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Serum-dependent processing of late apoptotic cells and their immunogenicity

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Abstract

The execution phase of apoptosis involves many processes which modify cellular molecules for an efficient and quiet elimination of the dead cell. These include exposure and secretion of “eat-me” signals, to attract phagocytes, as well as degradation of immune-stimulating cell debris. During this phase apoptotic microparticles (MPs) are released from the dying cell. The remaining cell remnant forms large late apoptotic cell-derived membranous vesicles (ACMVL) on its surface which remain attached. Phagocytosis is enhanced by cell non-autonomous factors such as complement component C1q and serum DNase I. We studied the formation and retraction of ACMVL and the influence of serum on their dynamics. We furthermore investigated the immunogenicity of cell remnants compared to released MPs. ACMVL were examined using time-lapse, electron microscopy and confocal microscopy. These blebs were observed on cell remnants with intact and with permeable membrane. This suggests that ACMVL remain on the surface by the time the cell remnant enters secondary necrosis. Bleb retraction could also be observed, but was radically enhanced in the presence of serum. Additionally, MPs stimulate peripheral blood mononuclear cells to produce similar IL-1beta, IL-6, IL-8, IL-10, and TNF-alpha levels as LPS. In contrast, cell remnants only induce high levels of IL-8. These data show that cell non-autonomous factors contribute to morphological rearrangements during late apoptosis. In addition, they implicate that apoptotic MPs are released to attract phagocytes, while apoptotic cell remnants further process their potentially immunogenic content to prevent an inflammatory response upon secondary necrosis.

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Acknowledgments

We thank Katharina Strasser, Hanna Birnleitner and Monika Sachet, for helpful discussions and proof reading of the manuscript. In addition we thank Andreas Spittler, Sabine Rauscher, Marion Gröger and Elisabeth Buchberger for their support in cell sorting and confocal microscopy. This study was partially supported by a Grant from the Comprehensive Cancer Center of the Medical University of Vienna.

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  1. Surgical Research Laboratories, Department of Surgery and Comprehensive Cancer Center, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria

    Ying Yu Liang, Desiree Rainprecht, Eva Eichmair, Barbara Messner & Rudolf Oehler

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Correspondence to Rudolf Oehler.

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Liang, Y.Y., Rainprecht, D., Eichmair, E. et al. Serum-dependent processing of late apoptotic cells and their immunogenicity. Apoptosis 20, 1444–1456 (2015). https://doi.org/10.1007/s10495-015-1163-8

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