Bioenergetic state regulates innate inflammatory responses through the transcriptional co-repressor CtBP

Yiguo Shen,Raymond A Swanson,Seok Joon Won,Angela M Minnella,David Kapfhamer,Yanting Chen,Ley Hian Low,Ji-Eun Kim,Stephen M Massa,Yong Huang

doi:10.1038/s41467-017-00707-0

Abstract

The innate inflammatory response contributes to secondary injury in brain trauma and other disorders. Metabolic factors such as caloric restriction, ketogenic diet, and hyperglycemia influence the inflammatory response, but how this occurs is unclear. Here, we show that glucose metabolism regulates pro-inflammatory NF-κB transcriptional activity through effects on the cytosolic NADH:NAD+ ratio and the NAD(H) sensitive transcriptional co-repressor CtBP. Reduced glucose availability reduces the NADH:NAD+ ratio, NF-κB transcriptional activity, and pro-inflammatory gene expression in macrophages and microglia. These effects are inhibited by forced elevation of NADH, reduced expression of CtBP, or transfection with an NAD(H) insensitive CtBP, and are replicated by a synthetic peptide that inhibits CtBP dimerization. Changes in the NADH:NAD+ ratio regulate CtBP binding to the acetyltransferase p300, and regulate binding of p300 and the transcription factor NF-κB to pro-inflammatory gene promoters. These findings identify a mechanism by which alterations in cellular glucose metabolism can influence cellular inflammatory responses.

Highlights

The innate inflammatory response contributes to secondary injury in brain trauma and other disorders
We show that changes in cytosolic NADH: NAD+ ratio influence inflammatory responses by regulating NF-κB transcriptional activity through a mechanism requiring C-terminal binding proteins (CtBP) dimerization
Our present findings demonstrate that CtBP couples metabolic state to the innate inflammatory response

Summary

Introduction

The innate inflammatory response contributes to secondary injury in brain trauma and other disorders Metabolic factors such as caloric restriction, ketogenic diet, and hyperglycemia influence the inflammatory response, but how this occurs is unclear. We show that glucose metabolism regulates pro-inflammatory NF-κB transcriptional activity through effects on the cytosolic NADH:NAD+ ratio and the NAD(H) sensitive transcriptional co-repressor CtBP. Changes in the NADH:NAD+ ratio regulate CtBP binding to the acetyltransferase p300, and regulate binding of p300 and the transcription factor NF-κB to pro-inflammatory gene promoters These findings identify a mechanism by which alterations in cellular glucose metabolism can influence cellular inflammatory responses. The early phase of this response involves release of pro-inflammatory cytokines, nitric oxide, and metalloproteinases, along with alterations in cell morphology and surface protein expression[1, 2] These responses are adaptive in the setting of infection, they can be deleterious in non-infectious injuries such as stroke and head trauma. Increased NADH levels promote the formation of CtBP dimers and higher order oligomers, and thereby modulate CtBP association with its binding partners[26]

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