Depletion of microglia and macrophages with clodronate liposomes attenuates zymosan-induced Fos expression and hypothermia in the adult mouse.

Toll-like receptor 2 (TLR2) recognizes a wide range of microbial molecules and plays critical roles in the initiation of innate immune responses. In the present study, we aimed to investigate whether the depletion of microglia and macrophages with clodronate liposomes (Clod-Lips) attenuates the activation of mouse brain circuits for TLR2-mediated inflammation and hypothermia. The peripheral administration of the TLR2 agonist zymosan induced nuclear factor-κB activation in microglia and macrophages and Fos expression in astrocytes/tanycytes and neurons in the circumventricular organs (CVOs). The depletion of microglia and macrophages with Clod-Lips markedly decreased zymosan-induced Fos expression in astrocytes/tanycytes and neurons in the CVOs. The treatment with Clod-Lips significantly attenuated zymosan-induced hypothermia. These results indicate that microglia and macrophages in the CVOs participate in the initiation and transmission of inflammatory responses after the peripheral administration of zymosan.

Activation of microglia and macrophages in the circumventricular organs of the mouse brain during TLR2-induced fever and sickness responses.

Toll-like receptor 2 (TLR2) recognizes cell wall components from Gram-positive bacteria. Until now, however, little has been known about the significance of brain TLR2 in controlling inflammation and thermoregulatory responses during systemic Gram-positive bacterial infection. In the present study, the TLR2 immunoreactivity was seen to be prominent in the microglia/macrophages of the circumventricular organs (CVOs) of the mouse brain. The intraperitoneal injection of Pam3CSK4, a TLR2 agonist, induced nuclear factor-κ B activation in the microglia/macrophages of the CVOs. The injection of Pam3CSK4 also produced the expression of Fos at astrocytes and neurons in the CVOs and the regions neighboring the CVOs. The Pam3CSK4 injection induced fever and sickness responses. Pretreatment with lipopolysaccharide, a TLR4 agonist, augmented the Pam3CSK4-induced fever together with the increased TLR2 immunoreactivity. These results indicate that the TLR2 in microglia/macrophages of the CVOs are possibly associated with initiating and transmitting inflammatory responses in the brain.

TLR4 in circumventricular neural stem cells is a negative regulator for thermogenic pathways in the mouse brain.

Toll-like receptor 4 (TLR4) recognizes bacteria-derived lipopolysaccharide (LPS). In the present study, we found that intraperitoneal LPS activated nuclear factor-κ B (NF-κB) in TLR4-expressing neural stem cells (NSCs) in the circumventricular brain regions of mice. Intracerebroventricular preadministration of low-dose TLR4 inhibitors significantly augmented hyperthermia together with the inhibition of NF-κB activation in circumventricular NSCs of LPS-inflamed animals. Moreover, intracerebroventricular administration of high-dose TLR4 inhibitors induced hyperthermia and Fos activation in circumventricular NSCs and hypothalamic neurons. These results suggest that TLR4 on circumventricular NSCs functions as a central regulator for thermogenesis under inflamed and normal conditions.