Date: Saturday, May 2, 2015
Session Time: 5:30pm-7:30pm
Presentation Time: 5:30pm-7:30pm
Location: Exhibit Hall E
Background: Although heme oxygenase-1 (HO-1) is known to induce alternative macrophage activation towards an anti-inflammatory M2 phenotype, the underlying mechanisms remain elusive. Autophagy may play an essential role in the regulation of monocyte-macrophage differentiation/function. This study explores mechanistic links between HO-1 signaling and autophagy program in regulating alternative macrophage activation after transferring ex-vivo generated HO-1 overexpressing bone marrow-derived macrophages (BMMs) in liver transplants. Methods: We used a mouse model of hepatic cold storage (20h) followed by orthotopic liver transplantation (OLT) in syngeneic (C57/BL6) hosts. BMMs (5×106) transfected with Ad-HO-1 or Ad-β-gal (2.5×109 pfu) were infused directly into liver grafts via portal vein immediately prior to reperfusion (n=4-6/gr). Mice were sacrificed at 6h post-transplantation. Results: OLTs conditioned with Ad-HO-1 BMMs showed minimal sinusoidal congestion, decreased edema/vacuolization and necrosis, as compared to those receiving Ad-β-gal-transfected BMMs. The hepatic architecture pattern correlated with decreased serum ALT levels in Ad-HO-1 treated hosts. Intra-hepatic transfer of Ad-HO-1 BMMs reduced neutrophil sequestration, pro-inflammatory cytokine/chemokine programs, and hepatocellular necrosis/apoptosis in OLTs. Moreover, Ad-HO-1 BMMs promoted macrophage activation towards M2 (Mrc-1/Arg-1+) while inhibiting M1 (Nos2+) phenotype, and increasing anti-inflammatory (TGF-β/IL-10) expression in well-functioning OLTs. Unlike in controls, Ad-HO-1 BMMs enhanced macrophage LC3B levels, accompanied by augmented expression of Sirt1, Smad4, Beclin1, and Atg7, yet depressed p62. Interestingly, chemically-induced Sirt1 inhibition exacerbated IR-stressed OLT damage despite concomitant transfer of Ad-HO-1 BMMs. Conclusion: Adoptive transfer of ex-vivo generated HO-1-modified BMMs triggered alternative macrophage activation by promoting macrophage Sirt1-mediated autophagy program in IR-stressed OLTs. Sirt1 induction activated TGF-β/Smad4 signaling to regulate macrophage differentiation and inhibit inflammation responses in IR-livers. These findings provide the rationale for a clinically attractive and novel strategy in which native BMMs modified ex-vivo to overexpress HO-1 gene can be applied to mitigate ischemic tissue damage in OLTs.
To cite this abstract in AMA style:Yue S, Huang J, Nakamura K, Zhou M, Shen X-D, Busuttil R, Ke B, Kupiec-Weglinski J. HO-1 Modified Macrophages Promote Autophagy by Activating Sirt1/TGF-β/Smad4 Signaling in Ischemia-Stressed Mouse Liver Transplants [abstract]. Am J Transplant. 2015; 15 (suppl 3). https://atcmeetingabstracts.com/abstract/ho-1-modified-macrophages-promote-autophagy-by-activating-sirt1tgf-smad4-signaling-in-ischemia-stressed-mouse-liver-transplants/. Accessed January 21, 2022.
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