Search

Neutrophils, the largest innate immune cell population in humans, are the primary proinflammatory sentinel in the ischemia-reperfusion injury (IRI) mechanism in orthotopic liver transplantation (OLT). Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1, CC1, or CD66a) is essential in neutrophil activation and serves as a checkpoint regulator of innate immune-driven IRI cascade in OLT. Although CC1 alternative splicing generates two functionally distinct short and long cytoplasmic isoforms, their role in neutrophil activation remains unknown. Here, we undertook molecular and functional studies to interrogate the significance of neutrophil CC1 signaling in mouse and human OLT recipients. In the experimental arm, we employed a mouse OLT model to document that ablation of recipient-derived neutrophil CC1-long (CC1-L) isotype aggravated hepatic IRI by promoting neutrophil extracellular traps (NETs). Notably, by regulating the S1P-S1PR2/S1PR3 axis, neutrophil CC1-L determined susceptibility to NET formation via autophagy signaling. In the clinical arm, liver grafts from 55 transplant patients selectively enriched for neutrophil CC1-L showed relative resistance to ischemia-reperfusion (IR) stress/tissue damage, improved hepatocellular function, and clinical outcomes. In conclusion, despite neutrophils being considered a principal villain in peritransplant tissue injury, their CC1-L isoform may serve as a regulator of IR stress resistance/NETosis in human and mouse OLT recipients.

Although glycogen synthase kinase β (Gsk3β) has been shown to regulate tissue inflammation, whether and how it regulates inflammation resolution versus inflammation activation is unclear. In a murine liver, partial warm ischemia/reperfusion injury (IRI) model, we found that Gsk3β inhibitory phosphorylation increased at both the early-activation and late-resolution stages of the disease. Myeloid Gsk3β deficiency not only alleviated liver injuries, it also facilitated the restoration of liver homeostasis. Depletion of Kupffer cells prior to the onset of liver ischemia diminished the differences between the WT and Gsk3β-KO mice in the activation of liver IRI. However, the resolution of liver IRI remained accelerated in Gsk3β-KO mice. In CD11b-DTR mice, Gsk3β-deficient BM-derived macrophages (BMMs) facilitated the resolution of liver IRI as compared with WT cells. Furthermore, Gsk3β deficiency promoted the reparative phenotype differentiation in vivo in liver-infiltrating macrophages and in vitro in BMMs. Gsk3 pharmacological inhibition promoted the resolution of liver IRI in WT, but not myeloid MerTK-deficient, mice. Thus, Gsk3β regulates liver IRI at both activation and resolution stages of the disease. Gsk3 inactivation enhances the proresolving function of liver-infiltrating macrophages in an MerTK-dependent manner.

Background and aimsLiver ischemia reperfusion injury (IRI) remains an unresolved clinical problem. This study dissected roles of liver-resident macrophage Kupffer cells (KCs), with a functional focus on efferocytosis receptor T-cell immunoglobulin and mucin domain-containing protein-4 (TIM-4), in both the activation and resolution of IRI in a murine liver partial warm ischemia model.Approach and resultsFluorescence-activated cell sorting results showed that TIM-4 was expressed exclusively by KCs, but not infiltrating macrophages (iMФs), in IR livers. Anti-TIM-4 antibody depleted TIM-4+ macrophages in vivo, resulting in either alleviation or deterioration of liver IRI, which was determined by the repopulation kinetics of the KC niche with CD11b+ macrophages. To determine the KC-specific function of TIM-4, we reconstituted clodronate-liposome-treated mice with exogenous wild-type or TIM-4-deficient KCs at either 0 hour or 24 hours postreperfusion. TIM-4 deficiency in KCs resulted in not only increases in the severity of liver IRI (at 6 hours postreperfusion), but also impairment of the inflammation resolution (at 7 days postreperfusion). In vitro analysis revealed that TIM-4 promoted KC efferocytosis to regulate their Toll-like receptor response by up-regulating IL-10 and down-regulating TNF-α productions.ConclusionsTIM-4 is critical for KC homeostatic function in both the activation and resolution of liver IRI by efferocytosis.

