Changes in intracellular [Ca2+] are key regulators of the activities of ion transporters and channels involved in transepithelial fluid secretion in airway epithelia. Dysregulated intracellular Ca2+ homeostasis in CF bronchial epithelial cells has been claimed as a potential druggable target to compensate for CFTR Cl- transport defect and/or to reduce excessive CF lung inflammation (as a summary see the Figure). However, the precise identification of the Ca2+ transporter/channel to be targeted is contradictory and requires further understanding on the pros and cons of pharmacological modulation of intracellular Ca2+ mobilization. Here we present results focusing on the role of some of the intracellular Ca2+ modulators activated upon interaction of P. aeruginosa with bronchial epithelial cells, inducing the classical intracellular pro-inflammatory signaling leading toupregulation of IL-8, IL-1β, IL-6 and TNF-α release. We previously showed that direct interaction of P. aeruginosa with toll-like receptors (TLR2, 5 and 4) strongly overexpresses the IL-8 gene by MyD88/dependent phosphorylation of mitogen activated protein kinases ERK1/2, p38, JNK, and downstream kinases RSK1/2 and HSP27, leading to intranuclear translocation of transcription factors such as NF-kB, NF-IL6, AP-1, CREB and CHOP. Release of ATP in the extracellular milieu is able to sustain a P2Y purinergic receptors- and phospolipase C beta 3-dependent release of intracellular Ca2+ which potentiates the MyD88-dependent inflammatory pathways. More recently, we observed that flagellin from P. aeruginosa alters in a CF-specific manner the Ca2+ homeostasis, leading to mitochondrial perturbation with increased Ca2+ influx and production of reactive oxygen species, which drives to exaggerated inflammasome activation and the release of IL-1b. This opens further questions on the role of the different intracellular Ca2+ compartments and subcellular domains, widening the panel of candidate molecular targets to be considered. Supported by Italian Cystic Fibrosis Research Foundation to GC, RG and PP, grants FFC #18/2009, FFC #12/2010, FFC #19/2011, FFC #17/2014.
INTRACELLULAR CALCIUM MOBILIZATION AND THE INFLAMMATORY RESPONSE IN CF BRONCHIAL EPITHELIAL CELLS
FABBRI, Enrica;MONTAGNER, Giulia;FINOTTI, Alessia;LAMPRONTI, Ilaria;RIMESSI, Alessandro;GAMBARI, Roberto;PINTON, Paolo
2016
Abstract
Changes in intracellular [Ca2+] are key regulators of the activities of ion transporters and channels involved in transepithelial fluid secretion in airway epithelia. Dysregulated intracellular Ca2+ homeostasis in CF bronchial epithelial cells has been claimed as a potential druggable target to compensate for CFTR Cl- transport defect and/or to reduce excessive CF lung inflammation (as a summary see the Figure). However, the precise identification of the Ca2+ transporter/channel to be targeted is contradictory and requires further understanding on the pros and cons of pharmacological modulation of intracellular Ca2+ mobilization. Here we present results focusing on the role of some of the intracellular Ca2+ modulators activated upon interaction of P. aeruginosa with bronchial epithelial cells, inducing the classical intracellular pro-inflammatory signaling leading toupregulation of IL-8, IL-1β, IL-6 and TNF-α release. We previously showed that direct interaction of P. aeruginosa with toll-like receptors (TLR2, 5 and 4) strongly overexpresses the IL-8 gene by MyD88/dependent phosphorylation of mitogen activated protein kinases ERK1/2, p38, JNK, and downstream kinases RSK1/2 and HSP27, leading to intranuclear translocation of transcription factors such as NF-kB, NF-IL6, AP-1, CREB and CHOP. Release of ATP in the extracellular milieu is able to sustain a P2Y purinergic receptors- and phospolipase C beta 3-dependent release of intracellular Ca2+ which potentiates the MyD88-dependent inflammatory pathways. More recently, we observed that flagellin from P. aeruginosa alters in a CF-specific manner the Ca2+ homeostasis, leading to mitochondrial perturbation with increased Ca2+ influx and production of reactive oxygen species, which drives to exaggerated inflammasome activation and the release of IL-1b. This opens further questions on the role of the different intracellular Ca2+ compartments and subcellular domains, widening the panel of candidate molecular targets to be considered. Supported by Italian Cystic Fibrosis Research Foundation to GC, RG and PP, grants FFC #18/2009, FFC #12/2010, FFC #19/2011, FFC #17/2014.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
