Mature human eosinophils express functional Notch ligands mediating eosinophil autocrine regulation.
Eosinophil chemotaxis and survival within tissues are key components in the development of tissue eosinophilia and subsequent effector responses. In this study, we demonstrate a novel mechanism of eosinophil autoregulation affecting migration and survival mediated through Notch signaling. We show for the first time that human blood eosinophils express Notch receptors and Notch ligands, expressions of which are influenced by the presence of eosinophil-activating granulocyte-macrophage colony-stimulating factor (GM-CSF). Evidence of Notch receptor activation and subsequent transcription of the Notch-responsive gene HES1 were observed in GM-CSF-stimulated eosinophils, confirming functionality of eosinophil-expressed Notch-signaling components. Moreover, by inhibiting Notch signaling with gamma-secretase inhibitors or Notch receptor-specific neutralizing antibodies, we demonstrate that autocrine Notch signaling enhances stimulus-mediated actin rearrangement and eosinophil chemokinesis, and impairs eosinophil viability. Taken together, these data suggest autocrine Notch signaling, enhanced in response to tissue- or inflammatory-derived signals, influences eosinophil activity and longevity, which may ultimately contribute to the development of tissue eosinophilia and exacerbation or remediation of eosinophil effector functions.
Radke
Amy L
AL
Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Reynolds
Lauren E
LE
Melo
Rossana C N
RC
Dvorak
Ann M
AM
Weller
Peter F
PF
Spencer
Lisa A
LA
D019898:Autocrine Communication / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D010450:Endopeptidases; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004804:Eosinophils / Q000378:metabolism* / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D000072101:Jagged-2 Protein; D008024:Ligands; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D010447:Peptide Hydrolases; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D000072099:Serrate-Jagged Proteins; D052067:Soluble N-Ethylmaleimide-Sensitive Factor Attachment Proteins / Q000037:antagonists & inhibitors
D002135:Calcium-Binding Proteins; D004791:Enzyme Inhibitors; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; C490504:JAG2 protein, human; D000072101:Jagged-2 Protein; D008024:Ligands; D008565:Membrane Proteins; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins; D052067:Soluble N-Ethylmaleimide-Sensitive Factor Attachment Proteins; C064045:delta protein; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; C475154:APH1A protein, human; D010450:Endopeptidases; D010447:Peptide Hydrolases