The role of TRPV1 and TRPM2 in warm temperature detection

Ambient temperature is detected via specialized sensory nerve ending in the skin. The transduction of thermal stimuli into action potentials relies on the activity of temperature sensitive ion channels located in the membranes of sensory nerve endings. The molecular mechanism of cold and heat transduction is well characterized. However, the ion channels responsible for the detection of innocuous warmth are still a matter of debate. TRPV1 and TRPM2 are temperature sensitive cation channels belonging to the family of transient receptor potential (TRP) channels. Recent findings implicate a role for both TRPV1 and TRPM2 in warm-temperature detection. Cellular data from animals lacking TRPV1 and TRPM2 or pharmacological inhibition support this idea. However, in vivo assessment of TRPV1- and TRPM2-involvement in temperature detection yields seemingly contradictory results. In this study, the role of TRPV1 and TRPM2 in warmth detection was evaluated in vitro and in vivo under comparable conditions

Group B Streptococcal Toxic Shock Syndrome and covR/S Mutations Revisited

Gene mutations in the virulence regulator CovR/S of group A Streptococcus play a substantial role in the pathogenesis of streptococcal toxic shock syndrome. We screened 25 group B Streptococcus (GBS) isolates obtained from patients with streptococcal toxic shock syndrome and found only 1 GBS clone harboring this kind of mutation

Human Stem Cell-Derived TRPV1-Positive Sensory Neurons : A New Tool to Study Mechanisms of Sensitization

Somatosensation, the detection and transduction of external and internal stimuli such as temperature or mechanical force, is vital to sustaining our bodily integrity. But still, some of the mechanisms of distinct stimuli detection and transduction are not entirely understood, especially when noxious perception turns into chronic pain. Over the past decade major progress has increased our understanding in areas such as mechanotransduction or sensory neuron classification. However, it is in particular the access to human pluripotent stem cells and the possibility of generating and studying human sensory neurons that has enriched the somatosensory research field. Based on our previous work, we describe here the generation of human stem cell-derived nociceptor-like cells. We show that by varying the differentiation strategy, we can produce different nociceptive subpopulations with different responsiveness to nociceptive stimuli such as capsaicin. Functional as well as deep sequencing analysis demonstrated that one protocol in particular allowed the generation of a mechano-nociceptive sensory neuron population, homogeneously expressing TRPV1. Accordingly, we find the cells to homogenously respond to capsaicin, to become sensitized upon inflammatory stimuli, and to respond to temperature stimulation. The efficient and homogenous generation of these neurons make them an ideal translational tool to study mechanisms of sensitization, also in the context of chronic pain.Funding Agencies|German Research Foundation [SCHR1523/2-1, SFB-1158]; Intramural Program of the NIH, the National Center for Complementary and Integrative Health</p

Trail (TNF-related apoptosis-inducing ligand) induces an inflammatory response in human adipocytes

Abstract High serum concentrations of TNF-related apoptosis-inducing ligand (TRAIL), a member of the tumor necrosis factor protein family, are found in patients with increased BMI and serum lipid levels. In a model of murine obesity, both the expression of TRAIL and its receptor (TRAIL-R) is elevated in adipose tissue. Accordingly, TRAIL has been proposed as an important mediator of adipose tissue inflammation and obesity-associated diseases. The aim of this study was to investigate if TRAIL regulates inflammatory processes at the level of the adipocyte. Using human Simpson-Golabi-Behmel syndrome (SGBS) cells as a model system, we found that TRAIL induces an inflammatory response in both preadipocytes and adipocytes. It stimulates the expression of interleukin 6 (IL-6), interleukin 8 (IL-8) as well as the chemokines monocyte chemoattractant protein-1 (MCP-1) and chemokine C-C motif ligand 20 (CCL-20) in a time- and dose-dependent manner. By using small molecule inhibitors, we found that both the NFκB and the ERK1/2 pathway are crucial for mediating the effect of TRAIL. Taken together, we identified a novel pro-inflammatory function of TRAIL in human adipocytes. Our findings suggest that targeting the TRAIL/TRAIL-R system might be a useful strategy to tackle obesity-associated adipose tissue inflammation