Early treatment with C-reactive protein-derived peptide reduces septic acute kidney injury in mice via controlled activation of kidney macrophages.

The mortality rate for acute kidney injury (AKI) due to sepsis remains high, and effective therapies based on its pathogenesis remain elusive. Macrophages are crucial for clearing bacteria from vital organs, including the kidney, under septic conditions. Excessive macrophage activation results in organ injury.

Mouse Liver B Cells Phagocytose and Initiate Immune Responses against Their Antigens.

Recent studies have revealed that mammalian B cells ingest particulate Ags, such as bacteria, although little is known about the effect of this function on acquired immunity. We investigated the role of bacterium-phagocytosing B cells in acquired host immune responses. Cultured mouse liver B cells substantially phagocytosed serum-opsonized and produced IgM.

Effects of L-Carnitine Treatment on Kidney Mitochondria and Macrophages in Mice with Diabetic Nephropathy.

Introduction: In diabetic nephropathy (DN), mitochondrial dysfunction and leakage of mitochondrial DNA (mtDNA) are caused by the downregulation of superoxide dismutase 2 (SOD2). mtDNA induces the activation of Toll-like receptor (TLR) 9, which is present in macrophages (Mφs), and triggers their activation.

Methods: We orally administered L-carnitine, which exerts protective effects on the mitochondria, to obesity-induced DN (db/db) mice for 8 weeks.

Infections, Reactions of Natural Killer T Cells and Natural Killer Cells, and Kidney Injury.

Natural killer T (NKT) cells and NK cells are representative innate immune cells that perform antitumor and antimicrobial functions. The involvement of these cells in various renal diseases, including acute kidney injury (AKI), has recently become evident. Murine NKT cells are activated and cause AKI in response to various stimuli, such as their specific ligand, cytokines, and bacterial components.

Liver X receptors regulate natural killer T cell population and antitumor activity in the liver of mice.

The nuclear receptors liver X receptor α (LXRα) and LXRβ are lipid sensors that regulate lipid metabolism and immunity. Natural killer T (NKT) cells, a T cell subset expressing surface markers of both natural killer cells and T lymphocytes and involved in antitumor immunity, are another abundant immune cell type in the liver. The potential function of the metabolic regulators LXRα/β in hepatic NKT cells remains unknown.

Lipopolysaccharide Preconditioning Augments Phagocytosis of Malaria-Parasitized Red Blood Cells by Bone Marrow-Derived Macrophages in the Liver, Thereby Increasing the Murine Survival after Plasmodium yoelii Infection.

Malaria remains a grave concern for humans, as effective medical countermeasures for infection have yet to be developed. Phagocytic clearance of parasitized red blood cells (pRBCs) by macrophages is an important front-line innate host defense against infection. We previously showed that repeated injections of low-dose lipopolysaccharide (LPS) prior to bacterial infection, called LPS preconditioning, strongly augmented phagocytic/bactericidal activity in murine macrophages.

The Efficacy of Posttreatment with Synthetic C-Reactive Protein in Murine Bacterial Peritonitis via Activation of FcγRI-Expressing Kupffer Cells.

Pretreatment with synthetic C-reactive protein (CRP), a functional CRP peptide, has the potential to augment macrophage phagocytosis by bacterial challenge. However, the posttreatment is clinically ideal. We investigated the efficacy of posttreatment with synthetic CRP on murine cecal ligation and puncture (CLP), focusing on liver macrophages.

Lipopolysaccharide preconditioning reduces liver metastasis of Colon26 cells by enhancing antitumor activity of natural killer cells and natural killer T cells in murine liver.

Background And Aim: Lipopolysaccharide (LPS) preconditioning drastically augments bactericidal activity but reduces the host inflammatory response. Therefore, it may be beneficial to prevent postoperative infectious complications and mitigate host damage by surgical stress. Considering its clinical application, how LPS preconditioning influences the antitumor effect in the liver is an important issue.

Immune Mechanisms Underlying Susceptibility to Endotoxin Shock in Aged Hosts: Implication in Age-Augmented Generalized Shwartzman Reaction.

In recent decades, the elderly population has been rapidly increasing in many countries. Such patients are susceptible to Gram-negative septic shock, namely endotoxin shock. Mortality due to endotoxin shock remains high despite recent advances in medical care.

Combination therapy using fibrinogen γ-chain peptide-coated, ADP-encapsulated liposomes and hemoglobin vesicles for trauma-induced massive hemorrhage in thrombocytopenic rabbits.

Background: We previously developed substitutes for red blood cells (RBCs) and platelets (PLTs) for transfusion. These substitutes included hemoglobin vesicles (HbVs) and fibrinogen γ-chain (dodecapeptide HHLGGAKQAGDV, H12)-coated, adenosine diphosphate (ADP)-encapsulated liposomes [H12-(ADP)-liposomes]. Here, we examined the efficacy of combination therapy using these substitutes instead of RBC and PLT transfusion in a rabbit model with trauma-induced massive hemorrhage with coagulopathy.

Chitinase 3-like 1 deficiency ameliorates liver fibrosis by promoting hepatic macrophage apoptosis.

Aim: Chitinase 3-like 1 (CHI3L1), an 18-glycosyl hydrolase-related molecule, is a member of the enzymatically inactive chitinase-like protein family. Serum levels of CHI3L1 are strongly correlated with hepatic fibrosis progression during many liver diseases. Therefore, this protein could be involved in the development of hepatic fibrosis pathology; however, its role has not been elucidated.

Roles of Natural Killer T Cells and Natural Killer Cells in Kidney Injury.

