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Nonclassical IL-1β Secretion Stimulated by P2X7 Receptors Is Dependent on Inflammasome Activation and Correlated with Exosome Release in Murine Macrophages
Abstract
Several mechanistically distinct models of nonclassical secretion, including exocytosis of secretory lysosomes, shedding of plasma membrane microvesicles, and direct efflux through plasma membrane transporters, have been proposed to explain the rapid export of caspase-1-processed IL-1β from monocytes/macrophages in response to activation of P2X7 receptors (P2X7R) by extracellular ATP. We compared the contribution of these mechanisms to P2X7R-stimulated IL-1β secretion in primary bone marrow-derived macrophages isolated from wild-type, P2X7R knockout, or apoptosis-associated speck-like protein containing a C-terminal CARD knockout mice. Our experiments revealed the following: 1) a novel correlation between IL-1β secretion and the release of the MHC-II membrane protein, which is a marker of plasma membranes, recycling endosomes, multivesicular bodies, and released exosomes; 2) a common and absolute requirement for inflammasome assembly and active caspase-1 in triggering the cotemporal export of IL-1β and MHC-II; and 3) mechanistic dissociation of IL-1β export from either secretory lysosome exocytosis or plasma membrane microvesicle shedding on the basis of different requirements for extracellular Ca2+ and differential sensitivity to pharmacological agents that block activation of caspase-1 inflammasomes. Thus, neither secretory lysosome exocytosis nor microvesicle shedding models constitute the major pathways for nonclassical IL-1β secretion from ATP-stimulated murine macrophages. Our findings suggest an alternative model of IL-1β release that may involve the P2X7R-induced formation of multivesicular bodies that contain exosomes with entrapped IL-1β, caspase-1, and other inflammasome components.
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“Additionally, exocytosis of P2X7R-positive multivesicular bodies containing exosomes has also been reported to play an important role in the release of this cytokine (39).”
From Macrophage Cytokines: Involvement in Immunity and Infectious Diseases (2014) · cites this paper as [39]
In the citing paper
“The P2X7 receptor is a major activator of the NLRP3 inflammasome in several cell types [16], including macrophages and microglial cells [72, 74–76].”
From Hyperactivation of P2X7 receptors as a culprit of COVID-19 neuropathology (2021) · cites this paper as [75]
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Metadata
- Authors
- Qu, Y., Franchi, L., Nunez, G., & Dubyak, G. R.
- Affiliations
- Case Western Reserve University (US)
- University of Michigan (US)
- Department of Pathology, University of Michigan , Ann Arbor, MI 48109
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2007-08-01
- Volume
- 179
- Issue
- 3
- Pages
- 1913-1925
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W2100358971
- Cited by
- 563
- References
- 75
- Citations by year
- 2026: 16 · 2025: 21 · 2024: 21 · 2023: 26 · 2022: 24 · 2021: 27 · 2020: 36 · 2019: 28 · 2018: 36 · 2017: 30 · 2016: 30 · 2015: 43 · 2014: 37 · 2013: 36 · 2012: 38
- FWCI
- 9.93
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of General Medical Sciences (GM-36387, R01GM036387)
- National Institute of Allergy and Infectious Diseases (AI 064748, AI063331, R01AI064748)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Adenosine and Purinergic Signaling
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- P2X7 receptor, inflammasome, caspase-1, exosomes, macrophages, extracellular ATP, multivesicular bodies, extracellular calcium
- MeSH terms
- Adenosine Triphosphate, Animals, Cathepsin B, Cells, Cultured, Enzyme Activation, Exocytosis, Inflammation, Lysosomes, Macrophages, Mice, Inbred BALB C, Mice, Inbred C57BL, Endosomes, Signal Transduction, Receptors, Purinergic P2, Mice, Knockout, Models, Immunological, Caspase 1, Multiprotein Complexes, Mice, Interleukin-1beta, Receptors, Purinergic P2X7
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