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Type of publication: Journal Article
Type of document: Full Paper

Year: 2017

Authors: Ebner, F; Sedlyarov, V; Tasciyan, S; Ivin, M; Kratochvill, F; Gratz, N; Kenner, L; Villunger, A; Sixt, M; Kovarik, P

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

Source: J Clin Invest. 2017; 127(6):2051-2065



Authors Vetmeduni Vienna:

Kenner Lukas

Vetmed Research Units
Institute of Pathology, Pathology of Laboratory Animals


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.

Keywords Pubmed: Animals
Apoptosisimmunology
Cells, Cultured
Gene Expression Regulationimmunology
Immunity, Innate
Mice, Inbred C57BL
Mice, Transgenic
Myeloid Cell Leukemia Sequence 1 Proteingeneticsmetabolism
Neutrophilsimmunologymetabolism
Protein Binding
RNA Stability
Streptococcal Infectionsimmunologymetabolism
Streptococcus pyogenesimmunology
Transcriptomeimmunology
Tristetraprolinphysiology

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