Aberrant actin depolymerization triggers the pyrin inflammasome and autoinflammatory disease that is dependent on IL-18, not IL-1beta

Man Lyang Kim, Jae Jin Chae, Yong Hwan Park, Dominic De Nardo, Roslynn A Stirzaker, Hyun-Ja Ko, Hazel Tye, Louise Cengia, Ladina Di Rago, Donald Metcalf, Andrew W Roberts, Daniel L Kastner, Andrew M Lew, Dena Lyras, Benjamin T. Kile, Ben A Croker, Seth L Masters

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Gain-of-function mutations that activate the innate immune system can cause systemic autoinflammatory diseases associated with increased IL-1beta production. This cytokine is activated identically to IL-18 by an intracellular protein complex known as the inflammasome; however, IL-18 has not yet been specifically implicated in the pathogenesis of hereditary autoinflammatory disorders. We have now identified an autoinflammatory disease in mice driven by IL-18, but not IL-1beta, resulting from an inactivating mutation of the actin-depolymerizing cofactor Wdr1. This perturbation of actin polymerization leads to systemic autoinflammation that is reduced when IL-18 is deleted but not when IL-1 signaling is removed. Remarkably, inflammasome activation in mature macrophages is unaltered, but IL-18 production from monocytes is greatly exaggerated, and depletion of monocytes in vivo prevents the disease. Small-molecule inhibition of actin polymerization can remove potential danger signals from the system and prevents monocyte IL-18 production. Finally, we show that the inflammasome sensor of actin dynamics in this system requires caspase-1, apoptosis-associated speck-like protein containing a caspase recruitment domain, and the innate immune receptor pyrin. Previously, perturbation of actin polymerization by pathogens was shown to activate the pyrin inflammasome, so our data now extend this guard hypothesis to host-regulated actin-dependent processes and autoinflammatory disease.
Original languageEnglish
Pages (from-to)927-938
Number of pages12
JournalJournal of Experimental Medicine
Volume212
Issue number6
DOIs
Publication statusPublished - 2015

Cite this

Kim, Man Lyang ; Chae, Jae Jin ; Park, Yong Hwan ; De Nardo, Dominic ; Stirzaker, Roslynn A ; Ko, Hyun-Ja ; Tye, Hazel ; Cengia, Louise ; Di Rago, Ladina ; Metcalf, Donald ; Roberts, Andrew W ; Kastner, Daniel L ; Lew, Andrew M ; Lyras, Dena ; Kile, Benjamin T. ; Croker, Ben A ; Masters, Seth L. / Aberrant actin depolymerization triggers the pyrin inflammasome and autoinflammatory disease that is dependent on IL-18, not IL-1beta. In: Journal of Experimental Medicine. 2015 ; Vol. 212, No. 6. pp. 927-938.
@article{35c3351c58544953ac4c930d06dff199,
title = "Aberrant actin depolymerization triggers the pyrin inflammasome and autoinflammatory disease that is dependent on IL-18, not IL-1beta",
abstract = "Gain-of-function mutations that activate the innate immune system can cause systemic autoinflammatory diseases associated with increased IL-1beta production. This cytokine is activated identically to IL-18 by an intracellular protein complex known as the inflammasome; however, IL-18 has not yet been specifically implicated in the pathogenesis of hereditary autoinflammatory disorders. We have now identified an autoinflammatory disease in mice driven by IL-18, but not IL-1beta, resulting from an inactivating mutation of the actin-depolymerizing cofactor Wdr1. This perturbation of actin polymerization leads to systemic autoinflammation that is reduced when IL-18 is deleted but not when IL-1 signaling is removed. Remarkably, inflammasome activation in mature macrophages is unaltered, but IL-18 production from monocytes is greatly exaggerated, and depletion of monocytes in vivo prevents the disease. Small-molecule inhibition of actin polymerization can remove potential danger signals from the system and prevents monocyte IL-18 production. Finally, we show that the inflammasome sensor of actin dynamics in this system requires caspase-1, apoptosis-associated speck-like protein containing a caspase recruitment domain, and the innate immune receptor pyrin. Previously, perturbation of actin polymerization by pathogens was shown to activate the pyrin inflammasome, so our data now extend this guard hypothesis to host-regulated actin-dependent processes and autoinflammatory disease.",
author = "Kim, {Man Lyang} and Chae, {Jae Jin} and Park, {Yong Hwan} and {De Nardo}, Dominic and Stirzaker, {Roslynn A} and Hyun-Ja Ko and Hazel Tye and Louise Cengia and {Di Rago}, Ladina and Donald Metcalf and Roberts, {Andrew W} and Kastner, {Daniel L} and Lew, {Andrew M} and Dena Lyras and Kile, {Benjamin T.} and Croker, {Ben A} and Masters, {Seth L}",
year = "2015",
doi = "10.1084/jem.20142384",
language = "English",
volume = "212",
pages = "927--938",
journal = "Journal of Experimental Medicine",
issn = "0022-1007",
publisher = "Rockefeller University Press",
number = "6",

