title: Anoctamin 6 mediates effects essential for innate immunity downstream of P2X7 receptors in macrophages.
abstract: Purinergic P2X7 receptors (P2X7R) are fundamental to innate immune response. In macrophages, transient stimulation of P2X7R activates several transport mechanisms and induces the scrambling of phospholipids with subsequent membrane blebbing and apoptosis. These processes support phagocytosis and subsequent killing of phagocytosed bacteria. Here we demonstrate that the stimulation of P2X7 receptors activates anoctamin 6 (ANO6, TMEM16F), a protein that functions as Ca(2+) dependent phospholipid scramblase and Ca(2+)-activated Cl(-) channel. Inhibition or knockdown of ANO6 attenuates ATP-induced cell shrinkage, cell migration and phospholipid scrambling. In mouse macrophages, Ano6 produces large ion currents by stimulation of P2X7 receptors and contributes to ATP-induced membrane blebbing and apoptosis, which is largely reduced in macrophages from Ano6-/- mice. ANO6 supports bacterial phagocytosis and killing by mouse and human THP-1 macrophages. Our data demonstrate that anoctamin 6 is an essential component of the immune defense by macrophages.
authors: Physiological Institute, University of Regensburg, Universitätsstraße 31, D-93053 Regensburg, Germany.
authors: Jiraporn
authors: J
authors: Ousingsawat
authors: Physiological Institute, University of Regensburg, Universitätsstraße 31, D-93053 Regensburg, Germany.
authors: Podchanart
authors: P
authors: Wanitchakool
authors: Physiological Institute, University of Regensburg, Universitätsstraße 31, D-93053 Regensburg, Germany.
authors: Arthur
authors: A
authors: Kmit
authors: Physiological Institute, University of Regensburg, Universitätsstraße 31, D-93053 Regensburg, Germany.
authors: Ana M
authors: AM
authors: Romao
authors: Physiological Institute, University of Regensburg, Universitätsstraße 31, D-93053 Regensburg, Germany.
authors: Walailak
authors: W
authors: Jantarajit
authors: Physiological Institute, University of Regensburg, Universitätsstraße 31, D-93053 Regensburg, Germany.
authors: Rainer
authors: R
authors: Schreiber
authors: Physiological Institute, University of Regensburg, Universitätsstraße 31, D-93053 Regensburg, Germany.
authors: Karl
authors: K
authors: Kunzelmann
mesh_terms: D000818:Animals; D000075368:Anoctamins; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D002118:Calcium / Q000378:metabolism; D002465:Cell Movement; D048429:Cell Size; D005786:Gene Expression Regulation; D006801:Humans; D007113:Immunity, Innate; D017136:Ion Transport; D008262:Macrophage Activation; D008264:Macrophages / Q000166:cytology / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D009865:Oocytes / Q000166:cytology / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010587:Phagocytosis / Q000235:genetics; D049294:Phospholipid Transfer Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D058486:Receptors, Purinergic P2X7 / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction; D014982:Xenopus laevis
chemical_list: C555078:ANO6 protein, human; D000075368:Anoctamins; C546468:P2RX7 protein, human; D049294:Phospholipid Transfer Proteins; D034741:RNA, Small Interfering; D058486:Receptors, Purinergic P2X7; D002118:Calcium