CIBICI   14215
CENTRO DE INVESTIGACION EN BIOQUIMICA CLINICA E INMUNOLOGIA
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
PI3K inhibitors prevent TLR2-mediated myeloid leukocyte recruitment, pro-inflammatory gene expression and the presence of LC3B+ puncta in the CNS.
Autor/es:
PERALTA RAMOS, JAVIER MARÍA; CANCELA, LM; ARROYO, DS; BUSSI, C; IRIBARREN, P; GAVIGLIO, EA; AVALOS, MARIA P.
Lugar:
Mar del Plata
Reunión:
Congreso; Reunión conjunta SAIC SAI SAFIS 2018; 2018
Institución organizadora:
SAIC SAI SAFIS
Resumen:
PI3K inhibitors prevent TLR2-mediated myeloid leukocyte recruitment, pro-inflammatory gene expression and the presence of LC3B+ puncta in the CNS. Acute brain injury leads to the recruitment and activation of immune cells including resident microglia and infiltrating peripheral myeloid cells, which contribute to the inflammatory response involved in neuronal damage. Here, we reported that TLR2 stimulation by peptidoglycan (PGN) from Staphylococcus aureus, in vitro and in vivo, induced microglial cell activation followed by autophagy induction. Furthermore, we evaluated if phosphatidyl-inositol-3 kinase (PI3K) pharmacological inhibitors LY294200 and 3-methyladenine (3-MA) can modulate the innate immune response to PGN in the central nervous system. We found that injection of PGN into the mouse brain parenchyma (caudate putamen) triggered an inflammatory reaction, which involved activation of microglial cells, recruitment of infiltrating myeloid cells to the injection site, production of pro-inflammatory mediators, and neuronal injury. In addition, we observed the accumulation of LC3B+ CD45+cells and colocalization of LC3B and lysosomal-associated membrane protein 1 in brain cells. Besides, we found that pharmacological inhibitors of PI3K, including the classical autophagy inhibitor 3-MA, reduced the recruitment of myeloid cells, microglial cell activation, and neurotoxicity induced by brain PGN injection. Collectively, our results suggest that PI3K pathways and autophagic response may participate in the PGN-induced microglial activation and myeloid cells recruitment to the brain. Thus, inhibition of these pathways could be therapeutically targeted to control acute brain inflammatory conditions.