Background/Aim: Although anti-inflammatory macrophage differentiation (M2) from pro-inflammatory (M1) phenotype is critical for heme oxygenase-1 (HO-1) cytoprotection, the role of cell type-specific HO-1 induction remains unknown. Here, we analyzed the function of myeloid-specific HO-1 induction in murine hepatic IRI; and in human liver transplantation. Methods/Results: [Mouse] Groups of WT, myeloid specific HO-1 transgenic (mHO-1 Tg) and myeloid specific HO-1 knockout (mHO-1 KO) mice (C57/BL6) were subjected to liver warm ischemia (90min) and reperfusion (6h). Unlike in WT, myeloid HO-1 overexpression ameliorated liver IRI, evidenced by decreased (p<0.05) sALT levels, Suzuki's histological grading and frequency of TUNEL+ cells; with concomitantly decreased mRNA levels coding for CXCL10, MCP1, IL1β (p<0.05) yet increased Arg1 and CD163 (p<0.05). In marked contrast, livers with myeloid-specific disruption of HO-1 signaling were more susceptible to IRI (sALT, Suzuki's grading, TUNEL, p<0.05) along with augmented CXCL10, MCP1, IL1β (p<0.05) but decreased Arg1 and CD163 (p<0.05). These in vivo findings correlated with bone marrow-derived macrophage (BMM) cultures, in which HO-1 Tg (but not HO-1 KO) BMM were characterized by depressed CXCL10, MCP1, IL1β (p<0.05) and increased Arg1 and CD163 (p<0.05) levels. [Human] Liver biopsies (Bx) were collected from twenty-one adult primary liver transplant patients (2h after reperfusion), divided into “high” (n=10) vs. “low” (n=11) HO-1 expression groups, and then screened for M1 (CXCL10, MCP1, IL1β) and M2 (Arg1, CD163) markers by RT-PCR. High HO-1 Bx samples were characterized by decreased CXCL10 (0.36±0.1 vs. 1.00±0.24, p<0.05), MCP1 (0.57±0.21 vs. 1.00±0.33), IL1β (0.75±0.24 vs. 1.00±0.30), with simultaneously increased Arg1 (1.37±0.27 vs. 1.00±0.22) and CD163 (1.54±0.43 vs. 1.00±0.17). Immunofluorescence stains of "high" HO-1 Bx revealed strong HO-1/CD206 expression co-localized predominantly on liver transplant-infiltrating macrophages, whereas "low" HO-1 Bx liver grafts exhibited relatively weak HO-1/CD206 expression. Conclusion: This translation study is the first to document the significance of HO-1 mediated macrophage M2 differentiation in myeloid-specific mutant murine models and clinical liver transplantation.

CITATION INFORMATION: Nakamura K, Zhang M, Kageyama S, Ke B, Sosa R, Reed E, Zarrinpar A, Busuttil R, Araujo J, Kupiec-Weglinski J. Myeloid HO-1 Regulates M2 Macrophage Activation in Liver Ischemia-Reperfusion Injury (IRI). Am J Transplant. 2017;17 (suppl 3).

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