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Volcanic Ash Activates the NLRP3 Inflammasome in Murine and Human Macrophages

Damby, D.E.; Horwell, C.J.; Baxter, P.J.; Kueppers, U.; Schnurr, M.; Dingwell, D.B.; Duewell, P.

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D.E. Damby

P.J. Baxter

U. Kueppers

M. Schnurr

D.B. Dingwell

P. Duewell


Volcanic ash is a heterogeneous mineral dust that is typically composed of a mixture of amorphous (glass) and crystalline (mineral) fragments. It commonly contains an abundance of the crystalline silica (SiO2) polymorph cristobalite. Inhalation of crystalline silica can induce inflammation by stimulating the NLRP3 inflammasome, a cytosolic receptor complex that plays a critical role in driving inflammatory immune responses. Ingested material results in the assembly of NLRP3, ASC, and caspase-1 with subsequent secretion of the interleukin-1 family cytokine IL-1β. Previous toxicology work suggests that cristobalite-bearing volcanic ash is minimally reactive, calling into question the reactivity of volcanically derived crystalline silica, in general. In this study, we target the NLRP3 inflammasome as a crystalline silica responsive element to clarify volcanic cristobalite reactivity. We expose immortalized bone marrow-derived macrophages of genetically engineered mice and primary human peripheral blood mononuclear cells (PBMCs) to ash from the Soufrière Hills volcano as well as representative, pure-phase samples of its primary componentry (volcanic glass, feldspar, cristobalite) and measure NLRP3 inflammasome activation. We demonstrate that respirable Soufrière Hills volcanic ash induces the activation of caspase-1 with subsequent release of mature IL-1β in a NLRP3 inflammasome-dependent manner. Macrophages deficient in NLRP3 inflammasome components are incapable of secreting IL-1β in response to volcanic ash ingestion. Cellular uptake induces lysosomal destabilization involving cysteine proteases. Furthermore, the response involves activation of mitochondrial stress pathways leading to the generation of reactive oxygen species. Considering ash componentry, cristobalite is the most reactive pure-phase with other components inducing only low-level IL-1β secretion. Inflammasome activation mediated by inhaled ash and its potential relevance in chronic pulmonary disease was further evidenced in PBMC using the NLRP3 small-molecule inhibitor CP-456,773 (CRID3, MCC950). Our data indicate the functional activation of the NLRP3 inflammasome by volcanic ash in murine and human macrophages in vitro. Cristobalite is identified as the apparent driver, thereby contesting previous assertions that chemical and structural imperfections may be sufficient to abrogate the reactivity of volcanically derived cristobalite. This is a novel mechanism for the stimulation of a pro-inflammatory response by volcanic particulate and provides new insight regarding chronic exposure to environmentally occurring particles.


Damby, D., Horwell, C., Baxter, P., Kueppers, U., Schnurr, M., Dingwell, D., & Duewell, P. (2018). Volcanic Ash Activates the NLRP3 Inflammasome in Murine and Human Macrophages. Frontiers in Immunology, 8, Article 2000.

Journal Article Type Article
Acceptance Date Dec 22, 2017
Online Publication Date Jan 22, 2018
Publication Date Jan 22, 2018
Deposit Date Feb 5, 2018
Publicly Available Date Feb 6, 2018
Journal Frontiers in Immunology
Publisher Frontiers Media
Peer Reviewed Peer Reviewed
Volume 8
Article Number 2000


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Copyright Statement
Copyright: © 2018 Damby, Horwell, Baxter, Kueppers, Schnurr, Dingwell and Duewell. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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