BackgroundA major discrepancy between clinical and most experimental settings of liver ischemia-reperfusion injury (IRI) is the allogenicity.MethodsIn the current study, we first established a murine model of allogeneic orthotopic liver transplantation with extended cold ischemia time (18 h). Roles of CD4 T cells in the pathogenesis of IRI in liver allografts were determined using a depleting anti-CD4 antibody. The clinical relevance of CD4 as a marker of liver IRI was analyzed retrospectively in 55 liver transplant patients.ResultsCD4 depletion in both donors and recipients resulted in the most effective protection of liver allografts from IRI, as measured by serum transaminase levels and liver histology. CD4 depletion inhibited IR-induced intragraft neutrophil/macrophage infiltration and proinflammatory gene expressions. Quantitative reverse-transcriptase polymerase chain reaction analysis of human liver biopsies (2 h postreperfusion) revealed that posttransplant, rather than pretransplant, CD4 transcript levels correlated positively with proinflammatory gene expression profile. When we divided patients into subgroups according to intragraft CD4 levels, the high CD4 cohort developed a more severe hepatocellular damage than that with low CD4 levels.ConclusionsCD4 T cells play a key pathogenic role in IRI of allogeneic liver transplants, and intragraft CD4 levels in the early postreperfusion phase may serve as a potential biomarker and therapeutic target to ameliorate liver IRI and improve orthotopic liver transplantation outcomes.

Glycogen synthase kinase 3 (Gsk3) α and β are both constitutively active and inhibited upon stimulation by N-terminal serine phosphorylation. Although roles of active Gsk3 in liver ischemia reperfusion injury (IRI) have been well appreciated, whether Gsk3 N-terminal serine phosphorylation has any functional significance in the disease process remains unclear. In a murine liver partial warm ischemia model, we studied Gsk3 N-terminal serine mutant knock-in (KI) mice and showed that liver IRI was decreased in Gsk3αS21A but increased in Gsk3βS9A mutant KI mice. Bone marrow chimeric experiments revealed that the Gsk3α, but not β, mutation in liver parenchyma protected from IRI, and both mutations in bone marrow-derived cells exacerbated liver injuries. Mechanistically, mutant Gsk3α protected hepatocytes from inflammatory (TNF-α) cell death by the activation of HIV-1 TAT-interactive protein 60 (TIP60)-mediated autophagy pathway. The pharmacological inhibition of TIP60 or autophagy diminished the protection of the Gsk3α mutant hepatocytes from inflammatory cell death in vitro and the Gsk3α mutant KI mice from liver IRI in vivo. Thus, Gsk3 N-terminal serine phosphorylation inhibits liver innate immune activation but suppresses hepatocyte autophagy in response to inflammation. Gsk3 αS21, but not βS9, mutation is sufficient to sustain Gsk4 activities in hepatocytes and protect livers from IRI via TIP60 activation.

Farnesoid X receptor (FXR) is the nuclear receptor of bile acids and is involved in innate immune regulation. FXR agonists have been shown to protect multiple organs from inflammatory tissue injuries. Because liver expresses high levels of FXR, we explored the potential therapeutic benefits and underlying mechanisms of pharmacologic FXR activation in a murine model of partial liver warm ischemia. Pretreatment of mice with FXR agonist 3-(2,6-dichlorophenyl)-4-(3'-carboxy-2-chlorostilben-4-yl)oxymethyl-5-isopropylisoxazole (GW4064) attenuated liver ischemia/reperfusion injuries (IRIs) in wild-type but not FXR knockout mice. Posttreatment with GW4064 facilitated liver recovery from IRI. Mechanistically, Kupffer cells (KCs) expressed much higher levels of FXR than bone marrow-derived macrophages (BMMs). Pretreatment of KCs but not BMMs with GW4064 resulted in lower tumor necrosis factor α but higher interleukin-10 expressions following toll-like receptor stimulation. FXR-targeted gene small heterodimer partner (SHP) was critical for the regulation of KC response by GW4064. In vivo, the depletion of KCs but not cluster of differentiation (CD) 11b+ cells or knockdown of SHP diminished the immune regulatory effect of GW4064 in liver IRI. Thus, FXR activation protects liver from IRI by up-regulating SHP in KCs to inhibit the liver proinflammatory response.

