LDK378 inhibits the recruitment of myeloid-derived suppressor cells to spleen via the p38-GRK2-CCR2 pathway in mice with sepsis.
Immunol Cell Biol
; 97(10): 902-915, 2019 11.
Article
en En
| MEDLINE
| ID: mdl-31472096
ABSTRACT
Myeloid-derived suppressor cells (MDSCs) are functionally immunosuppressive cells that are persistently increased in abundance and associated with adverse clinical outcomes in sepsis. Here, we investigated the therapeutic potential of an anaplastic lymphoma kinase inhibitor, LDK378, in cecal ligation and puncture (CLP)-induced polymicrobial sepsis and examined its effects on the recruitment of MDSCs. LDK378 significantly improved the survival of CLP-induced polymicrobial septic mice, which was paralleled by reduced organ injury, decreased release of inflammatory cytokines and decreased recruitment of MDSCs to the spleen. Importantly, LDK378 inhibited the migration of MDSCs to the spleen by blocking the CLP-mediated upregulation of CC chemokine receptor 2 (CCR2), a chemokine receptor critical for the recruitment of MDSCs. Mechanistically, LDK378 treatment blocked the CLP-induced CCR2 upregulation of MDSCs via partially inhibiting the phosphorylation of p38 and G-protein-coupled receptor kinase-2 (GRK2) in bone marrow MDSCs of septic mice. Furthermore, in vitro experiments also showed that lipopolysaccharide (LPS)-induced migration of MDSCs was similarly owing to the activation of GRK2 and upregulation of CCR2 by LPS, whereas the treatment with LDK378 partially blocked the LPS-induced phosphorylation of p38 and GRK2 and decreased the expression of CCR2 on the cell surface, therefore leading to the suppression of MDSC migration. Together, these findings unravel a novel function of LDK378 in the host response to infection and suggest that LDK378 could be a potential therapeutic agent for sepsis.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Pirimidinas
/
Bazo
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Sulfonas
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Sepsis
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Proteínas Quinasas p38 Activadas por Mitógenos
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Quinasa 2 del Receptor Acoplado a Proteína-G
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Receptores CCR2
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Células Supresoras de Origen Mieloide
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Immunol Cell Biol
Asunto de la revista:
ALERGIA E IMUNOLOGIA
Año:
2019
Tipo del documento:
Article
País de afiliación:
China