Semaphorin 6D reverse signaling controls macrophage lipid metabolism and anti-inflammatory polarization

Nature Immunology
Sujin KangAtsushi Kumanogoh

Abstract

Polarization of macrophages into pro-inflammatory or anti-inflammatory states has distinct metabolic requirements, with mechanistic target of rapamycin (mTOR) kinase signaling playing a critical role. However, it remains unclear how mTOR regulates metabolic status to promote polarization of these cells. Here we show that an mTOR-Semaphorin 6D (Sema6D)-Peroxisome proliferator receptor γ (PPARγ) axis plays critical roles in macrophage polarization. Inhibition of mTOR or loss of Sema6D blocked anti-inflammatory macrophage polarization, concomitant with severe impairments in PPARγ expression, uptake of fatty acids, and lipid metabolic reprogramming. Macrophage expression of the receptor Plexin-A4 is responsible for Sema6D-mediated anti-inflammatory polarization. We found that a tyrosine kinase, c-Abl, which associates with the cytoplasmic region of Sema6D, is required for PPARγ expression. Furthermore, Sema6D is important for generation of intestinal resident CX3CR1hi macrophages and prevents development of colitis. Collectively, these findings highlight crucial roles for Sema6D reverse signaling in macrophage polarization, coupling immunity, and metabolism via PPARγ.

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Datasets Mentioned

BETA
GSE99047
GSE99046

Methods Mentioned

BETA
PCR
flow cytometry
RNA-seq
FACS
FCS
protein assay

Software Mentioned

XFe Wave
Ingenuity Pathway Analysis ( IPA
Bowtie2
Ingenuity Pathway Analysis
Cuffnorm
GraphPad PRISM
TopHat

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