TY - JOUR
T1 - Tristetraprolin expression by keratinocytes controls local and systemic inflammation
AU - Andrianne, Mathieu
AU - Assabban, Assiya
AU - La, Caroline
AU - Mogilenko, Denis
AU - Salle, Delphine Staumont
AU - Fleury, Sébastien
AU - Doumont, Gilles
AU - Van Simaeys, Gaëtan
AU - Nedospasov, Sergei A.
AU - Blackshear, Perry J.
AU - Dombrowicz, David
AU - Goriely, Stanislas
AU - Van Maele, Laurye
N1 - Publisher Copyright:
© 2017 American Society for Clinical Investigation. All rights reserved.
PY - 2017
Y1 - 2017
N2 - Tristetraprolin (TTP, encoded by the Zfp36 gene) regulates the mRNA stability of several important cytokines. Due to the critical role of this RNA-binding protein in the control of inflammation, TTP deficiency leads to the spontaneous development of a complex inflammatory syndrome. So far, this phenotype has been largely attributed to dysregulated production of TNF and IL-23 by myeloid cells, such as macrophages or DCs. Here, we generated mice with conditional deletion of TTP in keratinocytes (Zfp36fl/flK14-Cre mice, referred to herein as Zfp36ΔEP mice). Unlike DC-restricted (CD11c-Cre) or myeloid cell–restricted (LysM-Cre) TTP ablation, these mice developed exacerbated inflammation in the imiquimod-induced psoriasis model. Furthermore, Zfp36ΔEP mice progressively developed a spontaneous pathology with systemic inflammation, psoriatic-like skin lesions, and dactylitis. Finally, we provide evidence that keratinocyte-derived TNF production drives these different pathological features. In summary, these findings expand current views on the initiation of psoriasis and related arthritis by revealing the keratinocyte-intrinsic role of TTP.
AB - Tristetraprolin (TTP, encoded by the Zfp36 gene) regulates the mRNA stability of several important cytokines. Due to the critical role of this RNA-binding protein in the control of inflammation, TTP deficiency leads to the spontaneous development of a complex inflammatory syndrome. So far, this phenotype has been largely attributed to dysregulated production of TNF and IL-23 by myeloid cells, such as macrophages or DCs. Here, we generated mice with conditional deletion of TTP in keratinocytes (Zfp36fl/flK14-Cre mice, referred to herein as Zfp36ΔEP mice). Unlike DC-restricted (CD11c-Cre) or myeloid cell–restricted (LysM-Cre) TTP ablation, these mice developed exacerbated inflammation in the imiquimod-induced psoriasis model. Furthermore, Zfp36ΔEP mice progressively developed a spontaneous pathology with systemic inflammation, psoriatic-like skin lesions, and dactylitis. Finally, we provide evidence that keratinocyte-derived TNF production drives these different pathological features. In summary, these findings expand current views on the initiation of psoriasis and related arthritis by revealing the keratinocyte-intrinsic role of TTP.
UR - http://www.scopus.com/inward/record.url?scp=85041047378&partnerID=8YFLogxK
U2 - 10.1172/jci.insight.92979
DO - 10.1172/jci.insight.92979
M3 - Article
C2 - 28570274
AN - SCOPUS:85041047378
SN - 0021-9738
VL - 2
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 11
M1 - e92979
ER -