Microglia are macrophages that reside in the central nervous system. Aberrant activation of microglia and the ensuing inflammatory response are thought to contribute to pathology of neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases. Burguillos et al. investigated the mechanisms underlying microglial activation. Treatment of mouse microglia BV2 cells with lipopolysaccharide (LPS) induced cleavage of caspase-3 and increased activity of caspase-3 and caspase-7 (caspase-3/7). Caspases are serine proteases that are best characterized for their role as initiators and executioners of cell death, but LPS-treated cells did not appear to be undergoing cell death. Instead, they showed signs of activation, including increased abundance of proinflammatory molecules such as iNOS. Knocking down caspase-3 or caspase-7 by siRNA inhibited LPS-induced activation. LPS treatment of BV2 cells triggered cell death in cocultured mouse dopaminergic MN9D cells, and fewer MN9D cells died when caspase-3 or caspase-7 was silenced in BV2 cells before LPS treatment. Caspase-8 can activate caspase-3/7, and LPS treatment increased caspase-8 activity in BV2 cells, which required Toll-like receptor 4 (TLR4, a receptor that recognizes LPS). Activation of caspase-8 in BV2 cells was required for caspase-3/7 activity and production of proinflammatory molecules in response to LPS and other proinflammatory treatments. Activation of protein kinase C δ (PKCδ) by caspase-3/7–mediated cleavage was required for LPS-induced activation of BV2 cells. Injection of LPS into the substantia nigra of rats increased caspase-8 and caspase-3 activity, and pharmacological inhibition of caspase-3/7 prevented production of cytokines and proinflammatory molecules in response to LPS. In addition, LPS-induced increases in iNOS abundance were attenuated by coinjection of inhibitors of caspase-8, caspase-3/7, or PKCδ. Injection of mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces pathophysiology that resembles Parkinson’s disease, and pharmacological inhibition of caspase-8 conferred a modest degree of protection against MPTP-induced neuronal death. The abundance of cleaved caspase-3 or caspase-8 was increased in microglia in individuals with Alzheimer’s or Parkinson’s disease. Thus, caspase activation in microglia does not trigger cell death, but rather mediates microglial activation and inflammatory responses.
M. A. Burguillos, T. Deierborg, E. Kavanagh, A. Persson, N. Hajji, A. Garcia-Quintanilla, J. Cano, P. Brundin, E. Englund, J. L. Venero, B. Joseph, Caspase signalling controls microglia activation and neurotoxicity. Nature 472, 319–324 (2011). [PubMed]