Poly(I:C) promotes TNFa/TNFR1-dependent oligodendrocyte death in mixed glial cultures

Steelman, Andrew J; Li, Jianrong

Our above data demonstrate that stimulation of mixed glial cultures with poly(I:C), a mimic of double-stranded RNA viral infection, is toxic to preOLs. Similar to what we have shown previously after LPS challenge [24, 25] , the toxicity triggered by poly(I:C) is also dependent on the TNFα/TNFR1 pathway. Because ligation of other TLRs on microglia can also induce TNFα production [31] , we questioned whether stimulation of mixed glia with additional TLR ligands could also result in reduced preOL viability. Indeed, stimulation of mixed cultures with TLR1/2 agonist Pam3CSK4 or TLR7/8 agonist R848 triggered TNFα production (Table 1) with LPS stimulation causing significantly more TNFα production than any other TLR agonists tested. All tested TLR agonists resulted in a significant reduction in O4 + cell viability that was most pronounced following treatment with LPS and R848 ( Figure 6 ). Together, these data support a role for aberrant TNFα production in mediating preOL death.