Background & aimsGlycogen synthase kinase 3β (Gsk3β [Gsk3b]) is a ubiquitously expressed kinase with distinctive functions in different types of cells. Although its roles in regulating innate immune activation and ischaemia and reperfusion injuries (IRIs) have been well documented, the underlying mechanisms remain ambiguous, in part because of the lack of cell-specific tools in vivo.MethodsWe created a myeloid-specific Gsk3b knockout (KO) strain to study the function of Gsk3β in macrophages in a murine liver partial warm ischaemia model.ResultsCompared with controls, myeloid Gsk3b KO mice were protected from IRI, with diminished proinflammatory but enhanced anti-inflammatory immune responses in livers. In bone marrow-derived macrophages, Gsk3β deficiency resulted in an early reduction of Tnf gene transcription but sustained increase of Il10 gene transcription on Toll-like receptor 4 stimulation in vitro. These effects were associated with enhanced AMP-activated protein kinase (AMPK) activation, which led to an accelerated and higher level of induction of the novel innate immune negative regulator small heterodimer partner (SHP [Nr0b2]). The regulatory function of Gsk3β on AMPK activation and SHP induction was confirmed in wild-type bone marrow-derived macrophages with a Gsk3 inhibitor. Furthermore, we found that this immune regulatory mechanism was independent of Gsk3β Ser9 phosphorylation and the phosphoinositide 3-kinase-Akt signalling pathway. In vivo, myeloid Gsk3β deficiency facilitated SHP upregulation by ischaemia-reperfusion in liver macrophages. Treatment of Gsk3b KO mice with either AMPK inhibitor or SHP small interfering RNA before the onset of liver ischaemia restored liver proinflammatory immune activation and IRI in these otherwise protected hosts. Additionally, pharmacological activation of AMPK protected wild-type mice from liver IRI, with reduced proinflammatory immune activation. Inhibition of the AMPK-SHP pathway by liver ischaemia was demonstrated in tumour resection patients.ConclusionsGsk3β promotes innate proinflammatory immune activation by restraining AMPK activation.Lay summaryGlycogen synthase kinase 3β promotes macrophage inflammatory activation by inhibiting the immune regulatory signalling of AMP-activated protein kinase and the induction of small heterodimer partner. Therefore, therapeutic targeting of glycogen synthase kinase 3β enhances innate immune regulation and protects liver from ischaemia and reperfusion injury.

Although mechanisms of immune activation against liver ischemia reperfusion (IR) injury (IRI) have been studied extensively, questions regarding liver-resident macrophages, that is, Kupffer cells (KCs), remain controversial. Recent progress in the biology of tissue-resident macrophages implicates homeostatic functions of KCs. This study aims to dissect responses and functions of KCs in liver IRI. In a murine liver partial warm ischemia model, we analyzed liver-resident versus infiltrating macrophages by FACS and immunofluorescence staining. Our data showed that liver immune activation by IR was associated with not only infiltrations/activations of peripheral macrophages, but also necrotic depletion of KCs. Inhibition of receptor-interacting protein 1 (RIP1) by necrostatin-1s protected KCs from ischemia-induced depletion, resulting in the reduction of macrophage infiltration, suppression of proinflammatory immune activation, and protection of livers from IRI. The depletion of KCs by clodronate liposomes abrogated the effect of necrostatin-1s. Additionally, liver reconstitutions with KCs postischemia exerted anti-inflammatory/cytoprotective effects against IRI. These results reveal a unique response of KCs against liver IR, that is, RIP1-dependent necrosis, which constitutes a novel mechanism of liver inflammatory immune activation in the pathogenesis of liver IRI.

BACKGROUND. Orthotopic liver transplant (OLT) is the primary therapy for end-stage liver disease and acute liver failure. However, ischemia/reperfusion injury (IRI) can severely compromise allograft survival. To understand the evolution of immune responses underlying OLT-IRI, we evaluated longitudinal cytokine expression profiles from adult OLT recipients before transplant through 1 month after transplant. METHODS. We measured the expression of 38 cytokines, chemokines, and growth factors in preoperative and postoperative recipient circulating systemic blood (before transplant and 1 day, 1 week, and 1 month after transplant) and intraoperative portal blood (before and after reperfusion) of 53 OLT patients and analyzed this expression in relation to biopsy-proven IRI (n = 26 IRI+; 27 IRI-), clinical liver function tests early (days 1-7) after transplant, and expression of genes encoding cytokine receptors in biopsies of donor allograft taken before and after reperfusion. RESULTS. Bilirubin and arginine transaminase levels early after transplant correlated with IRI. Fourteen cytokines were significantly increased in the systemic and/or portal blood of IRI+ recipients that shifted from innate to adaptive-immune responses over time. Additionally, expression of cognate receptors for 10 of these cytokines was detected in donor organ biopsies by RNAseq. CONCLUSION. These results provide a mechanistic roadmap of the early immunological events both before and after IRI and suggest several candidates for patient stratification, monitoring, and treatment. FUNDING. Ruth L. Kirschstein National Research Service Award T32CA009120, Keck Foundation award 986722, and a Quantitative & Computational Biosciences Collaboratory Postdoctoral Fellowship.

