Tristetraprolin expression by keratinocytes controls local and systemic inflammation
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
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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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 7

Loss of tristetraprolin expression by keratinocytes leads to the spontaneous development of local and systemic inflammation.

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Loss of tristetraprolin expression by keratinocytes leads to the spontan...
Zfp36ΔEP (n = 17), Zfp36–/– (n = 7), and Zfp36ΔEPTnfΔEP mice (n = 7) and their respective littermate controls, Zfp36flfl (n = 17), Zfp36+/+ (n = 7), and Zfp36fl/flTnf fl/fl mice (n = 4), were monitored weekly for clinical features. (A) Phenotypical presentation: macroscopic views of representative Zfp36ΔEP, Zfp36fl/fl, and Zfp36–/– mice, showing, from left to right, neck skin, tail, front paw, and back paw. (B) Incidence of skin lesions. (C) Incidence of arthritis. (D and E) Weight curves. (F–H) Features of skin inflammation of 10- to 12-month-old male mice. (F) Histological view of MGG-stained section of upper thoracic skin samples (representative of 17 animals by group). (G) Proportion of neutrophils and (H) IL-17A–producing cells in the skin of Zfp36ΔEP (n = 13) and Zfp36fl/fl (n = 10) mice. (I–K) Characteristics of joint inflammation. (I) Histological view of MGG-stained section of a front paw of 10- to 12-month-old male mice. Arrows indicate the entheseal regions (representative of 17 animals by group). (J) High-resolution CT scan and (K) PET-CT scan of the front paw of 6-month-old male mice injected with [18F]-FDG (1 representative of 4 mice). Arrows indicate bone disruption. (L) G-CSF levels in the serum, (M) proportion of myeloid cells (CD45+CD19–CD3–CD11b+) in the spleen, and (N) N-GAL levels in the sera (note the log scale for y axis) of Zfp36ΔEP (n = 7) and Zfp36fl/fl (n = 10) mice or Zfp36+/+ (n = 9) and Zfp36–/– (n = 14) mice at 10 to 12 months old. Each dot represents data from an individual mouse. Results are given as mean ± SEM. Statistical significance (*P < 0.05, **P < 0.01, ***P < 0.001) was assessed by 2-tailed Mann-Whitney compared with the Zfp36fl/fl mock group (if not specified) (**P < 0.01, ***P < 0.001, ****P < 0.0001). Results are representative of 2 experiments (see also Supplemental Figure 5). Original magnification: ×200 (F and I).