Microglia and Astrocyte Activation by Toll-Like Receptor Ligands: Modulation by PPAR-γAgonists

Abstract

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-γ 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-γ agonists to modulate glial activation. For example, 15d-PGJ2 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-PGJ2, 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.

Critical Role of TLR4 Response in the Activation of Microglia Induced by Ethanol

“…Furthermore, our results strongly support the notion that TLR4 receptors are crucial in ethanol-induced inflammatory events in microglia since ethanol induces neither MAPK phosphorylation nor the production of TNF-␣ in microglial cells of TLR4-deficient mice. Several studies have demonstrated that endogenous molecules, such as injured and dying cells, can activate TLR4 via MyD88-dependent pathways during brain damage (43,44). Under our in vitro conditions, however, this possibility did not seem to occur, because the supernatant of the ethanol-treated TLR4 Ϫ/Ϫ microglia did not induce the TLR4 signaling in wild-type microglia.…”

“…Finally, as microglia can be activated by endogenous TLR ligands (43,44), we evaluated the possibility of ethanol being able to release endogenous TLR4 ligands from microglia, which could, on TLR4 wild-type microglia, act in an autocrine-or a paracrinelike manner, leading to the activation of the TLR4 pathway. To investigate this possibility, the supernatants from TLR4 Ϫ/Ϫ microglia treated with or without 50 mM ethanol for 24 and 48 h were added to wild-type microglia plates in the presence or absence of PMBS, and P-ERK and iNOS levels were assessed after 30 min and 3 h of incubation, respectively.…”

Physiology of Microglia

“…The Toll-like receptors are widely expressed in microglia. Structural (mRNA and protein detection) and functional (responses to agonists) evidence was presented for TLR1 to 9 receptors, for coreceptors, like CD14 and for TLR signaling components, such as MyD88 in the mouse and human system by both in vitro and in vivo approaches (56,96,146,226,232,233,253,340,353,422,432,508,510,677,728,738,903,918).…”

New advances on glial activation in health and disease

“…TLRs, type I transmembrane receptors most commonly found in innate immune cells, are highly expressed in microglia and have also been observed in astrocytes [125] . Under resting physiological conditions, astrocytes express TLR3 [126] as well as low levels of TLR2, TLR4, TLR5, and TLR9 [127,128] . Binding of PAMPs to TLRs on astrocytes alters cytokine secretion, cytoskeletal protein expression, and adhesion [126] .…”