PI3K inhibitors prevent TLR2-mediated myeloid leukocyte recruitment, pro-inflammatory gene expression and the presence of LC3B+ puncta in the CNS.

ARROYO DANIELA S; GAVIGLIO, EMILIA A.; PERALTA RAMOS JAVIER M; BUSSI CLAUDIO; AVALOS, MARIA P.; CANCELA, LILIANA M.; IRIBARREN, PABLO

Congreso; LXVI Reunión Anual de la Sociedad Argentina de Inmunología; 2018

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 PI3Kpathways 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.