Polyamine metabolism impacts T cell dysfunction in the oral mucosa of people living with HIV.

Metabolic changes in immune cells contribute to both physiological and pathophysiological outcomes of immune reactions. Here, by comparing protein expression, transcriptome, and salivary metabolome profiles of uninfected and HIV+ individuals, we found perturbations of polyamine metabolism in the oral mucosa of HIV+ patients. Mechanistic studies using an in vitro human tonsil organoid infection model revealed that HIV infection of T cells also resulted in increased polyamine synthesis, which was dependent on the activities of caspase-1, IL-1ß, and ornithine decarboxylase-1. HIV-1 also led to a heightened expression of polyamine synthesis intermediates including ornithine decarboxylase-1 as well as an elevated dysfunctional regulatory T cell (TregDys)/T helper 17 (Th17) cell ratios. Blockade of caspase-1 and polyamine synthesis intermediates reversed the TregDys phenotype showing the direct role of polyamine pathway in altering T cell functions during HIV-1 infection. Lastly, oral mucosal TregDys/Th17 ratios and CD4 hyperactivation positively correlated with salivary putrescine levels, which were found to be elevated in the saliva of HIV+ patients. Thus, by revealing the role of aberrantly increased polyamine synthesis during HIV infection, our study unveils a mechanism by which chronic viral infections could drive distinct T cell effector programs and Treg dysfunction.

Inflammation triggers production of dimethylsphingosine from oligodendrocytes.

Neuropathic pain is a chronic, refractory condition that arises after damage to the nervous system. We previously showed that an increased level of the endogenous metabolite N,N-dimethylsphingosine (DMS) in the central nervous system (CNS) is sufficient to induce neuropathic pain-like behavior in rats. However, several important questions remain. First, it has not yet been demonstrated that DMS is produced in humans and its value as a therapeutic target is therefore unknown. Second, the cell types within the CNS that produce DMS are currently unidentified. Here we provide evidence that DMS is present in human CNS tissue. We show that DMS levels increase in demyelinating lesions isolated from patients with multiple sclerosis, an autoimmune disease in which the majority of patients experience chronic pain. On the basis of these results, we hypothesized that oligodendrocytes may be a cellular source of DMS. We show that human oligodendrocytes produce DMS in culture and that the levels of DMS increase when oligodendrocytes are challenged with agents that damage white matter. These results suggest that damage to oligodendrocytes leads to increased DMS production which in turn drives inflammatory astrocyte responses involved in sensory neuron sensitization. Interruption of this pathway in patients may provide analgesia without the debilitating side effects that are commonly observed with other chronic pain therapies.

Nanostructure-initiator mass spectrometry (NIMS) imaging of brain cholesterol metabolites in Smith-Lemli-Opitz syndrome.

Cholesterol is an essential component of cellular membranes that is required for normal lipid organization and cell signaling. While the mechanisms associated with maintaining cholesterol homeostasis in the plasma and peripheral tissues have been well studied, the role and regulation of cholesterol biosynthesis in normal brain function and development have proven much more challenging to investigate. Smith-Lemli-Opitz syndrome (SLOS) is a disorder of cholesterol synthesis characterized by mutations of 7-dehydrocholesterol reductase (DHCR7) that impair the reduction of 7-dehydrocholesterol (7DHC) to cholesterol and lead to neurocognitive deficits, including cerebellar hypoplasia and austism behaviors. Here we have used a novel mass spectrometry-based imaging technique called cation-enhanced nanostructure-initiator mass spectrometry (NIMS) for the in situ detection of intact cholesterol molecules from biological tissues. We provide the first images of brain sterol localization in a mouse model for SLOS (Dhcr7(-/-)). In SLOS mice, there is a striking localization of both 7DHC and residual cholesterol in the abnormally developing cerebellum and brainstem. In contrast, the distribution of cholesterol in 1-day old healthy pups was diffuse throughout the cerebrum and comparable to that of adult mice. This study represents the first application of NIMS to localize perturbations in metabolism within pathological tissues and demonstrates that abnormal cholesterol biosynthesis may be particularly important for the development of these brain regions.

Multiple sclerosis: emerging opportunities for therapeutic intervention.

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system of unknown etiology. Two of the major therapies for the treatment of MS, interferon-beta and glatiramer acetate, show only limited evidence that long-term treatment slows disability. There is a great need for new drugs that will halt, reverse, and prevent the development of MS. This article reviews therapies currently in use and describes innovative strategies being developed to alter the disease course. New technologies in gene expression profiling offer hopeful directions toward the design of successful drug therapies and diagnostic testing for MS. Additionally, the new fields of genomics and proteomics offer the promise of novel treatments, and should help to reveal the mechanisms of disease initiation and pathological progression.