Liver ischemia reperfusion activates innate immune system to drive the full development of inflammatory hepatocellular injury. Damage-associated molecular patterns (DAMPs) stimulate myeloid and dendritic cells via pattern recognition receptors (PRRs) to initiate the immune response. Complex intracellular signaling network transduces inflammatory signaling to regulate both innate immune cell activation and parenchymal cell death. Recent studies have revealed that DAMPs may trigger not only proinflammatory but also immune regulatory responses by activating different PRRs or distinctive intracellular signaling pathways or in special cell populations. Additionally, tissue injury milieu activates PRR-independent receptors which also regulate inflammatory disease processes. Thus, the innate immune mechanism of liver ischemia-reperfusion injury involves diverse molecular and cellular interactions, subjected to both endogenous and exogenous regulation in different cells. A better understanding of these complicated regulatory pathways/network is imperative for us in designing safe and effective therapeutic strategy to ameliorate liver ischemia-reperfusion injury in patients.

High‐performance and air‐stable single‐molecule magnets (SMMs) can offer great convenience for the fabrication of information storage devices. However, the controversial requisition of high stability and magnetic axiality is hard to balance for lanthanide‐based SMMs. Here, a family of dysprosium(III) crown ether complexes possessing hexagonal‐bipyramidal (pseudo‐D6h symmetry) local coordination geometry with tunable air stability and effective energy barrier for magnetization reversal (Ueff) are shown. The three complexes share the common formula of [Dy(18‐C‐6)L2][I3] (18‐C‐6 = 1,4,7,10,13,16‐hexaoxacyclooctadecane; L = I, 1; L = OtBu 2 and L = 1‐AdO 3). 1 is highly unstable in the air. 2 can survive in the air for a few minutes, while 3 remains unchanged in the air for more than 1 week. This is roughly in accordance with the percentage of buried volumes of the axial ligands. More strikingly, 2 and 3 show progressive enhancement of Ueff and 3 exhibits a record high Ueff of 2427(19) K, which significantly contributes to the 100 s blocking temperature up to 11 K for Yttrium‐diluted sample, setting a new benchmark for solid‐state air‐stable SMMs. [ABSTRACT FROM AUTHOR]

Background: Cancer patients are increasingly affected by chemotherapy‐related cardiac dysfunction. The reported incidence of this condition vary significantly across different studies. Hypothesis: A better comprehensive understanding of chemotherapy‐related cardiac dysfunction incidence in cancer patients is imperative. Therefore, we performed a meta‐analysis to establish the overall incidence of chemotherapy‐related cardiac dysfunction in cancer patients. Methods: We searched articles in PubMed and EMBASE from database inception to May 1, 2023. Studies that reported the incidence of chemotherapy‐related cardiac dysfunction in cancer patients were included. Results: A total of 53 studies involving 35 651 individuals were finally included in the meta‐analysis. The overall pooled incidence of chemotherapy‐related cardiac dysfunction in cancer patients was 63.21 per 1000 person‐years (95% CI: 57.28−69.14). The chemotherapy‐related cardiac dysfunction incidence increased steeply within half a year of cancer chemotherapy. Also, the trend of chemotherapy‐related cardiac dysfunction incidence appeared to have plateaued after a longer duration of follow‐up. In addition, chemotherapy‐related cardiac dysfunction incidence rates are significantly higher among patients with age ≥50 years versus patients with age <50 years (99.96 vs. 34.48 per 1000 person‐years). The incidence rate of cardiac dysfunction was higher among breast cancer patients (72.97 per 1000 person‐years), leukemia patients (65.21 per 1000 person‐years), and lymphoma patients (55.43 per 1000 person‐years). Conclusion: Our meta‐analysis unveiled a definitive overall incidence rate of chemotherapy‐related cardiac dysfunction in cancer patients. In addition, it was found that the risk of developing this condition escalates within the initial 6 months postchemotherapy, subsequently tapering off to become statistically insignificant after a duration of 6 years. [ABSTRACT FROM AUTHOR]

