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

Rahul Shinde; Kebria Hezaveh; Marie Jo Halaby; Andreas Kloetgen; Ankur Chakravarthy; Tiago da Silva Medina; Reema Deol; Kieran P Manion; Yuriy Baglaenko; Maria Eldh; Sara Lamorte; Drew Wallace; Sathi Babu Chodisetti; Buvana Ravishankar; Haiyun Liu; Kapil Chaudhary; David H Munn; Aristotelis Tsirigos; Michael Madaio; Susanne Gabrielsson; Zahi Touma; Joan Wither; Daniel D De Carvalho; Tracy L McGaha

doi:10.1038/s41590-018-0107-1

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

Nat Immunol. 2018 Jun;19(6):571-582. doi: 10.1038/s41590-018-0107-1. Epub 2018 May 14.

Authors

Rahul Shinde^{1

2}, Kebria Hezaveh^{1

2}, Marie Jo Halaby^{1

2}, Andreas Kloetgen³, Ankur Chakravarthy⁴, Tiago da Silva Medina¹, Reema Deol¹, Kieran P Manion^{2

5}, Yuriy Baglaenko^{2

5}, Maria Eldh⁶, Sara Lamorte^{1

2}, Drew Wallace¹, Sathi Babu Chodisetti⁷, Buvana Ravishankar⁸, Haiyun Liu⁹, Kapil Chaudhary¹⁰, David H Munn¹¹, Aristotelis Tsirigos^{3

12

13}, Michael Madaio¹⁴, Susanne Gabrielsson⁶, Zahi Touma^{15

16

17}, Joan Wither^{2

5

17}, Daniel D De Carvalho^{1

4}, Tracy L McGaha^{18

19}

Affiliations

¹ Tumor Immunotherapy Program, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
² Department of Immunology, University of Toronto, Toronto, ON, Canada.
³ Department of Pathology, New York University School of Medicine, New York, NY, USA.
⁴ Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
⁵ Krembil Research Institute, University Health Network, Toronto, ON, Canada.
⁶ Department of Medicine, Unit for Immunology and Allergy, Karolinska Institute, Stockholm, Sweden.
⁷ Department of Immunology, Pennsylvania State University School of Medicine, Hershey, PA, USA.
⁸ Department of Cancer Immunology, Genentech, San Francisco, CA, USA.
⁹ Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁰ Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
¹¹ Department of Paediatrics, Medical College of Georgia, Augusta, GA, USA.
¹² Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, New York, NY, USA.
¹³ Applied Bioinformatics Laboratories, New York University School of Medicine, New York, NY, USA.
¹⁴ Department of Medicine, Medical College of Georgia, Augusta, GA, USA.
¹⁵ University of Toronto Lupus Clinic, University of Toronto, Toronto, ON, Canada.
¹⁶ Centre for Prognosis Studies in Rheumatic Diseases, Toronto Western Hospital, University Health Network, Toronto, ON, Canada.
¹⁷ Department of Medicine, University of Toronto, Toronto, ON, Canada.
¹⁸ Tumor Immunotherapy Program, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. tmcgaha@uhnresearch.ca.
¹⁹ Department of Immunology, University of Toronto, Toronto, ON, Canada. tmcgaha@uhnresearch.ca.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis / immunology*
Humans
Immune Tolerance / immunology*
Lupus Erythematosus, Systemic / immunology*
Macrophages / immunology*
Mice
Receptors, Aryl Hydrocarbon / immunology*
Signal Transduction / immunology
Toll-Like Receptor 9 / immunology

Substances

Receptors, Aryl Hydrocarbon
Toll-Like Receptor 9

Abstract

Publication types

MeSH terms

Substances

Grants and funding