News and Highlights

On this page we present recently published research carried out by SSEP members

Identification of potent and selective small molecule inhibitors of the cation channel TRPM4

Ozhathil LC, Delalande C, Bianchi B, Nemeth G, Kappel S, Thomet U, Ross-Kaschitza D, Simonin C, Rubin M, Gertsch J, Lochner M, Peinelt C, Reymond JL, Abriel H

(2018) Br J Pharmacol, 10.1111/bph.14220

Ion channels are membrane proteins found in virtually every cell allowing the passage of different ions such as Na+, K+ and Ca2+ and Cl-. Many drugs are modulating their function. In this study, we looked for new chemical compounds able to block the ion channel called TRPM4 found at the membrane of many cell types such as cardiac and cancer cells. In particular, we developed a novel fluorescence-based cellular assay and screened a library of ~800 compounds to identify a potent and selective blocker of TRPM4 channel. Our data also demonstrate that the identified compound in addition to being a blocker of TRPM4 also rescues the membrane trafficking of TRPM4 loss-of-expression mutants found in cardiac patients. The new chemical structure identified in our study will be useful to understand the role of TRPM4 in disease and possibly develop new clinical drug candidates.

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ROS and glutathionylation balance cytoskeletal dynamics in neutrophil extracellular trap formation

Stojkov D, Amini P, Oberson K, Sokollik C, Duppenthaler A, Simon HU, Yousefi S

(2017) J Cell Biol 216: 4073-4090

Neutrophils represent the most prominent cells in the blood circulation and their antimicrobial defense activity has been defined by their ability to phagocytose microbes or to form Neutrophil Extracellular Traps (NETs) that can entrap and kill bacteria in the extracellular space. In our present manuscript, we report novel findings which indicate that a dynamic intracellular transport by the cytoskeleton plays a role in bringing granule proteins and mitochondrial DNA together to form NETs. Our data also demonstrate that reactive oxygen species (ROS), generated by the enzyme NADPH oxidase, act as signaling molecules involved in the regulation of the cytoskeleton. Overall, our work suggests that the activation of actin polymerization might be a new strategy for improving neutrophil function in NADPH oxidase deficiency.

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BH3 mimetics efficiently induce apoptosis in mouse basophils and mast cells

Reinhart R, Rohner L, Wicki S, Fux M, Kaufmann T

(2018) Cell Death Differ 25: 204-216

Basophils and mast cells are known to play critical roles in the pathogenesis of diverse allergic diseases. The survival of both cell types seems to strongly depend on distinct pro-survival proteins of the Bcl-2 family. We thus hypothesized that a novel class of small molecule inhibitors specifically targeting individual Bcl-2 family members, co-called BH3 mimetics, may be useful to induce apoptosis in naïve or activated basophils and mast cells. Indeed, our work revealed the crucial importance of BCL-2 and BCL-XL for survival of in vitro differentiated mouse basophils, whereas mouse mast cells and human basophils highly depended on BCL-2 and MCL-1, respectively. Cell survival was strongly increased by the key cytokine IL-3, but this effect could still be counteracted by the right combination of BH3 mimetic compounds. In conclusion, our results indicate that BH3 mimetics, besides their application in anti-cancer therapy, may have a potential worthwhile exploring in the treatment of basophil and mast cell mediated allergic disorders.

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Evidence of an abnormal epithelial barrier in active, untreated and corticosteroid-treated eosinophilic esophagitis

Simon D, Page B, Vogel M, Bussmann C, Blanchard C, Straumann A, Simon HU

(2017) Allergy, 10.1111/all.13244

Eosinophilic esophagitis (EoE) is a chronic, immune-mediated disease characterized by symptoms related to esophageal dysfunction and an eosinophil-predominant inflammation. Here, we asked the question whether Candida albicans colonization and sensitization observed in pediatric and adult EoE patients is the consequence of an epithelial dysfunction associated with the disease and/or is a consequence of the treatment with corticosteroids (CS) that is the first line therapy for EoE. Using immunofluorescence techniques on esophageal tissue sections, we observed increased numbers of eosinophils and mast cells, higher expression levels of alarmins, antimicrobial peptides, and proteases in EoE as compared with controls, while reduced expression of a protease inhibitor and barrier proteins, i.e. filaggrin, E-cadherin, claudin, occludin, demoglein-1 was found, independent of CS therapy. CS seemed to have selective effects on improving the epithelial barrier. Instead, CS reduced the expression of cathelicidin as well as the numbers of LHC and eosinophils, thereby possibly even further promoting Candida albicans colonization and invasion.

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IVIG regulates the survival of human but not mouse neutrophils

Schneider C, Wicki S, Graeter S, Timcheva TM, Keller CW, Quast I, Leontyev D, Djoumerska-Alexieva IK, Kasermann F, Jakob SM, Dimitrova PA, Branch DR, Cummings RD, Lunemann JD, Kaufmann T, Simon HU, von Gunten S

(2017) Sci Rep 7: 1296

Intravenous immunoglobulin (IVIG) has anti-inflammatory effects when administered at high concentrations to patients with chronic inflammatory and autoimmune disorders. IVIG is a pluripotent drug and a number of immunoregulatory mechanisms have been described including induced cell death of activated neutrophils. Schneider C et al. found that latter mechanism is specific, Fab but not Fc-mediated, and occurs in human, but not mouse neutrophils. In addition to xenogeneic effects of human IVIG if used in mice, this finding highlights potential species-differences in the mechanisms of IVIG action depending on the experimental disease model in vivo.

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Conformational dynamics and role of the acidic pocket in ASIC pH-dependent gating

Vullo S, Bonifacio G, Roy S, Johner N, Berneche S, Kellenberger S

(2017) Proc Natl Acad Sci U S A 114: 3768-3773

Acid-sensing ion channels (ASICs) are neuronal Na channels that are activated by a drop in extracellular pH. They contribute to physiological and pathological processes such as learning, fear and pain sensation, and neuronal death after ischemic stroke. Although ASICs are potentially interesting drug targets, their activation mechanism is only poorly understood. This study shows that pH sensing in a channel domain that had been proposed as the ligand binding site of ASICs, the “acidic pocket”, has only a modulatory, but not an essential role for the activation of these channels. The study further describes the mechanisms of the ASIC regulation by the acidic pocket, which remains an interesting target site for drug candidates acting on ASICs.

Your article could stand here ! Let us know if you have recently published exciting research results that are of a major impact and that could be of interest to other SSEP members.