Apoptotic cell-induced AhR activity is required for immunological tolerance and suppression of systemic lupus erythematosus in mice and humans

Nature Immunology
Rahul ShindeTracy L McGaha

Abstract

The transcription factor AhR modulates immunity at multiple levels. Here we report that phagocytes exposed to apoptotic cells exhibited rapid activation of AhR, which drove production of the cytokine IL-10. Activation of AhR was dependent on interactions between apoptotic-cell DNA and the pattern-recognition receptor TLR9 that was required for the prevention of immune responses to DNA and histones in vivo. Moreover, disease progression in mouse systemic lupus erythematosus (SLE) correlated with strength of the AhR signal, and the disease course could be altered by modulation of AhR activity. Deletion of AhR in the myeloid lineage caused systemic autoimmunity in mice, and an enhanced AhR transcriptional signature correlated with disease in patients with SLE. Thus, AhR activity induced by apoptotic cell phagocytes maintains peripheral tolerance.

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Datasets Mentioned

BETA
PRJEB19473

Methods Mentioned

BETA
nuclear translocation
flow cytometry
immunoprecipitation
ELISA
PCR
transgenic
PMA
electron microscopy
lavage
thermal dissociation

Software Mentioned

QIAGEN
TreeStar
bedtools multibamcov
GraphPad
FlowJo
Ensembl Genes
edgeR
Image
STAR
fastq

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