Carbon monoxide potently prevents ischemia-induced high-mobility group box 1 translocation and release and protects against lethal renal ischemia–reperfusion injury

Abstract

High-mobility group box 1 (HMGB1) is a chromatin-binding nuclear molecule that has potent proinflammatory effects once released by damaged cells. In some disease models, carbon monoxide (CO) exhibits anti-inflammatory and protective properties. Here, we investigated whether the protective effect of CO on renal ischemia-reperfusion injury is associated with the inhibition of HMGB1 translocation and release. A renal ischemia-reperfusion injury model was established with a 100% mortality rate in untreated mice. Pretreatment with the CO-releasing molecule-2 (CORM-2) resulted in 100% survival, maximal preservation of renal function, a marked reduction in pathological damage, and blunted upregulation of TLR4, RAGE, TNF-α, IL-1β, IL-6, and MCP1 mRNA. Interestingly, CORM-2 pretreatment almost completely inhibited ischemia-induced HMGB1 nucleocytoplasmic shuttling and release. This inhibition was associated with a decrease in nuclear histone acetyltransferase activity. Indeed, CORM-2 pretreatment inhibited the acetylation and release of HMGB1 during hypoxic culture of primary mouse renal tubular epithelia cells in vitro. Using the same renal ischemia-reperfusion injury model, neutralization of HMGB1 was protective, and administration of exogenous HMGB1 largely reversed the protective effect of CORM-2 on kidney ischemia-reperfusion injury. Thus, CORM-2-delivered CO protects against lethal renal ischemia-reperfusion injury. This protection is correlated with the prevention of HMGB1 nuclear-cytoplasmic translocation and release.

Kupffer cell inactivation by carbon monoxide bound to red blood cells preserves hepatic cytochrome P450 via anti-oxidant and anti-inflammatory effects exerted through the HMGB1/TLR-4 pathway during resuscitation from hemorrhagic shock

“…Based on the present and previous findings, the mechanism of CYP protection by the CO-RBC in the later phase after hemorrhagic shock and resuscitation appears to involve the prevention of inflammatory cytokines as a result of the suppression of both HMGB-1 release from parenchymal cells and TLR-4 expression on Kupffer cells by CO derived from CO-RBC. This proposed mechanism is supported by previous studies which showed that CO has the potential to attenuate HMGB-1 release and TLR-4 activation under other pathological conditions [25][26][27].…”

High-pressure carbon monoxide preserves rat kidney grafts from apoptosis and inflammation

“…17 Similar protective results can be achieved after storage of grafts in a UW solution saturated with CO. 18,19 Sener et al 20 demonstrated that carbon monoxide releasing molecules (CORM) supplementation in UW solution has a significant impact on decreasing cellular and graft injury, and improving rat kidney graft survival through its anti-apoptotic effects. Recently, Ruan Y et al 21 reported the protective effect of CO from CORM on renal ischemia-reperfusion injury is associated with the inhibition of high-mobility group box 1 (HMGB1) translocation and release. In addition to its antiinflammatory and anti-apoptotic effects, CO reduced graft immunogenicity and inhibited chronic allograft nephropathy in a rat kidney transplantation model.…”

The Heme Metabolite Carbon Monoxide Facilitates KSHV Infection by Inhibiting TLR4 Signaling in Endothelial Cells

“…Heme oxygenase-1 and the heme metabolite CO have been shown to inhibit TLR4 signaling to reduce cytokine-driven inflammatory outcomes and protect cells against oxidative stress (Liu et al, 2002; Otterbein et al, 2005; Nakahira et al, 2006; Tsiftsoglou et al, 2006; Lin et al, 2009; Wang et al, 2009; Ruan et al, 2014; Xue and Habtezion, 2014). In addition to TLR4, CO also inhibits the activation of TLR2, TLR5, and TLR9 (Nakahira et al, 2006).…”

“…HO-1 is thought to contribute to cytoprotection and proliferation through the catabolism of heme, a pro-oxidant molecule that is cytotoxic in excess, into metabolites with anti-oxidant, pro-angiogenic, anti-apoptotic, and anti-inflammatory activities (Ryter and Tyrrell, 2000; Ryter et al, 2006; Ryter and Choi, 2009). Of particular relevance to the current study, the endogenous gasotransmitter CO participates in intracellular signaling pathways that culminate in anti-inflammatory, anti-coagulative and pro-survival outcomes (Liu et al, 2002; Pae et al, 2004; Otterbein et al, 2005; Nakahira et al, 2006; Ryter and Choi, 2009; Ruan et al, 2014; Yang et al, 2014; Xue and Habtezion, 2014; Riquelme et al, 2015). The discovery of compounds categorized as “carbon monoxide releasing molecules” (CORM) has allowed for further mechanistic insight into the role of CO in biological systems (Ryter and Choi, 2015).…”