Mouse natural killer T (NKT) cells and natural killer (NK) cells are innate immune cells that are highly abundant in the liver. In addition to their already-known antitumor and antimicrobial functions, their pathophysiological roles in the kidney have recently become evident. Under normal circumstances, the proportion of activated NKT cells in the kidney increases with age.

Pioglitazone improves phagocytic activity of liver recruited macrophages in elderly mice possibly by promoting glucose catabolism.

Recent studies have revealed that the immunological function of leukocytes is dependent on their cellular metabolism, and some researchers have advocated the beneficial effects of pioglitazone against sepsis in young mice, although bacterial infections are more prevalent in elderly hosts. Here, we investigated pioglitazone’s preventative effect against sepsis induced by intravenous injection of a lethal dose of in elderly mice (50–60 wk old) and examined its immunological and metabolic effects on liver leukocytes. Pioglitazone improved bacterial elimination in the peripheral blood, lowered serum pro-inflammatory cytokines (TNF-α, IL-12, IFN-γ), and prevented septic death.

Frontline Science: Concanavalin A-induced acute hepatitis is attenuated in vitamin D receptor knockout mice with decreased immune cell function.

The vitamin D receptor (VDR) is a nuclear receptor for the active form of vitamin D, 1α,25-dihydroxyvitamin D , and regulates various physiologic processes, such as bone and calcium metabolism, cellular proliferation and differentiation, and immunity. VDR is highly expressed in the intestine, kidney, bone, and macrophages, but is expressed at a low level in the liver. The liver is a major metabolic organ and also acts as an immune gateway for dietary nutrients and xenobiotics.

Efficacy of Resuscitative Transfusion With Hemoglobin Vesicles in the Treatment of Massive Hemorrhage in Rabbits With Thrombocytopenic Coagulopathy and Its Effect on Hemostasis by Platelet Transfusion.

Introduction: We have developed hemoglobin vesicles (HbVs) as a substitute for red blood cells (RBCs). We investigated the efficacy of HbV transfusion in the treatment of massive hemorrhage in rabbits in the setting of thrombocytopenic coagulopathy, focusing on the efficacy of hemostasis by subsequent platelet transfusion.

Methods: Thrombocytopenic coagulopathy was induced in rabbits by repeated blood withdrawal and isovolemic retransfusion of autologous RBC (platelet counts <45,000/μL).

Activated natural killer T cells in mice induce acute kidney injury with hematuria through possibly common mechanisms shared by human CD56 T cells.

Although activation of mouse natural killer T (NKT) cells by α-galactosylceramide (α-GalCer) causes failure of multiple organs, including the kidneys, the precise mechanisms underlying kidney injury remain unclear. Here, we showed that α-GalCer-activated mouse NKT cells injured both kidney vascular endothelial cells and tubular epithelial cells in vitro, causing acute kidney injury (AKI) with hematuria in middle-aged mice. The perforin-mediated pathway was mainly involved in glomerular endothelial cell injury, whereas the TNF-α/Fas ligand pathway played an important role in the injury of tubular epithelial cells.

Liver X receptors regulate hepatic F4/80 CD11b Kupffer cells/macrophages and innate immune responses in mice.

The liver X receptors (LXRs), LXRα and LXRβ, are nuclear receptors that regulate lipid homeostasis. LXRs also regulate inflammatory responses in cultured macrophages. However, the role of LXRs in hepatic immune cells remains poorly characterized.

Repeated administration of alpha-galactosylceramide ameliorates experimental lupus nephritis in mice.

Lupus nephritis is a crucial complication of systemic lupus erythematosus. In this study, we investigated the roles of mouse natural killer T (NKT) cells in lupus nephritis. From 24 weeks of age, NZB/NZW F1 mice were injected with alpha-galactosylceramide (α-GalCer) or vehicle once a week for four weeks.

Dysregulation of Kupffer Cells/Macrophages and Natural Killer T Cells in Steatohepatitis in LXRα Knockout Male Mice.

Liver X receptor (LXR) α expression is mainly localized to metabolic tissues, such as the liver, whereas LXRβ is ubiquitously expressed. LXRα is activated by oxysterols and plays an important role in the regulation of lipid metabolism in metabolic tissues. In macrophages, LXRs stimulate reverse cholesterol transport and regulate immune responses.

In vivo Lipopolysaccharide Tolerance Recruits CD11b+ Macrophages to the Liver with Enhanced Bactericidal Activity and Low Tumor Necrosis Factor-Releasing Capability, Resulting in Drastic Resistance to Lethal Septicemia.

Objectives: In vivo lipopolysaccharide (LPS) tolerance on bacterial infection was investigated, focusing on liver macrophages.

Methods: LPS tolerance was induced by intraperitoneal injections with 5 μg/kg of LPS for 3 consecutive days, and then mice were intravenously infected with Escherichia coli.

Results: All LPS-primed mice survived lethal bacterial infection.

Activation and increase of radio-sensitive CD11b+ recruited Kupffer cells/macrophages in diet-induced steatohepatitis in FGF5 deficient mice.

We have recently reported that Kupffer cells consist of two subsets, radio-resistant resident CD68+ Kupffer cells and radio-sensitive recruited CD11b+ Kupffer cells/macrophages (Mφs). Non-alcoholic steatohepatitis (NASH) is characterized not only by hepatic steatosis but also chronic inflammation and fibrosis. In the present study, we investigated the immunological mechanism of diet-induced steatohepatitis in fibroblast growth factor 5 (FGF5) deficient mice.