IL-6 is an important cytokine involved in metabolic, immunological, and cell-fate responses. It is released upon stimulation by skeletal muscle cells through partially characterized mechanisms. In some cell types, IL-6 has been reported to activate a positive feedback loop involving endocytic vesicles, but evidence is mostly based on transcription and signal transduction mechanisms and is very scarce in muscle cells. Our aim was to directly demonstrate the presence of positive feedback in the ATP-induced release of IL-6 into the supernatant of human skeletal muscle cultures. The total release (production) of IL-6 was reduced for higher volumes of supernatant, when the secreted IL-6 molecules are more diluted, and enhanced when the supernatant volume was lower. In addition, secretion was impaired both by tocilizumab, a blocker of human IL-6 receptors, and by the soluble form of the receptor. The secretion in response to ATP was also inhibited by treatment with the endocytosis inhibitor dynasore, and by disruption of the acidic gradient of the endocytic compartment using different methods (chloroquine, NH4Cl or monensin). IL-6 secretion was also impaired by NED-19, a specific inhibitor of the two pore channels receptor mediating Ca2+ release from the endolysosomal compartment. IL-6 and ATP increased IL-6 mRNA levels, an effect blocked by tocilizumab. Altogether, our results demonstrate that ATP-secreted IL-6 activates a positive loop based on IL-6 receptors, endocytosis, two pore channels and IL-6 transcription. Given the importance of muscle IL-6 as a systemic regulator and as an inflammatory mediator, our study can help to understand muscle pathophysiology.

01 Oct 2024·Experimental Eye Research

Dynasore modulates store-operated calcium entry and mitochondrial calcium release in corneal epithelial cells

Article

Author: Fini, M Elizabeth ; Martínez-Carrasco, Rafael

Dysregulation of calcium homeostasis can precipitate a cascade of pathological events that lead to tissue damage and cell death. Dynasore is a small molecule that inhibits endocytosis by targeting classic dynamins. In a previous study, we showed that dynasore can protect human corneal epithelial cells from damage due to tert-butyl hydroperoxide (tBHP) exposure by restoring cellular calcium (Ca²⁺) homeostasis. Here we report results of a follow-up study aimed at identifying the source of the damaging Ca²⁺. Store-operated Ca²⁺ entry (SOCE) is a cellular mechanism to restore intracellular calcium stores from the extracellular milieu. We found that dynasore effectively blocks SOCE in cells treated with thapsigargin (TG), a small molecule that inhibits pumping of Ca²⁺ into the endoplasmic reticulum (ER). Unlike dynasore however, SOCE inhibitor YM-58483 did not interfere with the cytosolic Ca²⁺ overload caused by tBHP exposure. We also found that dynasore effectively blocks Ca²⁺ release from internal sources. The inefficacy of inhibitors of ER Ca²⁺ channels suggested that this compartment was not the source of the Ca²⁺ surge caused by tBHP exposure. However, using a Ca²⁺-measuring organelle-entrapped protein indicator (CEPIA) reporter targeted to mitochondria, we found that dynasore can block mitochondrial Ca²⁺ release due to tBHP exposure. Our results suggest that dynasore exerts multiple effects on cellular Ca²⁺ homeostasis, with inhibition of mitochondrial Ca²⁺ release playing a key role in protection of corneal epithelial cells against oxidative stress due to tBHP exposure.

01 Oct 2024·Stem Cell Reports

Breaking the burst: Unveiling mechanisms behind fragmented network bursts in patient-derived neurons

Article

Author: Levers, Marloes R ; van Putten, Michel J.A.M. ; Levers, Marloes R. ; Doorn, Nina ; van Putten, Michel J A M ; Voogd, Eva J H F ; Frega, Monica ; Voogd, Eva J.H.F.

Fragmented network bursts (NBs) are observed as a phenotypic driver in many patient-derived neuronal networks on multi-electrode arrays (MEAs), but the pathophysiological mechanisms underlying this phenomenon are unknown. Here, we used our previously developed biophysically detailed in silico model to investigate these mechanisms. Fragmentation of NBs in our model simulations occurred only when the level of short-term synaptic depression (STD) was enhanced, suggesting that STD is a key player. Experimental validation with Dynasore, an STD enhancer, induced fragmented NBs in healthy neuronal networks in vitro. Additionally, we showed that strong asynchronous neurotransmitter release, NMDA currents, or short-term facilitation (STF) can support the emergence of multiple fragments in NBs by producing excitation that persists after high-frequency firing stops. Our results provide important insights into disease mechanisms and potential pharmaceutical targets for neurological disorders modeled using human induced pluripotent stem cell (hiPSC)-derived neurons.

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