Macrophages, which are key cellular components of the liver, have emerged as essential players in the maintenance of hepatic homeostasis and in injury and repair processes in acute and chronic liver diseases. Upon liver injury, resident Kupffer cells (KCs) sense disturbances in homeostasis, interact with hepatic cell populations and release chemokines to recruit circulating leukocytes, including monocytes, which subsequently differentiate into monocyte-derived macrophages (MoMϕs) in the liver. Both KCs and MoMϕs contribute to both the progression and resolution of tissue inflammation and injury in various liver diseases. The diversity of hepatic macrophage subsets and their plasticity explain their different functional responses in distinct liver diseases. In this review, we highlight novel findings regarding the origins and functions of hepatic macrophages and discuss the potential of targeting macrophages as a therapeutic strategy for liver disease.

Background:Exercise tolerance and cardiac output have a major impact on the quality of life (QOL) of patients experiencing heart failure (HF). Home-based cardiac rehabilitation can significantly improve not only exercise tolerance but also peak oxygen uptake ( peak), and the QOL in patients with HF. The aim of this prospective study was to evaluate the beneficial effects of home-based cardiac rehabilitation on the quality of medical care in patients with chronic HF.Methods:This study was a randomized prospective trial. HF patients with a left ventricular ejection fraction (LVEF) of less than 50% were included in this study. We randomly assigned patients to the control group (n = 18) and the interventional group (n = 19). Within the interventional group, we arranged individualized rehabilitation programs, including home-based cardiac rehabilitation, diet education, and management of daily activity over a 3-month period. Information such as general data, laboratory data, Cardiopulmonary Exercise Test (CPET) results, Six-minute Walk Test (6MWT) results, and the scores for the Minnesota Living with Heart Failure Questionnaire (MLHFQ) before and after the intervention, was collected from all patients in this study.Results:Patients enrolled in the home-based cardiac rehabilitation programs displayed statistically significant improvement in peak (18.2 ± 4.1 vs 20.9 ± 6.6 mL/kg/min, P = .02), maximal 6-Minute Walking Distance (6MWD) (421 ± 90 vs 462 ± 74 m, P = .03), anaerobic threshold (12.4 ± 2.5 vs 13.4 ± 2.6 mL/kg/min, P = .005), and QOL. In summary, patients receiving home-based cardiac rehabilitation experienced a 14.2% increase in peak, a 37% increase in QOL score, and an improvement of 41 m on the 6MWD test. The 90-day readmission rate for patients reduced to 5% from 14% after receiving cardiac rehabilitation.Conclusion:Home-based cardiac rehabilitation offered the most improved results in functional capacity, QOL, and a reduced the rate of readmission within 90 days.

Nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated induction of antioxidants has been implicated to have protective roles in ischemia-reperfusion (I/R) injury in many animal models. However, the in vivo effects of CDDO-imidazole (CDDO-Im) (1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oyl] imidazole), a Nrf2 activator, in hepatic I/R injury is lacking and its exact molecular mechanisms are still not very clear. The goals of this study were to determine whether CDDO-Im can prevent liver injury induced by I/R in the mouse, and to elucidate the molecular target of drug action. Mice were randomly equally divided into two groups and administered intraperitoneally with either DMSO control or CDDO-Im (2 mg/kg) 3 h before subjected to 90-min hepatic 70% ischemia followed by reperfusion. Subsequently, the Liver and blood samples of these mice were collected to evaluate liver injury. CDDO-Im pretreatment markedly improve hepatic I/R injury by attenuating hepatic necrosis and apoptosis, reducing reactive oxygen species (ROS) levels and inflammatory responses, and ameliorating mitochondrial dysfunction. Mechanistically, by using Nrf2 Knockout mice and hemeoxygenase 1 (HO-1) inhibitor, we found that these CDDO-Im protection effects are attributed to enhanced autophagy, which is mediated by activating Nrf2/HO-1 pathway. By accelerating autophagy and clearance of damaged mitochondria, CDDO-Im reduced the mtDNA release and ROS overproduction, and in turn decreased damage-associated molecular patterns induced inflammatory responses and the following secondary liver injury. These results indicate that by enhancing autophagy, CDDO-Im-mediated activation of Nrf2/HO-1 signaling could be a novel therapeutic strategy to minimize the adverse effects of hepatic I/R injury.

Osteopontin (OPN), a multifunctional protein, is involved in numerous pathological conditions including inflammation, immunity, angiogenesis, fibrogenesis and carcinogenesis in various tissues. Extensive studies have elucidated the critical role of OPN in cell signaling such as regulation of cell proliferation, migration, inflammation, fibrosis and tumor progression. In the liver, OPN interacts with integrins, CD44, vimentin and MyD88 signaling, thereby induces infiltration, migration, invasion and metastasis of cells. OPN is highlighted as a chemoattractant for macrophages and neutrophils during injury in inflammatory liver diseases. OPN activates hepatic stellate cells (HSCs) to exert an enhancer in fibrogenesis. The role of OPN in hepatocellular carcinoma (HCC) has also generated significant interests, especially with regards to its role as a diagnostic and prognostic factor. Interestingly, OPN acts an opposing role in liver repair under different pathological conditions. This review summarizes the current understanding of OPN in liver diseases. Further understanding of the pathophysiological role of OPN in cellular interactions and molecular mechanisms associated with hepatic inflammation, fibrosis and cancer may contribute to the development of novel strategies for clinical diagnosis, monitoring and therapy of liver diseases.

