Ammonia-Induced Brain Edema Requires Macrophage and T Cell Expression of Toll-Like Receptor 9.

Background & Aim: Ammonia is central in the pathogenesis of brain edema in acute liver failure (ALF) with infection and systemic inflammation expediting development of intracranial hypertension (ICH). Patients with acetaminophen-induced ALF have increased neutrophil TLR9 expression which can be induced by ammonia. We determined whether ammonia-induced brain edema and immune dysfunction are mediated by TLR9 and if this could be prevented in a TLR9-deficient mouse model.

β-Hydroxybutyrate protects from alcohol-induced liver injury via a Hcar2-cAMP dependent pathway.

Background & Aims: Sterile inflammation resulting in alcoholic hepatitis (AH) occurs unpredictably after many years of excess alcohol intake. The factors responsible for the development of AH are not known but mitochondrial damage with loss of mitochondrial function are common features. Hcar2 is a G-protein coupled receptor which is activated by β-hydroxybutyrate (BHB).

Digoxin Suppresses Pyruvate Kinase M2-Promoted HIF-1α Transactivation in Steatohepatitis.

Sterile inflammation after tissue damage is a ubiquitous response, yet it has the highest amplitude in the liver. This has major clinical consequences, for alcoholic and non-alcoholic steatohepatitis (ASH and NASH) account for the majority of liver disease in industrialized countries and both lack therapy. Requirements for sustained sterile inflammation include increased oxidative stress and activation of the HIF-1α signaling pathway.

Hepatocyte mitochondrial DNA drives nonalcoholic steatohepatitis by activation of TLR9.

Nonalcoholic steatohepatitis (NASH) is the most common liver disease in industrialized countries. NASH is a progressive disease that can lead to cirrhosis, cancer, and death, and there are currently no approved therapies. The development of NASH in animal models requires intact TLR9, but how the TLR9 pathway is activated in NASH is not clear.

Activation of N-methyl-d-aspartate receptor downregulates inflammasome activity and liver inflammation via a β-arrestin-2 pathway.

Activation of the cytosolic inflammasome machinery is responsible for acute and chronic liver inflammation, but little is known about its regulation. The N-methyl-d-aspartate (NMDA) receptor families are heterotetrameric ligand-gated ion channels that are activated by a range of metabolites, including aspartate, glutamate, and polyunsaturated fatty acids. In the brain NMDA receptors are present on neuronal and nonneuronal cells and regulate a diverse range of functions.

The inflammasome in liver injury and non-alcoholic fatty liver disease.

The liver possesses a strong inflammatory response, as seen experimentally and clinically with liver inflammation due to toxic and metabolic stress, sepsis and ischemia. Initiation of this inflammatory response requires the interaction of two types of extracellular signals which collectively upregulate and activate a cytosolic molecular complex termed the inflammasome. Signal 1 is via activation of pattern recognition receptors, and signal 2 is delivered by diverse stimuli including particulates and adenosine triphosphate.

Lactate reduces liver and pancreatic injury in Toll-like receptor- and inflammasome-mediated inflammation via GPR81-mediated suppression of innate immunity.

Background & Aims: The NACHT, LRR, and pyrin domain-containing protein 3 (NLRP3) inflammasome induces inflammation in response to organ injury, but little is known about its regulation. Toll-like receptors (TLRs) provide the first signal required for activation of the inflammasome and stimulate aerobic glycolysis to generate lactate. We examined whether lactate and the lactate receptor, Gi-protein-coupled receptor 81 (GPR81), regulate TLR induction of signal 1 and limit inflammasome activation and organ injury.

Adenosine is required for sustained inflammasome activation via the A₂A receptor and the HIF-1α pathway.

Inflammasome pathways are important in chronic diseases; however, it is not known how the signalling is sustained after initiation. Inflammasome activation is dependent on stimuli such as lipopolysaccharide (LPS) and ATP that provide two distinct signals resulting in rapid production of interleukin (IL)-1β, with the lack of response to repeat stimulation. Here we report that adenosine is a key regulator of inflammasome activity, increasing the duration of the inflammatory response via the A(2A) receptor.

Adenine induces differentiation of rat hepatic stellate cells.

Background And Aims: Adenine is a uric acid pathway metabolite of no known function, and has recently been identified as a ligand for a rat G protein-coupled receptor. Due to the known role of other uric acid pathway metabolites in HSC biology, we tested the ability of adenine to induce HSC differentiation.

Methods: RT-PCR was performed for adenine receptor expression in T-6 and primary rat HSC.

Inflammasome-mediated regulation of hepatic stellate cells.

The inflammasome is a cytoplasmic multiprotein complex that has recently been identified in immune cells as an important sensor of signals released by cellular injury and death. Analogous to immune cells, hepatic stellate cells (HSC) also respond to cellular injury and death. Our aim was to establish whether inflammasome components were present in HSC and could regulate HSC functionality.

Apoptotic hepatocyte DNA inhibits hepatic stellate cell chemotaxis via toll-like receptor 9.

Unlabelled: Apoptosis of hepatocytes results in the development of liver fibrosis, but the molecular signals mediating this are poorly understood. Degradation and modification of nuclear DNA is a central feature of apoptosis, and DNA from apoptotic mammalian cells is known to activate immune cells via Toll-like receptor 9 (TLR9). We tested if DNA from apoptotic hepatocytes can induce hepatic stellate cell (HSC) differentiation.

In vitro and in vivo protection of stellate cells from apoptosis by leptin.

Hepatic fibrogenesis is reduced in the absence of leptin. We hypothesized that leptin protects hepatic stellate cells (HSCs) from apoptosis and tested this in in vitro and in vivo systems. (i) Fas ligand (fas-L)-mediated apoptosis was induced in vitro in activated HSCs in the absence and presence of leptin.

Blocking intrahepatic deletion of activated CD8+ T cells by an altered peptide ligand.

Background: Activated CD8(+) T cells are retained by the healthy liver where the majority undergo apoptosis. The intrahepatic apoptosis of activated CD8(+) T cells is enhanced by the presence of SIINFEKL peptide. It is of great interest to identify strategies for maintaining intrahepatic T cell number and function in the presence of SIINFEKL peptides.

Kupffer cells required for high affinity peptide-induced deletion, not retention, of activated CD8+ T cells by mouse liver.

The immune response to foreign antigens in the liver is often suboptimal and this is clinically relevant in chronic persistence of hepatotropic viruses. In chronic infection with the hepatitis C virus, activated CD8+ T cells specific for viral epitopes are present in the peripheral blood and the liver, yet viral clearance is unusual. To define the fate of activated CD8+ entering the liver, we developed a mouse model of portal vein injection of activated CD8+ T cells in vivo.