Reducing TMPRSS6 ameliorates hemochromatosis and beta-thalassemia in mice

Brett Monia and Stefano Rivella discuss how reduction of TMPRSS6 expression with antisense oligonucleotides ameliorates iron metabolism disorders in mice. Highlights:

• Iron metabolism is a complex and heavily regulated process that is required for basic physiological functions, including hematopoiesis and host immune responses.
• Hemochromatosis and β-thalassemia are iron overload disorders caused by low levels of hepcidin, the hormone that regulates iron absorption.
• Antisense oligonucleotides (ASOs) lowered Tmprss6 RNA and elevated hepcidin levels.
• TMPRSS6 ASO treatment reversed anemia and iron overload in a mouse model of β-thalassemia.

The TGR5 receptor mediates bile acid-induced itch and analgesia

The liver secretes bile acids to aid in the digestion of fats. Cholestasis is a condition in which the bile flow from the liver to the duodenum is impeded. Patients with the disease exhibit itchiness (pruritis) and cannot sense pain (analgesia). The molecular mechanisms mediating these effects are unknown. Carlos Corvera of UCSF and Nigel Bunnett of Monash University discuss their study demonstrating that bile acids cause itch and analgesia by activating the TGR5 receptor in neurons. Highlights:

• TGR5 is expressed in neurons in mouse dorsal root ganglia and spinal cord, which transmit itch and pain signals.
• Stimulation of TGR5 induced the release of itch and analgesia transmitting molecules, including gastrin-releasing peptide and leucine-enkephalin.
• Intradermal injection of bile acids stimulated scratching behavior that was TGR5-dependent.
• Bile acids activate TGR5 on sensory nerves to transmit itch and analgesia, suggesting that these mechanisms contribute to pruritus and analgesia during cholestatic liver diseases.

Increased brain uptake and oxidation of acetate in heavy drinkers

Increased brain uptake and oxidation of acetate in heavy drinkers Graeme Mason of Yale University discusses how heavy drinking influences metabolism and leads to alternate fuel use in the brain. Highlights:

• Brain acetate consumption is inducible by conditions that can occur with heavy alcohol use.
• Heavy drinking is associated with enhanced ability to import and oxidize acetate.
• Systemic acetate provides a potential metabolic reward for drinking, possibly specific to glia.
• Acetate oxidation provides a mechanism to generate adenosine, whose loss may contribute to withdrawal symptoms.

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Brain-wide pathway for waste clearance captured by contrast enhanced MRI

Helene Benveniste of Stony Brook University discusses the use of contrast-enhanced MRI to visualize the glymphatic system, a paravascular pathway that facilitates the clearance of waste and solutes from the cerebrospinal fluid and interstitial fluid of the brain. Highlights:

• Glymphatic pathway function can be measured using dynamic contrast-enhanced MRI.
• Benveniste and colleagues used whole brain imaging to identify /confirm key features of the glymphatic pathway in rats.
• Many degenerative brain diseases are associated with the accumulation of proteins that form plaques (ie. Alzheimer’s disease). Clearance of these proteins is mediated by the glymphatic system.
• Contrast-enhanced MRI could potentially be used to evaluate 

iRHOM2 is a critical pathogenic mediator of inflammatory arthritis

Jane Salmon, Carl Blobel, Priya Darshinee Issuree, and Thorsten Maretzky of the Weill Cornell University Hospital for Special Surgery discuss the role of iRHOM2 in inflammatory arthritis. Highlights:

• TNF-α has been implicated in the pathology of rheumatoid arthritis (RA) and other inflammatory diseases. RA patients are currently treated with TNF inhibitors, but these therapeutics have many deleterious side effects.
• iRHOM2 regulates the maturation of TACE, and enzyme that cleaves and releases TNF-α from the surface of myeloid cells that mediate inflammation during arthritis.
• Inactivation of the gene that encodes iRHOM2 (Rhbdf2) protects mice from inflammatory arthritis.
• These findings suggest that iRHOM2 could be a suitable therapeutic target for the treatment of RA.