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Sensing of endogenous nucleic acids by ZBP1 induces keratinocyte necroptosis and skin inflammation

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Abstract
Aberrant detection of endogenous nucleic acids by the immune system can cause inflammatory disease. The scaffold function of the signaling kinase RIPK1 limits spontaneous activation of the nucleic acid sensor ZBP1. Consequently, loss of RIPK1 in keratinocytes induces ZBP1-dependent necroptosis and skin inflammation. Whether nucleic acid sensing is required to activate ZBP1 in RIPK1-deficient conditions and which immune pathways are associated with skin disease remained open questions. Using knock-in mice with disrupted ZBP1 nucleic acid–binding activity, we report that sensing of endogenous nucleic acids by ZBP1 is critical in driving skin pathology characterized by antiviral and IL-17 immune responses. Inducing ZBP1 expression by interferons triggers necroptosis in RIPK1-deficient keratinocytes, and epidermis-specific deletion of MLKL prevents disease, demonstrating that cell-intrinsic events cause inflammation. These findings indicate that dysregulated sensing of endogenous nucleic acid by ZBP1 can drive inflammation and may contribute to the pathogenesis of IL-17–driven inflammatory skin conditions such as psoriasis.
Keywords
Immunology, Immunology and Allergy, AICARDI-GOUTIERES-SYNDROME, CELL-DEATH, MUTATIONS, INNATE, HOMEOSTASIS, NECROSIS, RNA, IMMUNODEFICIENCY, APOPTOSIS, CASPASE-8

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MLA
Devos, Michael, et al. “Sensing of Endogenous Nucleic Acids by ZBP1 Induces Keratinocyte Necroptosis and Skin Inflammation.” JOURNAL OF EXPERIMENTAL MEDICINE, vol. 217, no. 7, 2020, doi:10.1084/jem.20191913.
APA
Devos, M., Tanghe, G., Gilbert, B., Dierick, E., Verheirstraeten, M., Nemegeer, J., … Maelfait, J. (2020). Sensing of endogenous nucleic acids by ZBP1 induces keratinocyte necroptosis and skin inflammation. JOURNAL OF EXPERIMENTAL MEDICINE, 217(7). https://doi.org/10.1084/jem.20191913
Chicago author-date
Devos, Michael, Giel Tanghe, Barbara Gilbert, Evelien Dierick, Maud Verheirstraeten, Josephine Nemegeer, Richard de Reuver, et al. 2020. “Sensing of Endogenous Nucleic Acids by ZBP1 Induces Keratinocyte Necroptosis and Skin Inflammation.” JOURNAL OF EXPERIMENTAL MEDICINE 217 (7). https://doi.org/10.1084/jem.20191913.
Chicago author-date (all authors)
Devos, Michael, Giel Tanghe, Barbara Gilbert, Evelien Dierick, Maud Verheirstraeten, Josephine Nemegeer, Richard de Reuver, Sylvie Lefebvre, Jolien De Munck, Jan Rehwinkel, Peter Vandenabeele, Wim Declercq, and Jonathan Maelfait. 2020. “Sensing of Endogenous Nucleic Acids by ZBP1 Induces Keratinocyte Necroptosis and Skin Inflammation.” JOURNAL OF EXPERIMENTAL MEDICINE 217 (7). doi:10.1084/jem.20191913.
Vancouver
1.
Devos M, Tanghe G, Gilbert B, Dierick E, Verheirstraeten M, Nemegeer J, et al. Sensing of endogenous nucleic acids by ZBP1 induces keratinocyte necroptosis and skin inflammation. JOURNAL OF EXPERIMENTAL MEDICINE. 2020;217(7).
IEEE
[1]
M. Devos et al., “Sensing of endogenous nucleic acids by ZBP1 induces keratinocyte necroptosis and skin inflammation,” JOURNAL OF EXPERIMENTAL MEDICINE, vol. 217, no. 7, 2020.
@article{8661649,
  abstract     = {{Aberrant detection of endogenous nucleic acids by the immune system can cause inflammatory disease. The scaffold function of the signaling kinase RIPK1 limits spontaneous activation of the nucleic acid sensor ZBP1. Consequently, loss of RIPK1 in keratinocytes induces ZBP1-dependent necroptosis and skin inflammation. Whether nucleic acid sensing is required to activate ZBP1 in RIPK1-deficient conditions and which immune pathways are associated with skin disease remained open questions. Using knock-in mice with disrupted ZBP1 nucleic acid–binding activity, we report that sensing of endogenous nucleic acids by ZBP1 is critical in driving skin pathology characterized by antiviral and IL-17 immune responses. Inducing ZBP1 expression by interferons triggers necroptosis in RIPK1-deficient keratinocytes, and epidermis-specific deletion of MLKL prevents disease, demonstrating that cell-intrinsic events cause inflammation. These findings indicate that dysregulated sensing of endogenous nucleic acid by ZBP1 can drive inflammation and may contribute to the pathogenesis of IL-17–driven inflammatory skin conditions such as psoriasis.}},
  articleno    = {{e20191913}},
  author       = {{Devos, Michael and Tanghe, Giel and Gilbert, Barbara and Dierick, Evelien and Verheirstraeten, Maud and Nemegeer, Josephine and de Reuver, Richard and Lefebvre, Sylvie and De Munck, Jolien and Rehwinkel, Jan and Vandenabeele, Peter and Declercq, Wim and Maelfait, Jonathan}},
  issn         = {{0022-1007}},
  journal      = {{JOURNAL OF EXPERIMENTAL MEDICINE}},
  keywords     = {{Immunology,Immunology and Allergy,AICARDI-GOUTIERES-SYNDROME,CELL-DEATH,MUTATIONS,INNATE,HOMEOSTASIS,NECROSIS,RNA,IMMUNODEFICIENCY,APOPTOSIS,CASPASE-8}},
  language     = {{eng}},
  number       = {{7}},
  pages        = {{14}},
  title        = {{Sensing of endogenous nucleic acids by ZBP1 induces keratinocyte necroptosis and skin inflammation}},
  url          = {{http://dx.doi.org/10.1084/jem.20191913}},
  volume       = {{217}},
  year         = {{2020}},
}

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