Inflammation-associated autophagy-related programmed necrotic death of human neutrophils characterized by organelle fusion events

Mihalache, Cristina C; Yousefi, Shida; Conus, Sébastien; Villiger, Peter M; Schneider, E Marion; Simon, Hans-Uwe (2011). Inflammation-associated autophagy-related programmed necrotic death of human neutrophils characterized by organelle fusion events. Journal of immunology, 186(11), pp. 6532-42. Bethesda, Md.: American Association of Immunologists 10.4049/jimmunol.1004055

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The most common form of neutrophil death, under both physiological and inflammatory conditions, is apoptosis. In this study, we report a novel form of programmed necrotic cell death, associated with cytoplasmic organelle fusion events, that occurs in neutrophils exposed to GM-CSF and other inflammatory cytokines upon ligation of CD44. Strikingly, this type of neutrophil death requires PI3K activation, a signaling event usually involved in cellular survival pathways. In the death pathway reported in this study, PI3K is required for the generation of reactive oxygen species, which somehow trigger the generation of large cytoplasmic vacuoles, generated by the fusion of CD44-containing endosomes with autophagosomes and secondary, but not primary, granules. Neutrophils demonstrating vacuolization undergo rapid cell death that depends on receptor-interacting protein 1 kinase activity and papain family protease(s), but not caspases, that are most likely activated and released, respectively, during or as a consequence of organelle fusion. Vacuolized neutrophils are present in infectious and autoimmune diseases under in vivo conditions. Moreover, isolated neutrophils from such patients are highly sensitive toward CD44-mediated PI3K activation, reactive oxygen species production, and cell death, suggesting that the newly described autophagy-related form of programmed neutrophil necrosis plays an important role in inflammatory responses.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Pharmacology
04 Faculty of Medicine > Department of Dermatology, Urology, Rheumatology, Nephrology, Osteoporosis (DURN) > Clinic of Rheumatology, Clinical Immunology and Allergology

UniBE Contributor:

Yousefi, Shida; Villiger, Peter and Simon, Hans-Uwe

ISSN:

0022-1767

Publisher:

American Association of Immunologists

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 14:18

Last Modified:

06 Dec 2013 13:26

Publisher DOI:

10.4049/jimmunol.1004055

PubMed ID:

21515790

Web of Science ID:

000290755700053

URI:

https://boris.unibe.ch/id/eprint/5502 (FactScience: 210250)

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