Format

Send to

Choose Destination
J Cell Biol. 2015 Sep 28;210(7):1153-64. doi: 10.1083/jcb.201503066.

mTOR and differential activation of mitochondria orchestrate neutrophil chemotaxis.

Author information

1
Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215.
2
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.

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.

PMID:
26416965
PMCID:
PMC4586745
DOI:
10.1083/jcb.201503066
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center