Aberrant actin depolymerization triggers the pyrin inflammasome and autoinflammatory disease that is dependent on IL-18, not IL-1β
| Autor: | Dena Lyras, Hyun-Ja Ko, Ben A. Croker, Andrew W. Roberts, Seth L. Masters, Ladina DiRago, Hazel Tye, Benjamin T. Kile, Daniel L. Kastner, Louise H. Cengia, Andrew M. Lew, Dominic De Nardo, Donald Metcalf, Yong Hwan Park, Jae Jin Chae, Man Lyang Kim, Roslynn A. Stirzaker |
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| Rok vydání: | 2015 |
| Předmět: |
Interleukin-1beta
Immunology Caspase 1 NALP3 Inflammation 030204 cardiovascular system & hematology Biology Pyrin domain Article 03 medical and health sciences 0302 clinical medicine medicine Animals Immunology and Allergy 030304 developmental biology 0303 health sciences Innate immune system Monocyte Hereditary Autoinflammatory Diseases Microfilament Proteins Inflammasome Cell Biology Actins 3. Good health Cell biology Cytoskeletal Proteins medicine.anatomical_structure biology.protein Signal transduction medicine.symptom medicine.drug |
| Zdroj: | The Journal of Experimental Medicine |
| ISSN: | 1540-9538 0022-1007 |
| Popis: | Kim et al. identify an autoinflammatory disease in mice that is driven by IL-18, resulting from an inactivating mutation in the actin-depolymerizing cofactor Wdr1. This alteration in actin dynamics is recognized by the pyrin inflammasome and results in exaggerated monocyte IL-18 production, whereas inflammasome activation in mature macrophages is unaltered. Gain-of-function mutations that activate the innate immune system can cause systemic autoinflammatory diseases associated with increased IL-1β 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-1β, 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. |
| Databáze: | OpenAIRE |
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