Neuron–Microglia Contacts Govern the PGE2 Tolerance through TLR4-Mediated de Novo Protein Synthesis

Author:

Kuo Hsing-ChunORCID,Lee Kam-Fai,Chen Shiou-LanORCID,Chiu Shu-Chen,Lee Li-Ya,Chen Wan-PingORCID,Chen Chin-Chu,Chu Chun-HsienORCID

Abstract

Cellular and molecular mechanisms of the peripheral immune system (e.g., macrophage and monocyte) in programming endotoxin tolerance (ET) have been well studied. However, regulatory mechanism in development of brain immune tolerance remains unclear. The inducible COX-2/PGE2 axis in microglia, the primary innate immune cells of the brain, is a pivotal feature in causing inflammation and neuronal injury, both in acute excitotoxic insults and chronic neurodegenerative diseases. This present study investigated the regulatory mechanism of PGE2 tolerance in microglia. Multiple reconstituted primary brain cells cultures, including neuron–glial (NG), mixed glial (MG), neuron-enriched, and microglia-enriched cultures, were performed and consequently applied to a treatment regimen for ET induction. Our results revealed that the levels of COX-2 mRNA and supernatant PGE2 in NG cultures, but not in microglia-enriched and MG cultures, were drastically reduced in response to the ET challenge, suggesting that the presence of neurons, rather than astroglia, is required for PGE2 tolerance in microglia. Furthermore, our data showed that neural contact, instead of its soluble factors, is sufficient for developing microglial PGE2 tolerance. Simultaneously, this finding determined how neurons regulated microglial PGE2 tolerance. Moreover, by inhibiting TLR4 activation and de novo protein synthesis by LPS-binding protein (LBP) manipulation and cycloheximide, our data showed that the TLR4 signal and de novo protein synthesis are necessary for microglia to develop PGE2 tolerance in NG cells under the ET challenge. Altogether, our findings demonstrated that neuron–microglia contacts are indispensable in emerging PGE2 tolerance through the regulation of TLR4-mediated de novo protein synthesis.

Funder

Ministry of Science and Technology

Publisher

MDPI AG

Subject

General Biochemistry, Genetics and Molecular Biology,Medicine (miscellaneous)

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