SREBP1 Contributes to Resolution of Pro-inflammatory TLR4 Signaling by Reprogramming Fatty Acid Metabolism

Publication date: Available online 29 December 2016
Source:Cell Metabolism
Author(s): Yumiko Oishi, Nathanael J. Spann, Verena M. Link, Evan D. Muse, Tobias Strid, Chantle Edillor, Matthew J. Kolar, Takashi Matsuzaka, Sumio Hayakawa, Jenhan Tao, Minna U. Kaikkonen, Aaron F. Carlin, Michael T. Lam, Ichiro Manabe, Hitoshi Shimano, Alan Saghatelian, Christopher K. Glass
Macrophages play pivotal roles in both the induction and resolution phases of inflammatory processes. Macrophages have been shown to synthesize anti-inflammatory fatty acids in an LXR-dependent manner, but whether the production of these species contributes to the resolution phase of inflammatory responses has not been established. Here, we identify a biphasic program of gene expression that drives production of anti-inflammatory fatty acids 12–24 hr following TLR4 activation and contributes to downregulation of mRNAs encoding pro-inflammatory mediators. Unexpectedly, rather than requiring LXRs, this late program of anti-inflammatory fatty acid biosynthesis is dependent on SREBP1 and results in the uncoupling of NFκB binding from gene activation. In contrast to previously identified roles of SREBP1 in promoting production of IL1β during the induction phase of inflammation, these studies provide evidence that SREBP1 also contributes to the resolution phase of TLR4-induced gene activation by reprogramming macrophage lipid metabolism.

Graphical abstract

Teaser

Oishi and Spann et al. identify a biphasic macrophage gene expression program underlying anti-inflammatory fatty acid production following TLR4 activation. The late anti-inflammatory program is dependent on SREBP1. This is surprising given the known roles of SREBP1 in promoting IL1β production during the induction of inflammation and highlights its dual roles.


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