Endoplasmic reticulum (ER) stress plays critical roles in the pathogenesis of liver ischemia-reperfusion injury (IRI). As ER stress triggers an adaptive cellular response, the question of what determines its functional outcome in liver IRI remains to be defined. In a murine liver partial warm ischemia model, we studied how transient (30 minutes) or prolonged (90 minutes) liver ischemia regulated local ER stress response and autophagy activities and their relationship with liver IRI. Effects of chemical chaperon 4-phenylbutyrate (4-PBA) or autophagy inhibitor 3-methyladenine (3-MA) were evaluated. Our results showed that although the activating transcription factor 6 branch of ER stress response was induced in livers by both types of ischemia, liver autophagy was activated by transient, but inhibited by prolonged, ischemia. Although 3-MA had no effects on liver IRI after prolonged ischemia, it significantly increased liver IRI after transient ischemia. The 4-PBA treatment protected livers from IRI after prolonged ischemia by restoring autophagy flux, and the adjunctive 3-MA treatment abrogated its liver protective effect. The same 4-PBA treatment, however, increased liver IRI and disrupted autophagy flux after transient ischemia. Although both types of ischemia activated 5' adenosine monophosphate-activated protein kinase and inactivated protein kinase B (Akt), prolonged ischemia also resulted in downregulations of autophagy-related gene 3 and autophagy-related gene 5 in ischemic livers. These results indicate a functional dichotomy of ER stress response in liver IRI via its regulation of autophagy. Transient ischemia activates autophagy to protect livers from IRI, whereas prolonged ischemia inhibits autophagy to promote the development of liver IRI.

Tumor recurrence remains an obstacle after liver surgery, especially in living donor liver transplantation (LDLT) for patients with hepatocellular carcinoma (HCC). The acute-phase liver graft injury might potentially induce poor response to chemotherapy in recurrent HCC after liver transplantation. We here intended to explore the mechanism and to identify a therapeutic target to overcome such chemoresistance. The associations among graft injury, overexpression of IP10 and multidrug resistant genes were investigated in a rat liver transplantation model, and further validated in clinical cohort. The role of IP10 on HCC cell proliferation and tumor growth under chemotherapy was studied both in vitro and in vivo. The underlying mechanism was revealed by detecting the activation of endoplasmic reticulum (ER) stress signaling pathways. Moreover, the effect of IP10 neutralizing antibody sensitizing cisplatin treatment was further explored. In rat liver transplantation model, significant up-regulation of IP10 associated with multidrug resistant genes was found in small-for-size liver graft. Clinically, high expression of circulating IP10 was significant correlated with tumor recurrence in HCC patients underwent LDLT. Overexpression of IP10 promoted HCC cell proliferation and tumor growth under cisplatin treatment by activation of ATF6/Grp78 signaling. IP10 neutralizing antibody sensitized cisplatin treatment in nude mice. The overexpression of IP10, which induced by liver graft injury, may lead to cisplatin resistance via ATF6/Grp78 ER stress signaling pathway. IP10 neutralizing antibody could be a potential adjuvant therapy to sensitize cisplatin treatment.

BackgroundAlthough rapamycin (RPM) have been studied extensively in ischemia models, its functional mechanisms remains to be defined.MethodsWe determined how RPM impacted the pathogenesis of ischemia-reperfusion injury (IRI) in a murine liver partial warm ischemia model, with emphasis on its regulation of hepatocyte death.ResultsRapamycin protected livers from IRI in the presence of fully developed liver inflammatory immune response. Rapamycin enhanced liver autophagy induction at the reperfusion stage. Dual mammalian (mechanistic) target of rapamycin (mTOR)1/2 inhibitor Torin 1, despite its ability to induced autophagy, failed to protect livers from IRI. The treatment with RPM, but not Torin 1, resulted in the enhanced activation of the mTORC2-Akt signaling pathway activation in livers after reperfusion. Inactivation of Akt by Triciribine abolished the liver protective effect of RPM. The differential cytoprotective effect of RPM and Torin 1 was confirmed in vitro in hepatocyte cultures. Rapamycin, but not Trin 1, protected hepatocytes from stress and tumor necrosis factor-α induced cell death; and inhibition of autophagy by chloroquine or Akt by Triciribine abolished RPM-mediated cytoprotection.ConclusionRapamycin protected livers from IRI by both autophagy and mTORC2-Akt activation mechanisms.

