TY - JOUR
T1 - Apoptotic cell-induced AhR activity is required for immunological tolerance and suppression of systemic lupus erythematosus in mice and humans article
AU - Shinde, Rahul
AU - Hezaveh, Kebria
AU - Halaby, Marie Jo
AU - Kloetgen, Andreas
AU - Chakravarthy, Ankur
AU - Da Silva Medina, Tiago
AU - Deol, Reema
AU - Manion, Kieran P.
AU - Baglaenko, Yuriy
AU - Eldh, Maria
AU - Lamorte, Sara
AU - Wallace, Drew
AU - Chodisetti, Sathi Babu
AU - Ravishankar, Buvana
AU - Liu, Haiyun
AU - Chaudhary, Kapil
AU - Munn, David H.
AU - Tsirigos, Aristotelis
AU - Madaio, Michael
AU - Gabrielsson, Susanne
AU - Touma, Zahi
AU - Wither, Joan
AU - De Carvalho, Daniel D.
AU - McGaha, Tracy L.
N1 - Funding Information:
We thank F. Barrat (Weill Cornell College of Medicine) for the TLR inhibitor and control oligonucleotides; M. Shlomchik, A. Marinov and Z. Rahman for assistance with the analysis of SLE-prone mice; N. Winegarden and the Princess Margaret Genomics Centre for assistance with sequence analysis; K. Hultenby and B. Calvieri for performing electron microscopy; J.C. Zuniga-Pflucker for advice during development of the research report; M. Butler for assistance with the acquisition of PBMCs from healthy control subjects; and P. Ohashi and D. Brooks for reading and critiquing the manuscript. Supported by the US National Institutes of Health (AI105500, AR067763 and CA190449), the Medicine by Design/Canada First Research Excellence Fund (T.L.M.), the Swedish Medical Research Council and the Karolinska Institute (S.G.).
Publisher Copyright:
© 2018 The Author(s).
PY - 2018/6/1
Y1 - 2018/6/1
N2 - 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.
AB - 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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U2 - 10.1038/s41590-018-0107-1
DO - 10.1038/s41590-018-0107-1
M3 - Article
C2 - 29760532
AN - SCOPUS:85046907069
VL - 19
SP - 571
EP - 582
JO - Nature Immunology
JF - Nature Immunology
SN - 1529-2908
IS - 6
ER -