Specific expression of heme oxygenase-1 by myeloid cells modulates renal ischemia-reperfusion injury

Abstract

Renal ischemia-reperfusion injury (IRI) is a major risk factor for delayed graft function in renal transplantation. Compelling evidence exists that the stress-responsive enzyme, heme oxygenase-1 (HO-1) mediates protection against IRI. However, the role of myeloid HO-1 during IRI remains poorly characterized. Mice with myeloid-restricted deletion of HO-1 (HO-1M-KO), littermate (LT), and wild-type (WT) mice were subjected to renal IRI or sham procedures and sacrificed after 24 hours or 7 days. In comparison to LT, HO-1M-KO exhibited significant renal histological damage, pro-inflammatory responses and oxidative stress 24 hours after reperfusion. HO-1M-KO mice also displayed impaired tubular repair and increased renal fibrosis 7 days after IRI. In WT mice, HO-1 induction with hemin specifically upregulated HO-1 within the CD11b+ F4/80lo subset of the renal myeloid cells. Prior administration of hemin to renal IRI was associated with significant increase of the renal HO-1+ CD11b+ F4/80lo myeloid cells in comparison to control mice. In contrast, this hemin-mediated protection was abolished in HO-1M-KO mice. In conclusion, myeloid HO-1 appears as a critical protective pathway against renal IRI and could be an interesting therapeutic target in renal transplantation.

Myeloid HO-1 modulates macrophage polarization and protects against ischemia-reperfusion injury

“…We found that myeloid-specific HO-1 deficiency exacerbated liver IRI and hepatic infiltration by macrophages and neutrophils, while increased HO-1 expression in Tg mice resulted in the amelioration of liver injury. This is consistent with comparable outcomes in the model of kidney IRI (24,25) where genetically induced HO-1 overexpression (24) or HO-1 induction by hemin administration (25) ameliorated IR damage, effects that were blunted when HO-1 had been deleted in myeloid cells (25). Importantly, our study enabled us to determine that HO-1-mediated protection was largely due to effects on myeloid functions.…”

“…The difference in overall HO-1 expression in myeloid cells between Tg and controls was much smaller than that exhibited by KOs versus controls, which was reflected by the lack of trends or any significant difference in HO-1 overall expression in tissues tested (Supplemental Figure 4). In the study by Rossi et al, administration of hemin 24 hours prior to the kidney IR induced HO-1 expression in CD11b + F4/80 lo myeloid cells, putative mediators of HO-1 protection (25). However, hemin was expected to induce HO-1 in a large variety of cells, not only those of the myeloid lineage.…”

HO-1hi patrolling monocytes protect against vaso-occlusion in sickle cell disease

“…We propose that heightened expression of HO-1, which degrades heme into CO and biliverdin, both with anti-inflammatory anti-cytotoxic properties, [39][40][41] is critical for the protective function of PMos against VOC. Consistent with this, inhibition of HO-1 activity exacerbated SCD vaso-occlusion, 14 and myeloid-specific HO-1 deletion induced inflammation during non-SCD reperfusion injury, 42 whereas HO-1 overexpression inhibited LPS-stimulated TNF-a expression in human monocytes. 43 Similarly, we found lower expression of proinflammatory TNF-a and IL-6 cytokines in HO-1 hi as compared with HO-1 low SCD PMos following stimulation ( Figure 1F).…”

New insights into the role of heme oxygenase-1 in acute kidney injury

“…Myeloid HO-1 expression in IRI was explored by Rossi et al [48]. HO-1 deficiency in myeloid cells in vivo inwww.krcp-ksn.org creased histological injury, inflammation, and oxidative stress 24 hours after IRI.…”