Microglial proliferation attenuates sickness responses in adult mice during endotoxin-induced inflammation.

We previously reported that the single peripheral administration of lipopolysaccharide (LPS) induced robust and transient microglial proliferation or increased the microglial population in the circumventricular organs (CVOs) and other regions, including the hypothalamus, medulla oblongata, and limbic system. However, the functional significance of an increased microglial population during endotoxin-induced inflammation remains unclear. The present study showed microglial proliferation in the mouse brain during inflammation induced by 50 mg/kg zymosan, 160 nmol/kg prostaglandin E2, and 5 mg/kg LPS. The inhibition of LPS-induced microglial proliferation with a continuous i.c.v. infusion of mitotic inhibitor cytosine arabinoside (AraC) caused persistent decreases in body weight and food and water intakes. The continuous infusion of AraC also prolonged LPS-induced sickness responses, such as lower locomotor activity and core body temperature. Collectively, the present results indicate that a transient increase in the microglial population is beneficial during endotoxin-induced inflammation in the mouse brain because it attenuates sickness responses.

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.