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

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 article

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 GabrielssonZahi Touma, Joan Wither, Daniel D. De Carvalho, Tracy L. McGaha

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121 Scopus citations

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.

Original language	English (US)
Pages (from-to)	571-582
Number of pages	12
Journal	Nature Immunology
Volume	19
Issue number	6
DOIs	https://doi.org/10.1038/s41590-018-0107-1
State	Published - Jun 1 2018

ASJC Scopus subject areas

Immunology and Allergy
Immunology

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Shinde, R., Hezaveh, K., Halaby, M. J., Kloetgen, A., Chakravarthy, A., Da Silva Medina, T., Deol, R., Manion, K. P., Baglaenko, Y., Eldh, M., Lamorte, S., Wallace, D., Chodisetti, S. B., Ravishankar, B., Liu, H., Chaudhary, K., Munn, D. H., Tsirigos, A., Madaio, M., ... McGaha, T. L. (2018). Apoptotic cell-induced AhR activity is required for immunological tolerance and suppression of systemic lupus erythematosus in mice and humans article. Nature Immunology, 19(6), 571-582. https://doi.org/10.1038/s41590-018-0107-1

Shinde, R, Hezaveh, K, Halaby, MJ, Kloetgen, A, Chakravarthy, A, Da Silva Medina, T, Deol, R, Manion, KP, Baglaenko, Y, Eldh, M, Lamorte, S, Wallace, D, Chodisetti, SB, Ravishankar, B, Liu, H, Chaudhary, K, Munn, DH, Tsirigos, A, Madaio, M, Gabrielsson, S, Touma, Z, Wither, J, De Carvalho, DD & McGaha, TL 2018, 'Apoptotic cell-induced AhR activity is required for immunological tolerance and suppression of systemic lupus erythematosus in mice and humans article', Nature Immunology, vol. 19, no. 6, pp. 571-582. https://doi.org/10.1038/s41590-018-0107-1

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

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.",

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

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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.

PY - 2018/6/1

Y1 - 2018/6/1

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

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