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 H 2 O 2 -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 that PDCD4 may serve as a hub regulatory molecule that simultaneously promotes the microglial inflammatory activation and the oxidative stress-induced neuronal apoptosis within CNS. The microglial PDCD4-MAPK-NF-κB positive feedback loop may act as pivotal signaling for neuroinflammation which subsequently exaggerates neuronal injury, and thus may become a potential therapeutic target for neuroinflammatory diseases.

Microglial Pdcd4 deficiency mitigates neuroinflammation-associated depression via facilitating Daxx mediated PPARγ/IL-10 signaling

“…Therefore, digging out the upstream regulatory mechanism for Pdcd4 expression helps us to uncover diverse re ections of brain areas on stress. Recently report found LPS required the MAPK/NF-κB signaling activation to boost Pdcd4 expression in microglia, perhaps digging out the NF-κB signaling response pattern during the LPS challenge will help us to answer that question [21]. Overall, we discovered only microglial Pdcd4 of the PFC was responsible for LPS-related depressive-like behavior, uncovering the diverse functions of Pdcd4 in nerve cells and brain regions, especially the immunoregulation role of Pdcd4 in PFC of the neuroin ammation associated depression.…”

Salidroside protects against intestinal barrier dysfunction in septic mice by regulating IL‑17 to block the NF‑κB and p38 MAPK signaling pathways

“…It has been reported that glucosamine attenuates lung injury and inflammation by suppressing the MAPK and NF-κB activation (51) and maresin 1 alleviates acute kidney injury in septic mice by blocking the NF-κB/STAT3/MAPK pathways (52). It is also reported that MAPK/NF-κB serves important roles in the inflammatory response and apoptosis regulation (53)(54)(55). Increase of Bcl-2 or inhibition of caspases also lead to an elevated survival in animal models of sepsis (56).…”

MiR-93-5p inhibits retinal neurons apoptosis by regulating PDCD4 in acute ocular hypertension model

“…PDCD4 is a regulatory factor and can increase apoptosis. PDCD4 might serve as a hub regulatory molecule that promoted neuronal apoptosis within central nervous system under neuroinflammatory conditions ( 43 ). PDCD4 facilitated lung tumor cell apoptosis by inhibiting p62-Nrf2 signaling pathway and up-regulating Keap1 expression ( 44 ).…”