The initial process in liver regeneration after partial hepatectomy involves the recruitment of immune cells and the release of cytokines. Osteopontin (OPN), a pro-inflammatory protein, plays critical roles in immune cell activation and migration. Although OPN has been implicated in the pathogenesis of many liver diseases, the role of OPN in liver regeneration remains obscure. In the present study, we found that serum and hepatic OPN protein levels were significantly elevated in wild-type (WT) mice after partial hepatectomy (PHx) and that bile ductal epithelia were the major cell source of hepatic OPN. Compared to WT mice, OPN knockout (KO) mice exhibited delayed liver regeneration after PHx. This delay in OPN-/- mice was attributed to impaired hepatic infiltration of macrophages and neutrophils, decreased serum and hepatic IL-6 levels, and blunted activation of macrophages after PHx. Furthermore, we demonstrate that the attenuated activation of macrophages is at least partially due to decreased hepatic and portal vein LPS levels in OPN-/- mice. In response to decreased IL-6 levels, the activation of signal transducer and transcription (Stat) 3 was reduced in hepatocytes of OPN-/- mice compared to WT mice after PHx. Consequently, hepatic activation of the downstream direct targets of IL6/Stat3, such as c-fos, c-jun, and c-myc, was also suppressed post-PHx in OPN-/- mice compared to WT mice. Collectively, these results support a unique role for OPN during the priming phase of liver regeneration, in which OPN enhances the recruitment of macrophages and neutrophils, and triggers hepatocyte proliferation through Kupffer cell-derived IL-6 release and the downstream activation of Stat3.

Inappropriate inflammation responses contribute to mortality during sepsis. Through Toll-like receptors (TLRs), reactive oxygen species (ROS) produced by NADPH oxidase could modulate the inflammation responses. Parkinson disease (autosomal recessive, early onset) 7 (Park7) has a cytoprotective role by eliminating ROS. However, whether Park7 could modulate inflammation responses and mortality in sepsis is unclear. Here, we show that, compared with wild-type mice, Park7 −/− mice had significantly increased mortality and bacterial burdens in sepsis model along with markedly decreased systemic and local inflammation, and drastically impaired macrophage phagocytosis and bacterial killing abilities. Surprisingly, LPS and phorbol-12-myristate-13-acetate stimulation failed to induce ROS and proinflammatory cytokine production in Park7 −/− macrophages and Park7-deficient RAW264.7 cells. Through its C-terminus, Park7 binds to p47 phox , a subunit of the NADPH oxidase, to promote NADPH oxidase-dependent production of ROS. Restoration of Park7 expression rescues ROS production and improves survival in LPS-induced sepsis. Together, our study shows that Park7 has a protective role against sepsis by controlling macrophage activation, NA-DPH oxidase activation and inflammation responses.

BaCKgRoUND aND aIMS: Acetaminophen (APAP) overdose represents the most frequent cause of acute liver failure, resulting in death or liver transplantation in more than one third of patients in the United States. The effectiveness of the only antidote, N-acetylcysteine, declines rapidly after APAP ingestion, long before patients are admitted to the clinic with symptoms of severe liver injury. The direct hepatotoxicity of APAP triggers a cascade of innate immune responses that may exacerbate or limit the progression of tissue damage. A better understanding of this complex mechanism will help uncover targets for therapeutic interventions. appRoaCH aND ReSUltS: We observed that APAP challenge caused stabilization of hypoxia-inducible factors (HIFs) in the liver and hepatic macrophages (MΦs), particularly HIF-2α. Genetic deletion of the HIF-2α gene in myeloid cells (HIF-2α mye/− ) markedly exacerbated APAP-induced liver injury (AILI) without affecting APAP bioactivation and detoxification. In contrast, hepatic and serum levels of the hepatoprotective cytokine interleukin 6 (IL-6), its downstream signal transducer and transcription factor 3 activation in hepatocytes, as well as hepatic MΦ IL-6 expression were markedly reduced in HIF-2α mye/− mice compared to wildtype mice post-APAP challenge. In vitro experiments revealed that hypoxia induced IL-6 production in hepatic MΦs and that such induction was abolished in HIF-2α-deleted hepatic MΦs. Restoration of IL-6 by administration of exogenous IL-6 ameliorated AILI in HIF-2α mye/− mice. Finally, IL-6-mediated hepatoprotection against AILI was abolished in hepatocyte-specific IL-6 receptor knockout mice. CoNClUSIoNS:The data demonstrate that APAP treatment leads to HIF-2α stabilization in hepatic MΦs and that HIF-2α subsequently reprograms hepatic MΦs to produce the hepatoprotective cytokine IL-6, thereby ameliorating AILI.

Eosinophils are a myeloid cell subpopulation that mediates type 2 T helper cell immune responses. Unexpectedly, we identified a rapid accumulation of eosinophils in 22 human liver grafts after hepatic transplantation. In contrast, no eosinophils were detectable in healthy liver tissues before transplantation. Studies with two genetic mouse models of eosinophil deficiency and a mouse model of antibody-mediated eosinophil depletion revealed exacerbated liver injury after hepatic ischemia and reperfusion. Adoptive transfer of bone marrow–derived eosinophils normalized liver injury of eosinophil-deficient mice and reduced hepatic ischemia and reperfusion injury in wild-type mice. Mechanistic studies combining genetic and adoptive transfer approaches identified a critical role of suppression of tumorigenicity (ST2)–dependent production of interleukin-13 by eosinophils in the hepatoprotection against ischemia-reperfusion–induced injury. Together, these data provide insight into a mechanism of eosinophil-mediated liver protection that could serve as a therapeutic target to improve outcomes of patients undergoing liver transplantation.