PDCD4 Simultaneously Promotes Microglia Activation via PDCD4 –MAPK–NF-κB Positive Loop and Facilitates Neuron Apoptosis During Neuroinflammation

Abstract—Neuroinflammation and neuron injury are common features of the central nervous system (CNS) diseases. It is of great significance to identify their shared key regulatory molecules and thus explore the potential therapeutic targets. Programmed cell death factor 4 (PDCD4), an apoptosis-related molecule, extensively participates in tumorigenesis and inflammatory diseases, but its expression and biological function during CNS neuroinflammation remain unclear. In the present study, utilizing the lipopolysaccharide (LPS)-induced neuroinflammation model in mice, we reported an elevated expression of PDCD4 both in injured neurons and activated microglia of the inflamed brain. A similar change in PDCD4 expression was observed in vitro in the microglial activation model. Silencing PDCD4 by shRNA significantly inhibited the phosphorylation of MAPKs (p38, ERK, and JNK), prevented the phosphorylation and nuclear translocation of NF- κB p65, and thus attenuated the LPS-induced microglial inflammatory activation. Interestingly, LPS also required the MAPK/NF-κB signaling activation to boost PDCD4 expression in microglia, indicating the presence of a positive loop. Moreover, a persistent elevation of PDCD4 expression was detected in the H2O2-induced neuronal oxidative damage model. Knocking down PDCD4 significantly inhibited the expression of pro-apoptotic proteins BAX and Cleaved-PARP, suggesting the proapoptotic activity of PDCD4 in neurons. Taken together, our data indicated t...
Source: Inflammation - Category: Allergy & Immunology Source Type: research