Microglia and astrocytes express numerous members of the
Toll-like receptor (TLR) family that are pivotal for recognizing conserved microbial motifs expressed by a wide array of pathogens. Despite the critical role for TLRs in pathogen recognition, when dysregulated these pathways can also exacerbate CNS tissue destruction. Therefore, a critical balance must be achieved to elicit sufficient immunity to combat CNS infectious insults and downregulate these responses to avoid pathological tissue damage. We performed a comprehensive survey on the efficacy of various
PPAR-gamma agonists to modulate proinflammatory mediator release from primary microglia and astrocytes in response to numerous TLR
ligands relevant to CNS
infectious diseases. The results demonstrated differential abilities of select
PPAR-gamma agonists to modulate glial activation. For example, 15d-PGJ(2) and
pioglitazone were both effective at reducing
IL-12 p40 release by TLR
ligand-activated glia, whereas CXCL2 expression was either augmented or inhibited by 15d-PGJ(2), effects that were dependent on the TLR
ligand examined.
Pioglitazone and
troglitazone demonstrated opposing actions on microglial CCL2 production that were TLR
ligand-dependent. Collectively, this information may be exploited to modulate the host immune response during
CNS infections to maximize host immunity while minimizing inappropriate bystander tissue damage that is often characteristic of such diseases.