The RNA-binding protein tristetraprolin schedules apoptosis of pathogen-engaged neutrophils during bacterial infection

F. Ebner, V. Sedlyarov, S. Tasciyan, M. Ivin, F. Kratochvill, N. Gratz, L. Kenner, A. Villunger, M.K. Sixt, P. Kovarik, The Journal of Clinical Investigation 127 (2017) 2051–2065.


Journal Article | Published | English

Scopus indexed
Author
Ebner, Florian; Sedlyarov, Vitaly; Tasciyan, SarenIST Austria; Ivin, Masa; Kratochvill, Franz; Gratz, Nina; Kenner, Lukas; Villunger, Andreas; Sixt, Michael KIST Austria ; Kovarik, Pavel
Department
Abstract
Protective responses against pathogens require a rapid mobilization of resting neutrophils and the timely removal of activated ones. Neutrophils are exceptionally short-lived leukocytes, yet it remains unclear whether the lifespan of pathogen-engaged neutrophils is regulated differently from that in the circulating steady-state pool. Here, we have found that under homeostatic conditions, the mRNA-destabilizing protein tristetraprolin (TTP) regulates apoptosis and the numbers of activated infiltrating murine neutrophils but not neutrophil cellularity. Activated TTP-deficient neutrophils exhibited decreased apoptosis and enhanced accumulation at the infection site. In the context of myeloid-specific deletion of Ttp, the potentiation of neutrophil deployment protected mice against lethal soft tissue infection with Streptococcus pyogenes and prevented bacterial dissemination. Neutrophil transcriptome analysis revealed that decreased apoptosis of TTP-deficient neutrophils was specifically associated with elevated expression of myeloid cell leukemia 1 (Mcl1) but not other antiapoptotic B cell leukemia/ lymphoma 2 (Bcl2) family members. Higher Mcl1 expression resulted from stabilization of Mcl1 mRNA in the absence of TTP. The low apoptosis rate of infiltrating TTP-deficient neutrophils was comparable to that of transgenic Mcl1-overexpressing neutrophils. Our study demonstrates that posttranscriptional gene regulation by TTP schedules the termination of the antimicrobial engagement of neutrophils. The balancing role of TTP comes at the cost of an increased risk of bacterial infections.
Publishing Year
Date Published
2017-06-01
Journal Title
The Journal of Clinical Investigation
Acknowledgement
This work was supported by grants from the Austrian Science Fund (FWF) (P27538-B21, I1621-B22, and SFB 43, to PK); by funding from the European Union Seventh Framework Programme Marie Curie Initial Training Networks (FP7-PEOPLE-2012-ITN) for the project INBIONET (INfection BIOlogy Training NETwork under grant agreement PITN-GA-2012-316682; and by a joint research cluster initiative of the University of Vienna and the Medical University of Vienna.
Volume
127
Issue
6
Page
2051 - 2065
ISSN
IST-REx-ID
679

Cite this

Ebner F, Sedlyarov V, Tasciyan S, et al. The RNA-binding protein tristetraprolin schedules apoptosis of pathogen-engaged neutrophils during bacterial infection. The Journal of Clinical Investigation. 2017;127(6):2051-2065. doi:10.1172/JCI80631
Ebner, F., Sedlyarov, V., Tasciyan, S., Ivin, M., Kratochvill, F., Gratz, N., … Kovarik, P. (2017). The RNA-binding protein tristetraprolin schedules apoptosis of pathogen-engaged neutrophils during bacterial infection. The Journal of Clinical Investigation, 127(6), 2051–2065. https://doi.org/10.1172/JCI80631
Ebner, Florian, Vitaly Sedlyarov, Saren Tasciyan, Masa Ivin, Franz Kratochvill, Nina Gratz, Lukas Kenner, Andreas Villunger, Michael K Sixt, and Pavel Kovarik. “The RNA-Binding Protein Tristetraprolin Schedules Apoptosis of Pathogen-Engaged Neutrophils during Bacterial Infection.” The Journal of Clinical Investigation 127, no. 6 (2017): 2051–65. https://doi.org/10.1172/JCI80631.
F. Ebner et al., “The RNA-binding protein tristetraprolin schedules apoptosis of pathogen-engaged neutrophils during bacterial infection,” The Journal of Clinical Investigation, vol. 127, no. 6, pp. 2051–2065, 2017.
Ebner F, Sedlyarov V, Tasciyan S, Ivin M, Kratochvill F, Gratz N, Kenner L, Villunger A, Sixt MK, Kovarik P. 2017. The RNA-binding protein tristetraprolin schedules apoptosis of pathogen-engaged neutrophils during bacterial infection. The Journal of Clinical Investigation. 127(6), 2051–2065.
Ebner, Florian, et al. “The RNA-Binding Protein Tristetraprolin Schedules Apoptosis of Pathogen-Engaged Neutrophils during Bacterial Infection.” The Journal of Clinical Investigation, vol. 127, no. 6, American Society for Clinical Investigation, 2017, pp. 2051–65, doi:10.1172/JCI80631.
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