title: mTOR and differential activation of mitochondria orchestrate neutrophil chemotaxis.
abstract: Neutrophils use chemotaxis to locate invading bacteria. Adenosine triphosphate (ATP) release and autocrine purinergic signaling via P2Y2 receptors at the front and A2a receptors at the back of cells regulate chemotaxis. Here, we examined the intracellular mechanisms that control these opposing signaling mechanisms. We found that mitochondria deliver ATP that stimulates P2Y2 receptors in response to chemotactic cues, and that P2Y2 receptors promote mTOR signaling, which augments mitochondrial activity near the front of cells. Blocking mTOR signaling with rapamycin or PP242 or mitochondrial ATP production (e.g., with CCCP) reduced mitochondrial Ca(2+) uptake and membrane potential, and impaired cellular ATP release and neutrophil chemotaxis. Autocrine stimulation of A2a receptors causes cyclic adenosine monophosphate accumulation at the back of cells, which inhibits mTOR signaling and mitochondrial activity, resulting in uropod retraction. We conclude that mitochondrial, purinergic, and mTOR signaling regulates neutrophil chemotaxis and may be a pharmacological target in inflammatory diseases.
authors.affiliation: Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215.
authors.forename: Yi
authors.initials: Y
authors.lastname: Bao
authors.affiliation: Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215.
authors.forename: Carola
authors.initials: C
authors.lastname: Ledderose
authors.affiliation: Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215.
authors.forename: Amelie F
authors.initials: AF
authors.lastname: Graf
authors.affiliation: Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215.
authors.forename: Bianca
authors.initials: B
authors.lastname: Brix
authors.affiliation: Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215.
authors.forename: Theresa
authors.initials: T
authors.lastname: Birsak
authors.affiliation: Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215.
authors.forename: Albert
authors.initials: A
authors.lastname: Lee
authors.affiliation: Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215.
authors.forename: Jingping
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215 Ludwig Boltzmann Institute for Traumatology, Vienna A-1200, Austria wjunger@bidmc.harvard.edu.
authors.forename: Wolfgang G
authors.initials: WG
authors.lastname: Junger
mesh_terms: D000255:Adenosine Triphosphate / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002633:Chemotaxis / Q000187:drug effects / Q000502:physiology*; D018922:HL-60 Cells; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D018375:Neutrophil Activation / Q000187:drug effects / Q000502:physiology; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism*; D011687:Purines / Q000494:pharmacology; D058473:Receptors, Purinergic P2Y2 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D007211:Indoles; D011687:Purines; D058473:Receptors, Purinergic P2Y2; D000255:Adenosine Triphosphate; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; C572919:PP242; D020123:Sirolimus