3K3A-Activated Protein C Prevents Microglia Activation, Inhibits NLRP3 Inflammasome and Limits Ocular Inflammation.
Int J Mol Sci
; 23(22)2022 Nov 17.
Article
en En
| MEDLINE
| ID: mdl-36430674
ABSTRACT
3K3A-Activated Protein C (APC) is a recombinant variant of the physiological anticoagulant APC with pleiotropic cytoprotective properties albeit without the bleeding risks. The anti-inflammatory activities of 3K3A-APC were demonstrated in multiple preclinical injury models, including various neurological disorders. We determined the ability of 3K3A-APC to inhibit ocular inflammation in a murine model of lipopolysaccharide (LPS)-induced uveitis. Leukocyte recruitment, microglia activation, NLRP3 inflammasome and IL-1ß levels were assessed using flow cytometry, retinal cryosection histology, retinal flatmount immunohistochemistry and vascular imaging, with and without 3K3A-APC treatment. LPS triggered robust inflammatory cell recruitment in the posterior chamber. The 3K3A-APC treatment significantly decreased leukocyte numbers and inhibited leukocyte extravasation from blood vessels into the retinal parenchyma to a level similar to controls. Resident microglia, which underwent an inflammatory transition following LPS injection, remained quiescent in eyes treated with 3K3A-APC. An inflammation-associated increase in retinal thickness, observed in LPS-injected eyes, was diminished by 3K3A-APC treatment, suggesting its clinical relevancy. Finally, 3K3A-APC treatment inhibited inflammasome activation, determined by lower levels of NLRP3 and its downstream effector IL-1ß. Our results highlight the anti-inflammatory properties of 3K3A-APC in ocular inflammation and suggest its potential use as a novel treatment for retinal diseases associated with inflammation.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Proteína C
/
Oftalmopatías
/
Inflamasomas
Límite:
Animals
Idioma:
En
Revista:
Int J Mol Sci
Año:
2022
Tipo del documento:
Article
País de afiliación:
Israel