Damage associated molecular pattern HMGB-1 effects in neuronal survival and propagation of reactive gliosis

LUKIN JERONIMO; ROSCISZEWSKI GERARDO; RAMOS ALBERTO JAVIER; CADENA VANESA

CABA

Congreso; 2nd FALAN Congress; 2016

Damage associated molecular pattern molecules such as HMGB-1 are intracellular components that are able to activate innate immune system. There is an oversimplification in considering reactive gliosis as an on/off mechanism with neurodegenerative consequences in the brain. Having in mind that brain ischemia induce a dramatic HMGB-1 release from necrotic neurons, we dissected here the HMGB-1 effects on astrocytes, microglia and primary neurons. Our results showed that purified primary cortical neurons exposed to HMGB-1 presented an increase in the number of synaptic puncta per neuron without significative increase in the MTT release or evidences of nuclear alterations with DAPI. On the other hand, HMGB-1 direct application on astrocytes induced NF-kB activation but lesser expression of proinflammatory genes such as iNOS compared with LPS exposure. On microglia we observed that HMGB-1 induced M2 profile genes and TREM-2 expression. Conditioned medium from HMGB-1 exposed astrocytes also showed synaptogenic and pro-survival effects on neurons and was anti-inflammatory in microglia. Finally, HMGB-1 effects were dependent of TLR2 but not TLR4 expression as showed in glial cultures from TLR-2 or -4 knock out mice and NF-kB dependent as they were blocked with BAY. We conclude that DAMP HMGB-1 induces innate immunity activation and reactive gliosis but without showing astroglial polarization to the proinflammatory-neurodegenerative profile and probably facilitating neuronal survival.