Neutrophil secondary necrosis is induced by LL-37 derived from cathelicidin.
Neutrophils represent the most common granulocyte subtype present in blood. The short half-life of circulating neutrophils is regulated by spontaneous apoptosis, and tissue infiltrating neutrophils die by apoptosis and secondary necrosis. The mechanism of neutrophil apoptosis has been the subject of many studies; however, the mechanism of neutrophil secondary necrosis is less clear. Human cathelicidin cationic peptide 18, proteolytically processed to its active form, LL-37, is secreted by neutrophils and epithelial cells and shown to have effects in addition to bacterial lysis. We demonstrate here that LL-37 affects neutrophil lifespan by the pathway of secondary necrosis, rapidly converting annexin V-positive (AV(+)), propidium iodide-negative (PI(-); apoptotic) cells into PI(+) (necrotic) cells with the release of IL-8, IL-1R antagonist, ATP, and intact granules. The effects of LL-37 on apoptotic neutrophils are neither energy-dependent nor affected by pretreatment with G-CSF, GM-CSF, TNF-alpha, and LPS and are partially inhibited by human serum. Moreover, LL-37 decreases CXCR2 expression of AV(-)PI(-) (live) neutrophils, suggesting an effect on the neutrophil response to its chemotactic factors, including IL-8. Thus, the lifespan and inflammatory functions of neutrophils are directly affected by LL-37.
Division of Immunology, Beckman Research Institute of the City of Hope, 1500E Duarte Rd., Duarte, CA 91010, USA.
Zhifang
Z
Zhang
Gregory
G
Cherryholmes
John E
JE
Shively
D000255:Adenosine Triphosphate / Q000378:metabolism; D017304:Annexin A5 / Q000378:metabolism; D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D005434:Flow Cytometry; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D009336:Necrosis; D018375:Neutrophil Activation / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D054804:Cathelicidins
D017304:Annexin A5; D023181:Antimicrobial Cationic Peptides; D016209:Interleukin-8; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D016179:Granulocyte Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D000255:Adenosine Triphosphate; D054804:Cathelicidins