BACKGROUND: Nuclear factor erythroid 2-related factor 2 (Nrf2), a master regulator of the antioxidant host defense, maintains the cellular redox homeostasis. METHODS: This study was designed to investigate the role and molecular mechanisms by which Nrf2 regulates toll-like receptor (TLR)4-driven inflammation response in a mouse model of hepatic warm ischemia (90 min) and reperfusion (6 hr) injury (IRI). RESULTS: Activation of Nrf2 after preconditioning of wild-type mouse recipients with cobalt protoporphyrin ameliorated liver IRI, evidenced by improved hepatocellular function (serum alanine aminotransferase levels), and preserved tissue architecture (histology Suzukis score). In marked contrast, ablation of Nrf2 signaling exacerbated IR-induced liver inflammation and damage in Nrf2 knockout hosts irrespective of adjunctive cobalt protoporphyrin treatment. The Nrf2 activation reduced macrophage and neutrophil trafficking, proinflammatory cytokine programs, and hepatocellular necrosis or apoptosis while increasing antiapoptotic functions in IR-stressed livers. At the molecular level, Nrf2 activation augmented heme oxygenase-1 expression and Stat3 phosphorylation and promoted PI3K-Akt while suppressing forkhead box O (Foxo)1 signaling. In contrast, Nrf2 deficiency diminished PI3K-Akt and enhanced Foxo1 expression in the ischemic livers. In parallel in vitro studies, Nrf2 knockdown in lipopolysaccharide-stimulated bone marrow-stimulated bone marrow-derived macrophages (BMMs) decreased heme oxygenase-1 and PI3K-Akt yet increased Foxo1 transcription, leading to enhanced expression of TLR4 proinflammatory mediators. Moreover, pretreatment of bone marrow-derived macrophages with PI3K inhibitor (LY294002) activated Foxo1 signaling, which in turn enhanced TLR4-driven innate responses in vitro. CONCLUSION: Activation of Nrf2 promoted PI3K-Akt, and inhibited Foxo1 activity in IR-triggered local inflammation response. By identifying a novel integrated Nrf2-Akt-Foxo1 signaling network in PI3K-dependent regulation of TLR4-driven innate immune activation, this study provides the rationale for refined therapeutic approaches to manage liver inflammation and IRI in transplant recipients.

Macrophages are instrumental in the pathophysiology of liver ischemia/reperfusion injury (IRI). Although Nrf2 regulates macrophage-specific heme oxygenase-1 (HO-1) antioxidant defense, it remains unknown whether HO-1 induction might rescue macrophage Nrf2-dependent antiinflammatory functions. This study explores the mechanisms by which the Nrf2-HO-1 axis regulates sterile hepatic inflammation responses after adoptive transfer of ex vivo modified HO-1 overexpressing bone marrow-derived macrophages (BMMs). Livers in Nrf2-deficient mice preconditioned with Ad-HO-1 BMMs, but not Ad-β-Gal-BMMs, ameliorated liver IRI (at 6 h of reperfusion after 90 min of warm ischemia), evidenced by improved hepatocellular function (serum alanine aminotransferase [sALT] levels) and preserved hepatic architecture (Suzuki histological score). Treatment with Ad-HO-1 BMMs decreased neutrophil accumulation, proinflammatory mediators and hepatocellular necrosis/apoptosis in ischemic livers. Moreover, Ad-HO-1 transfection of Nrf2-deficient BMMs suppressed M1 (Nos2(+)) while promoting the M2 (Mrc-1/Arg-1(+)) phenotype. Unlike in controls, Ad-HO-1 BMMs increased the expression of Notch1, Hes1, phosphorylation of Stat3 and Akt in IR-stressed Nrf2-deficient livers as well as in lipopolysaccharide (LPS)-stimulated BMMs. Thus, adoptive transfer of ex vivo generated Ad-HO-1 BMMs rescued Nrf2-dependent antiinflammatory phenotype by promoting Notch1/Hes1/Stat3 signaling and reprogramming macrophages toward the M2 phenotype. These findings provide the rationale for a novel clinically attractive strategy to manage IR liver inflammation/damage.

