ASK Family Kinases Are Required for Optimal NLRP3 Inflammasome Priming.
Am J Pathol
; 188(4): 1021-1030, 2018 04.
Article
en En
| MEDLINE
| ID: mdl-29353059
ABSTRACT
Activation of the multimeric inflammasome complex leads to inflammatory responses to biotic and abiotic triggers. The inflammasome sensor, Nod-like receptor family pyrin domain containing 3 (NLRP3), is activated by a range of stimuli and is tightly regulated to restrict excessive inflammation. Because NLRP3 responds broadly to cellular insults and regulates cell death similar to the stress-activated apoptosis signal-regulating kinases 1 and 2 (ASK1/2), we hypothesized that ASK1/2 may regulate NLRP3 activity. Although essential for mediating NLRP3 inflammasome activation, ASK1/2 were not required for NLRC4 or absent in melanoma 2 inflammasome activation. ASK1/2 was required for NLRP3 up-regulation after lipopolysaccharide treatment in primary bone marrow-derived macrophages and lung fibroblasts as well as during infection with Burkholderia thailandensis and influenza virus. Consistent with reduced NLRP3 expression in response to B. thailandensis, caspase-1 cleavage and cell death were reduced in infected bone marrow-derived macrophages, and mice lacking ASK1/2 were resistant to Burkholderia intranasal infection. Single knockouts of either ASK1 or ASK2 showed a partial role for both ASK1 and ASK2 in NLRP3 up-regulation in response to lipopolysaccharide or B. thailandensis, but ASK2 was required primarily to mediate lethal pathology during intranasal infection in vivo. Our findings identify the ASK1/2 complex as a regulator of NLRP3 activation and highlight a larger role for ASK2 in lung infection during B. thailandensis infection.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Quinasas Quinasa Quinasa PAM
/
MAP Quinasa Quinasa Quinasa 5
/
Inflamasomas
/
Proteína con Dominio Pirina 3 de la Familia NLR
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Am J Pathol
Año:
2018
Tipo del documento:
Article