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.

CXCR5+ T helper cells mediate protective immunity against tuberculosis

Shabaana Khader of the University of Pittsburgh discusses the identification of immune parameters that distinguish active and latent TB infections. Highlights:

• One third of the world's population is infected with Mycobacterium tuberculosis; however, only 5-10% will develop active infections.
• Individuals with latent infections have a 10% lifetime risk of developing active tuberculosis. This risk increases to 10% per year in the presence of HIV infection. It is therefore important to identify immunologic features that distinguish active TB from latent.
• Granulomas are immune cell aggregates that are a hallmark of TB infection. They play a protective role in latent TB, but can promote infection during active TB.
• Using human, non-human primate, and mouse models of TB infection, Khader and colleagues identified a subset of T helper cells (CXCR5+) that are associated with protective granulomas in latent TB.
• These results identify a previously unexpected role for CXCR5 in the control of TB infection and could be used to improve TB vaccine strategies.