Fenofibrate Inhibits LPS and Zymosan-induced Inflammatory Responses through Sonic Hedgehog in IMG Cells

Neuroinflammatory responses are strongly associated with the pathogenesis of progressive neurodegenerative conditions and mood disorders. Modulating microglial activation is a potential strategy for developing protective treatments for central nervous system (CNS)-related diseases. Fibrates, widely used in clinical practice as cholesterol-lowering medications, exhibit numerous biological activities, such as anticancer and antiinflammatory activities. However, the mechanisms underlying their beneficial effects on the CNS remain unclear.

This study investigated the mechanisms through which fibrates influence inflammatory and anti-inflammatory homeostasis in microglial cells.

Cell viability assay, nitric oxide measurement, Western blot analysis,, real-time PCR, and cell transfection were used in this study.

Fenofibrate, a well-known fibrate, reduced the production of nitric oxide and interleukin-6 and the expression of inducible nitric oxide synthase and cyclooxygenase-2 in microglial cells. It also inhibited the expression of various proinflammatory cytokines and chemokines, including tumor necrosis factor-ɑ and interleukin-1β, and chemokine (C-C) motif ligand 2 and chemokine (C-X-C motif) ligand 10. Notably, treatment of fenofibrate dramatically activated the sonic hedgehog (SHH) and sirtuin-1 (SIRT1). Furthermore, the inhibition of SHH or SIRT1 mitigated the anti-inflammatory effects of fenofibrate in IMG microglial cells.

Our findings suggest that fenofibrate may inhibit inflammatory responses by activating SIRT1 and SHH in IMG microglial cells. Our study suggests that fenofibrate or targeting SHH molecule is a promising therapeutic strategy for neuroinflammation-associated conditions. Further research with additional cell lines and in vivo models is needed to understand its therapeutic potential.