title: Extracellular acidification stimulates GPR68 mediated IL-8 production in human pancreatic β cells.
abstract: Acute or chronic metabolic complications such as diabetic ketoacidosis are often associated with extracellular acidification and pancreatic β-cell dysfunction. However, the mechanisms by which human β-cells sense and respond to acidic pH remain elusive. In this study, using the recently developed human β-cell line EndoC-βH2, we demonstrate that β-cells respond to extracellular acidification through GPR68, which is the predominant proton sensing receptor of human β-cells. Using gain- and loss-of-function studies, we provide evidence that the β-cell enriched transcription factor RFX6 is a major regulator of GPR68. Further, we show that acidic pH stimulates the production and secretion of the chemokine IL-8 by β-cells through NF-кB activation. Blocking of GPR68 or NF-кB activity severely attenuated acidification induced IL-8 production. Thus, we provide mechanistic insights into GPR68 mediated β-cell response to acidic microenvironment, which could be a new target to protect β-cell against acidosis induced inflammation.
authors.affiliation: INSERM, U1016, Institut Cochin, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, 75014, France.
authors.forename: Vikash
authors.initials: V
authors.lastname: Chandra
authors.affiliation: INSERM, U1016, Institut Cochin, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, 75014, France.
authors.forename: Angeliki
authors.initials: A
authors.lastname: Karamitri
authors.affiliation: INSERM, U1016, Institut Cochin, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, 75014, France.
authors.forename: Paul
authors.initials: P
authors.lastname: Richards
authors.affiliation: INSERM, U1016, Institut Cochin, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, 75014, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Cormier
authors.affiliation: INSERM, U1016, Institut Cochin, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, 75014, France.
authors.forename: Cyrille
authors.initials: C
authors.lastname: Ramond
authors.affiliation: INSERM, U1016, Institut Cochin, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, 75014, France.
authors.forename: Ralf
authors.initials: R
authors.lastname: Jockers
authors.affiliation: Cell Therapy Unit, Hôpital Saint Louis, AP-HP, and University Paris-Diderot, Paris, 75010, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Armanet
authors.affiliation: INSERM, U1016, Institut Cochin, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, 75014, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Albagli-Curiel
authors.affiliation: INSERM, U1016, Institut Cochin, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, 75014, France.
authors.forename: Raphael
authors.initials: R
authors.lastname: Scharfmann
mesh_terms: D000143:Acids / Q000378:metabolism*; D002460:Cell Line; D000242:Cyclic AMP / Q000096:biosynthesis; D005110:Extracellular Space / Q000737:chemistry*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D018836:Inflammation Mediators / Q000378:metabolism; D007295:Inositol Phosphates / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D016209:Interleukin-8 / Q000096:biosynthesis*; D016328:NF-kappa B / Q000378:metabolism; D009504:Neutrophils / Q000378:metabolism; D011522:Protons; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D000071701:Regulatory Factor X Transcription Factors / Q000378:metabolism
chemical_list: D000143:Acids; C486281:GPR68 protein, human; D018836:Inflammation Mediators; D007295:Inositol Phosphates; D016209:Interleukin-8; D016328:NF-kappa B; D011522:Protons; D043562:Receptors, G-Protein-Coupled; D000071701:Regulatory Factor X Transcription Factors; C547964:Rfx6 protein, human; D000242:Cyclic AMP