively, cellular bases have yet to be fully defined and roles of Kupffer cells (KCs) remain controversial. Recent findings on the unique lineage and function of tissue resident macrophages implicate that KCs may play homeostatic roles in liver IRI. This study aims to define how KCs respond to and function in IRI.
In a murine liver partial warm ischemia model, we analyzed liver macrophages by fluorescence-activated cell sorting (FACS) and immunofluorescence staining. Necrostatin analogue (Nec-1s, 4mg/kg, i.p.) was used to test functional significance of necroptosis in liver IRI both in the KC-repleted and -depleted (by clodronate liposomes, i.p. 48h prior to the onset of liver ischemia) conditions. Ischemic livers were reconstituted with exogenous KCs or bone marrow derived macrophages (BMMs) (2×106, via portal vein) to test directly their potential functions in liver IRI. Regulation of macrophage activation by necroptosis was also tested in vitro. KC resistance against IR-induced necroptosis as an immune regulatory mechanism in liver IRI was validated in Phosphatase and Tensin Homolog (PTEN)-deficient mice.
Liver immune activation by IR was associated with not only infiltrations/activations of monocyte-derived macrophages (iM[Oslash], F4/80+CD11b+), but also necrotic depletions of KCs (F4/80+CD11b–), as revealed by our FACS analysis of liver macrophage subsets and immunofluorescence staining of F4/80+ cells. Host pre-treatment with Nec-1s prevented this KC death, resulting in suppression of liver immune response and protection of livers from IRI. Codronate-mediated KC depletion annihilated the Nec-1s liver protective effect. Host reconstitution with KCs, but not BMMs, post liver ischemia protected livers from IRI. Necroptotic macrophages (BMMS in vitro) enhanced their pro-inflammatory immune responses against TLR stimulations. PTEN-deficient KCs were resistant to IR-induced necroptosis and protected livers from IRI.
KCs play homeostatic functions in liver IRI, and liver IR depleted KCs via necroptosis, which constitutes a novel mechanism of liver inflammatory immune activation in the pathogenesis of liver IRI.
CITATION INFORMATION: Yue S, Zhou H, Busuttil R, Kupiec-Weglinski J, Wang X, Zhai Y. Liver Ischemia Induces Kupffer Cell Necroptosis to Facilitate Liver Inflammatory Immune Activation. Am J Transplant. 2016;16 (suppl 3).
To cite this abstract in AMA style:Yue S, Zhou H, Busuttil R, Kupiec-Weglinski J, Wang X, Zhai Y. Liver Ischemia Induces Kupffer Cell Necroptosis to Facilitate Liver Inflammatory Immune Activation. [abstract]. Am J Transplant. 2016; 16 (suppl 3). https://atcmeetingabstracts.com/abstract/liver-ischemia-induces-kupffer-cell-necroptosis-to-facilitate-liver-inflammatory-immune-activation/. Accessed February 22, 2020.
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