}

Kim, ML, Chae, JJ, Park, YH, De Nardo, D, Stirzaker, RA, Ko, H-J, Tye, H, Cengia, L, Di Rago, L, Metcalf, D, Roberts, AW, Kastner, DL, Lew, AM, Lyras, D, Kile, BT, Croker, BA & Masters, SL 2015, 'Aberrant actin depolymerization triggers the pyrin inflammasome and autoinflammatory disease that is dependent on IL-18, not IL-1beta' Journal of Experimental Medicine, vol. 212, no. 6, pp. 927-938. https://doi.org/10.1084/jem.20142384

Aberrant actin depolymerization triggers the pyrin inflammasome and autoinflammatory disease that is dependent on IL-18, not IL-1beta. / Kim, Man Lyang; Chae, Jae Jin; Park, Yong Hwan; De Nardo, Dominic; Stirzaker, Roslynn A; Ko, Hyun-Ja; Tye, Hazel; Cengia, Louise; Di Rago, Ladina; Metcalf, Donald; Roberts, Andrew W; Kastner, Daniel L; Lew, Andrew M; Lyras, Dena; Kile, Benjamin T.; Croker, Ben A; Masters, Seth L.

In: Journal of Experimental Medicine, Vol. 212, No. 6, 2015, p. 927-938.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Aberrant actin depolymerization triggers the pyrin inflammasome and autoinflammatory disease that is dependent on IL-18, not IL-1beta

AU - Kim, Man Lyang

AU - Chae, Jae Jin

AU - Park, Yong Hwan

AU - De Nardo, Dominic

AU - Stirzaker, Roslynn A

AU - Ko, Hyun-Ja

AU - Tye, Hazel

AU - Cengia, Louise

AU - Di Rago, Ladina

AU - Metcalf, Donald

AU - Roberts, Andrew W

AU - Kastner, Daniel L

AU - Lew, Andrew M

AU - Lyras, Dena

AU - Kile, Benjamin T.

AU - Croker, Ben A

AU - Masters, Seth L

PY - 2015

Y1 - 2015

N2 - Gain-of-function mutations that activate the innate immune system can cause systemic autoinflammatory diseases associated with increased IL-1beta production. This cytokine is activated identically to IL-18 by an intracellular protein complex known as the inflammasome; however, IL-18 has not yet been specifically implicated in the pathogenesis of hereditary autoinflammatory disorders. We have now identified an autoinflammatory disease in mice driven by IL-18, but not IL-1beta, resulting from an inactivating mutation of the actin-depolymerizing cofactor Wdr1. This perturbation of actin polymerization leads to systemic autoinflammation that is reduced when IL-18 is deleted but not when IL-1 signaling is removed. Remarkably, inflammasome activation in mature macrophages is unaltered, but IL-18 production from monocytes is greatly exaggerated, and depletion of monocytes in vivo prevents the disease. Small-molecule inhibition of actin polymerization can remove potential danger signals from the system and prevents monocyte IL-18 production. Finally, we show that the inflammasome sensor of actin dynamics in this system requires caspase-1, apoptosis-associated speck-like protein containing a caspase recruitment domain, and the innate immune receptor pyrin. Previously, perturbation of actin polymerization by pathogens was shown to activate the pyrin inflammasome, so our data now extend this guard hypothesis to host-regulated actin-dependent processes and autoinflammatory disease.

AB - Gain-of-function mutations that activate the innate immune system can cause systemic autoinflammatory diseases associated with increased IL-1beta production. This cytokine is activated identically to IL-18 by an intracellular protein complex known as the inflammasome; however, IL-18 has not yet been specifically implicated in the pathogenesis of hereditary autoinflammatory disorders. We have now identified an autoinflammatory disease in mice driven by IL-18, but not IL-1beta, resulting from an inactivating mutation of the actin-depolymerizing cofactor Wdr1. This perturbation of actin polymerization leads to systemic autoinflammation that is reduced when IL-18 is deleted but not when IL-1 signaling is removed. Remarkably, inflammasome activation in mature macrophages is unaltered, but IL-18 production from monocytes is greatly exaggerated, and depletion of monocytes in vivo prevents the disease. Small-molecule inhibition of actin polymerization can remove potential danger signals from the system and prevents monocyte IL-18 production. Finally, we show that the inflammasome sensor of actin dynamics in this system requires caspase-1, apoptosis-associated speck-like protein containing a caspase recruitment domain, and the innate immune receptor pyrin. Previously, perturbation of actin polymerization by pathogens was shown to activate the pyrin inflammasome, so our data now extend this guard hypothesis to host-regulated actin-dependent processes and autoinflammatory disease.

UR - http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4451132/

U2 - 10.1084/jem.20142384

DO - 10.1084/jem.20142384

M3 - Article

VL - 212

SP - 927

EP - 938

JO - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

SN - 0022-1007

IS - 6

ER -