Although the role of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in regulating cell proliferation is well established, its function in immune responses remains to be fully appreciated. In the current study, we analyzed myeloid-specific PTEN function in regulating tissue inflammatory immune response in a murine liver partial warm ischemia model. Myeloid-specific PTEN knockout (KO) resulted in liver protection from ischemia reperfusion injury (IRI) by deviating the local innate immune response against ischemia reperfusion toward the regulatory type: expression of proinflammatory genes was selectively decreased and anti-inflammatory IL-10 was simultaneously increased in ischemia reperfusion livers of PTEN KO mice compared with those of wild-type (WT) mice. PI3K inhibitor and IL-10-neutralizing Abs, but not exogenous LPS, recreated liver IRI in these KO mice. At the cellular level, Kupffer cells and peritoneal macrophages isolated from KO mice expressed higher levels of M2 markers and produced lower TNF-α and higher IL-10 in response to TLR ligands than did their WT counterparts. They had enhanced Stat3- and Stat6-signaling pathway activation, but diminished Stat1-signaling pathway activation, in response to TLR4 stimulation. Inactivation of Kupffer cells by gadolinium chloride enhanced proinflammatory immune activation and increased IRI in livers of myeloid PTEN KO mice. Thus, myeloid PTEN deficiency protects livers from IRI by facilitating M2 macrophage differentiation.

Comprehensive Summary: One dihydride‐bridged dimeric Dy(III) guanidinate complex, formulated as [{(Me3Si)2NC(NiPr)2}2Dy(μ‐H)]2 (1Dy), was successfully isolated and the introduction of hydride bridges significantly reduces the intramolecular Dy(III)···Dy(III) distance to only 3.688(1) Å. To investigate the effect of such a short Dy(III)···Dy(III) distance on magnetism, we also prepared its dibromide‐bridged analogue [{(Me3Si)2NC(NiPr)2}2Dy(μ‐Br)]2 (2Dy), which has a much longer Dy(III)···Dy(III) distance of 4.605(4) Å. Surprisingly, 2Dy demonstrates much larger effective energy barrier for magnetization reversal (Ueff) and higher blocking temperature (TB). The worse performance of 1Dy is attributed to the concerted effect of strong antiferromagnetic interactions between Dy(III) ions (Jtotal = –2.683 cm–1) and the unparallel arrangement of magnetic principle axes of the Dy(III) ions for 1Dy. [ABSTRACT FROM AUTHOR]

Background & aimsThe Keap1-Nrf2 signaling pathway regulates host cell defense responses against oxidative stress and maintains the cellular redox balance.MethodsWe investigated the function/molecular mechanisms by which Keap1-Nrf2 complex may influence liver ischemia/reperfusion injury (IRI) in a mouse model of hepatic cold storage (20h at 4°C) followed by orthotopic liver transplantation (OLT).ResultsThe Keap1 hepatocyte-specific knockout (HKO) in the donor liver ameliorated post-transplant IRI, evidenced by improved hepatocellular function and OLT outcomes (Keap1 HKO→Keap1 HKO; 100% survival), as compared with controls (WT→WT; 50% survival; p

BackgroundAllograft tolerance of ACI (RT1(a)) recipients to WF (RT1(u)) hearts can be induced by allochimeric class I MHC molecules containing donor-type (RT1A(u)) immunogenic epitopes displayed on recipient-type (RT1A(a)) sequences. Here, we sought the mechanisms by which allochimeric sequences may affect responding T cells through T cell receptor (TCA) repertoire restriction.Methodology/principal findingsThe soluble [alpha(1h) (u)]-RT1.A(a) allochimeric molecule was delivered into ACI recipients of WF hearts in the presence of sub-therapeutic dose of cyclosporine (CsA). The TCR Vbeta spectrotyping of the splenocytes and cardiac allografts showed that the Vbeta gene families were differentially expressed within the TCR repertoire in allochimeric- or high-dose CsA-treated tolerant recipients at day +5 and +7 of post-transplantation. However, at day 30 of post-transplantation the allochimeric molecule-treated rats showed the restriction of TCR repertoire with altered dominant size peaks representing preferential clonal expansion of Vbeta7, Vbeta11, Vbeta13, Vbeta 14, and Vbeta15 genes. Moreover, we found a positive correlation between the alteration of Vbeta profile, restriction of TCR repertoire, and the establishment of allograft tolerance.ConclusionsOur findings indicate that presentation of allochimeric MHC class I sequences that partially mimic donor and recipient epitopes may induce unique tolerant state by selecting alloresponsive Vbeta genes.