Pyroptotic cells externalize eat-me and release find-me signals and are efficiently engulfed by macrophages
Abstract
Pathogenic intracellular bacteria often hijack macrophages for their propagation. The infected macrophages release IL-1β and IL-18 and simultaneously commit suicide, which is called pyroptosis; both responses require caspase-1. Here, we found that pyroptotic cells induced by microbial infection were efficiently engulfed by human monocytic THP-1-cell-derived macrophages or mouse peritoneal macrophages. This engulfment was inhibited by the D89E mutant of milk fat globule (MFG) epidermal growth factor (EGF) factor 8 (MFG-E8; a phosphatidylserine-binding protein) that has been shown previously to inhibit phosphatidylserine-dependent engulfment of apoptotic cells by macrophages, suggesting that the engulfment of pyroptotic cells by macrophages was also phosphatidylserine dependent. Using a pair of cell lines that respectively exhibited pyroptosis or apoptosis after muramyl dipeptide treatment, we showed that both pyroptotic and apoptotic cells bound to a T-cell immunoglobulin and mucin domain-containing 4 (Tim4; another phosphatidylserine-binding protein)-coated plate, whereas heat-killed necrotic cells did not, indicating that phosphatidylserine was externalized in pyroptosis and apoptosis but not in accidental necrosis. Macrophages engulfed apoptotic cells most efficiently, followed by pyroptotic and then heat-killed necrotic cells. Pyroptotic cells also released a macrophage attractant(s), ‘find-me’ signal, whose activity was diminished by apyrase that degrades nucleoside triphosphate to nucleoside monophosphate. Heat-killed necrotic cells and pyroptotic cells released ATP much more efficiently than apoptotic cells. These results suggest that pyroptotic cells, like apoptotic cells, actively induce phagocytosis by macrophages using ‘eat-me’ and find-me signals. Based on these results, a possible role of coordinated induction of pyroptosis and inflammatory cytokine production is discussed.
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Binding of lactadherin (MFG-E8) to PS on apoptotic corpses blocks efferocytosis.
“Binding of lactadherin (MFG-E8) to PS on apoptotic corpses blocks efferocytosis (138).”
From Macrophage defense mechanisms against intracellular bacteria (2015) · cites this paper as [138]
Pyroptosis is a special case of necrosis, initiated by caspase-1, and leads to release of the pro-inflammatory cytokines IL-1β and IL-18.
“Pyroptosis is a special case of necrosis, as it is initiated by caspase-1 and leads to release of the pro-inflammatory cytokines IL-1β and IL-18.”
From Macrophage defense mechanisms against intracellular bacteria (2015) · cites this paper as [138]
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- Authors
- Wang, Q., Imamura, R., Motani, K., Kushiyama, H., Nagata, S., & Suda, T.
- Affiliations
- Kanazawa University (JP)
- Kyoto University (JP)
- Venue
- International Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2013-02-26
- Volume
- 25
- Issue
- 6
- Pages
- 363-372
- ISSN
- 0953-8178 (ISSN-L)
- 1460-2377
- OpenAlex
- W2130002934
- Cited by
- 108
- References
- 21
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 13 · 2023: 13 · 2022: 13 · 2021: 20 · 2020: 7 · 2019: 4 · 2018: 7 · 2017: 3 · 2016: 8 · 2015: 4 · 2014: 7 · 2013: 3
- FWCI
- 4.04
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- International Immunology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Society for the Promotion of Science (23390092, 24590374, 22000013)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- pyroptosis, macrophage phagocytosis, phosphatidylserine exposure, eat-me signals, find-me signals, MFG-E8, TIM-4, ATP release, caspase-1, IL-1β, IL-18, apoptosis, necrosis, intracellular bacterial infection
- MeSH terms
- Animals, Cell Communication, Humans, Macrophages, Mice, Inbred C57BL, Phagocytosis, Cell Line, Tumor, Mice
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