Tristetraprolin expression by keratinocytes controls local and systemic inflammation
Mathieu Andrianne, … , Stanislas Goriely, Laurye Van Maele
Mathieu Andrianne, … , Stanislas Goriely, Laurye Van Maele
Published June 2, 2017
Citation Information: JCI Insight. 2017;2(11):e92979. https://doi.org/10.1172/jci.insight.92979.
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Research Article Dermatology Inflammation

Tristetraprolin expression by keratinocytes controls local and systemic inflammation

Abstract

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.

Authors

Mathieu Andrianne, Assiya Assabban, Caroline La, Denis Mogilenko, Delphine Staumont Salle, Sébastien Fleury, Gilles Doumont, Gaëtan Van Simaeys, Sergei A. Nedospasov, Perry J. Blackshear, David Dombrowicz, Stanislas Goriely, Laurye Van Maele

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Figure 1

Loss of tristetraprolin increases the severity of imiquimod-induced skin lesions.

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Loss of tristetraprolin increases the severity of imiquimod-induced skin...
Zfp36-deficient mice (Zfp36–/–) and their littermates (Zfp36+/+) were treated topically with imiquimod over 5 consecutive days (n = 5) or not (n = 3). Skin samples were collected 4 hours after the last application for analysis of epidermal thickness by histology (A), cell recruitment by flow cytometry (B), cytokine expression by intracellular protein staining (C), or transcript levels by RTqPCR (D and E). (A) Representative macroscopic images of the abdomen via MGG staining of skin sections (original magnification, ×200) from 13 mock Zfp36+/+, 21 imiquimod-treated Zfp36+/+, 13 mock Zfp36–/–, and 22 imiquimod-treated Zfp36–/– mice; Ki67 immunostaining (labeling index, n = 3 by group); and epidermal thickness. (B) Representative FACS plots and manual gating strategy for neutrophil and monocyte populations as well as neutrophil (CD45+CD19–CD3–CD11b+Ly6C+Ly6G+) and monocyte (CD45+CD19–CD3–CD11b+Ly6C+Ly6G–) recruitment into skin. Squares represent gates for neutrophil and monocyte populations. (C) IL-17A and IL-22 production by CD45+CD19–NK1.1–Gr1– cells and cytokine production by αβ T cells (CD45+CD19–NK1.1–Gr1–CD3+γδTCR–), γδ T cells (CD45+CD19–NK1.1–Gr1–CD3+γδTCR+), and innate lymphoid cells (ILCs) (CD45+CD19–NK1.1–Gr1–CD3–CD90+CD127+). Each dot represents total cytokine production in an individual mouse. (D and E) Total skin mRNA levels in mock-treated animals (D) (n = 7 mice by group, pooled from 2 experiments) and in imiquimod-treated animals (E) (n = 10 mice by group, pooled from 2 experiments) were normalized against Actb, Gapdh, and Hprt mRNA levels and expressed relative to the Zfp36+/+ mock group arbitrarily set to 1. Bars represent mean ± SEM. Statistical significance (*P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001) was assessed by 1-way ANOVA test with Bonferroni correction (A–C) or 2-tailed Mann-Whitney compared with mock-treated Zfp36+/+ group (D) or compared with imiquimod-treated Zfp36+/+ group (E). Results are representative of 5 independent experiments. Results observed with ear or dorsum were presented in Supplemental Figure 1A (see also Supplemental Figure 1).