Tristetraprolin expression by keratinocytes controls local and systemic inflammation

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

doi:10.1172/jci.insight.92979

Cited by 43 publications

(45 citation statements)

References 49 publications

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“…By studying transgenic mice with the deletion of tristetraprolin (TTP/Zfp36; a keratinocyte-specific gene), Andrianne et al [78] illustrate how TTP acts as an RNA-binding protein that downregulates the expression of genes that encode proinflammatory cytokines in the skin epidermis. Such mice developed a psoriasiform phenotype associated with a strong inflammatory reaction.…”

Section: Resultsmentioning

confidence: 99%

Psoriasis: Keratinocytes or Immune Cells – Which Is the Trigger?

2018

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Background: Psoriasis is a common, chronic inflammatory skin disorder, which can significantly impact quality of life. Despite major breakthroughs in our understanding of the pathogenesis of psoriasis, the chronological order of the underlying mechanisms leading to the development of psoriatic plaques remains to be completely understood. Summary: Although psoriasis is classically perceived as a T-cell disease, it is now well recognized that T lymphocytes do not function in exclusivity. This theory is supported by evidence from transgenic murine models that develop marked psoriasiform disease. In addition, immune cells and cytokines regulate both early and late events involved in the pathogenesis of psoriasis. Key Messages: Psoriasis is a complex disease – a dynamic interplay between immune cells, keratinocytes, and various other skin-resident cells, such as endothelial and immune cells. The contribution of each cell type is crucial in the initiation and maintenance phases of psoriatic alterations.

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Section: Resultsmentioning

confidence: 99%

Psoriasis: Keratinocytes or Immune Cells – Which Is the Trigger?

2018

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“…The LysM-Cre mouse model has successfully been used to study the role of specific genes in myeloid cells in the bone marrow (28), the lungs (29), the liver (30), the gut and the skin (31,32). However, LysM-cre does not seem to be effective in deleting genes in splenic myeloid cells during VL.…”

Section: Discussionmentioning

confidence: 99%

IRF-5 Expression in Myeloid Cells Is Required for Splenomegaly in L. donovani Infected Mice

et al. 2020

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Persistent Leishmania donovani infection is characterized by chronic inflammation, immune suppression, and splenomegaly. We have previously reported that the transcription factor interferon regulatory factor 5 (IRF-5) is largely responsible for inducing the inflammatory response and maintaining protective Th1 cells following L. donovani inoculation in mice. However, the cellular source responsible for these effects is yet unknown. In this study, we investigated the role of IRF-5 in myeloid cells during experimental visceral leishmaniasis (VL). First, we show that the LysM-Cre mouse model is not suited for investigating gene expression in splenic myeloid cells during experimental VL. Using the Cd11c-Cre mouse model, we demonstrate that Irf5 expression in CD11c + cells (monocytes, dendritic cells, activated macrophages) is essential for inducing splenomegaly and for recruiting myeloid cells to the spleen, but it is not required for the development or maintenance of parasite-specific IFNγ-producing CD4 T cells. CD11c-specific Irf5 −/− mice are more resistant to L. donovani infection, suggesting that the induction of splenomegaly is detrimental to the host.

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“…Our findings are in line with previous reports in other tissues. For instance, massive infiltration of neutrophils has been shown to occur in the skin of TTP KO mice subjected to psoriasis-like inflammation ( 30 ), whereas reduced airway neutrophilic infiltration was shown in mice genetically modified to express constitutively active endogenous unphosphorylated TTP following challenge with cigarette smoke ( 31 ).…”

Section: Discussionmentioning

confidence: 99%

“…Contribution of non-HPC-specific TTP toward modulation of inflammatory responses has also been suggested in previous reports. For instance, TTP regulation of TNF in keratinocytes, but not in myeloid or dendritic cells, was shown to protect mice from exacerbation of psoriasis-like pathology, development of spontaneous systemic inflammation, and dactylitis ( 30 ). Another study suggested a role of intestinal epithelial cell-specific TTP in exacerbation of acute colitis ( 49 ).…”

Section: Discussionmentioning

confidence: 99%

Tristetraprolin Overexpression in Non-hematopoietic Cells Protects Against Acute Lung Injury in Mice

Choudhary

Bathula

et al. 2020

Front. Immunol.

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Tristetraprolin (TTP) is a mRNA binding protein that binds to adenylate-uridylate-rich elements within the 3′ untranslated regions of certain transcripts, such as tumor necrosis factor ( Tnf ) mRNA, and increases their rate of decay. Modulation of TTP expression is implicated in inflammation; however, its role in acute lung inflammation remains unknown. Accordingly, we tested the role of TTP in lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice. LPS-challenged TTP-knockout (TTP KO ) mice, as well as myeloid cell-specific TTP-deficient (TTP myeKO ) mice, exhibited significant increases in lung injury, although these responses were more robust in the TTP KO . Mice with systemic overexpression of TTP (TTP ΔARE ) were protected from ALI, as indicated by significantly reduced neutrophilic infiltration, reduced levels of neutrophil chemoattractants, and histological parameters of ALI. Interestingly, while irradiated wild-type (WT) mice reconstituted with TTP KO hematopoietic progenitor cells (HPCs) showed exaggerated ALI, their reconstitution with the TTP ΔARE HPCs mitigated ALI. The reconstitution of irradiated TTP ΔARE mice with HPCs from either WT or TTP ΔARE donors conferred significant protection against ALI. In contrast, irradiated TTP ΔARE mice reconstituted with TTP KO HPCs had exaggerated ALI, but the response was milder as compared to WT recipients that received TTP KO HPCs. Finally, the reconstitution of irradiated TTP KO recipient mice with TTP ΔARE HPCs did not confer any protection to the TTP KO mice. These data together suggest that non-HPCs-specific overexpression of TTP within the lungs protects against ALI via downregulation of neutrophil chemoattractants and reduction in neutrophilic infiltration.

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Tristetraprolin expression by keratinocytes controls local and systemic inflammation

Cited by 43 publications

References 49 publications

Psoriasis: Keratinocytes or Immune Cells – Which Is the Trigger?

Psoriasis: Keratinocytes or Immune Cells – Which Is the Trigger?

IRF-5 Expression in Myeloid Cells Is Required for Splenomegaly in L. donovani Infected Mice

Tristetraprolin Overexpression in Non-hematopoietic Cells Protects Against Acute Lung Injury in Mice

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