Noncanonical Roles of Caspase-4 and Caspase-5 in Heme-Driven IL-1ß Release and Cell Death.
J Immunol
; 206(8): 1878-1889, 2021 04 15.
Article
en En
| MEDLINE
| ID: mdl-33741688
ABSTRACT
Excessive release of heme from RBCs is a key pathophysiological feature of several disease states, including bacterial sepsis, malaria, and sickle cell disease. This hemolysis results in an increased level of free heme that has been implicated in the inflammatory activation of monocytes, macrophages, and the endothelium. In this study, we show that extracellular heme engages the human inflammatory caspases, caspase-1, caspase-4, and caspase-5, resulting in the release of IL-1ß. Heme-induced IL-1ß release was further increased in macrophages from patients with sickle cell disease. In human primary macrophages, heme activated caspase-1 in an inflammasome-dependent manner, but heme-induced activation of caspase-4 and caspase-5 was independent of canonical inflammasomes. Furthermore, we show that both caspase-4 and caspase-5 are essential for heme-induced IL-1ß release, whereas caspase-4 is the primary contributor to heme-induced cell death. Together, we have identified that extracellular heme is a damage-associated molecular pattern that can engage canonical and noncanonical inflammasome activation as a key mediator of inflammation in macrophages.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Caspasas
/
Eritrocitos
/
Caspasas Iniciadoras
/
Inflamasomas
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Inflamación
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Anemia de Células Falciformes
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Macrófagos
Límite:
Humans
Idioma:
En
Revista:
J Immunol
Año:
2021
Tipo del documento:
Article