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Autophagy. 2016 Aug 2;12(8):1240-58. doi: 10.1080/15548627.2016.1179405. Epub 2016 May 12.

TFEB and TFE3 cooperate in the regulation of the innate immune response in activated macrophages.

Author information

1
a Department of Molecular and Human Genetics , Baylor College of Medicine , Houston , TX , USA.
2
b Jan and Dan Duncan Neurological Research Institute, Texas Children Hospital , Houston , TX , USA.
3
c Cell Biology and Physiology Center, National Heart, Lung, and Blood Institute, National Institutes of Health , Bethesda , MD , USA.
4
d Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health , Bethesda , MD , USA.
5
e Telethon Institute of Genetics and Medicine (TIGEM) , Naples , Italy.
6
f Medical Genetics, Department of Translational Medicine, Federico II University , Naples , Italy.

Abstract

The activation of transcription factors is critical to ensure an effective defense against pathogens. In this study we identify a critical and complementary role of the transcription factors TFEB and TFE3 in innate immune response. By using a combination of chromatin immunoprecipitation, CRISPR-Cas9-mediated genome-editing technology, and in vivo models, we determined that TFEB and TFE3 collaborate with each other in activated macrophages and microglia to promote efficient autophagy induction, increased lysosomal biogenesis, and transcriptional upregulation of numerous proinflammatory cytokines. Furthermore, secretion of key mediators of the inflammatory response (CSF2, IL1B, IL2, and IL27), macrophage differentiation (CSF1), and macrophage infiltration and migration to sites of inflammation (CCL2) was significantly reduced in TFEB and TFE3 deficient cells. These new insights provide us with a deeper understanding of the transcriptional regulation of the innate immune response.

KEYWORDS:

Tfe3; Tfeb; autophagy; immune response; macrophages

PMID:
27171064
PMCID:
PMC4968228
DOI:
10.1080/15548627.2016.1179405
[Indexed for MEDLINE]
Free PMC Article

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