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

The Journal of Clinical Investigation
Florian EbnerPavel Kovarik

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 apopt...Continue Reading

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Datasets Mentioned

BETA
GSE77801

Methods Mentioned

BETA
RNA-seq
GTPases
PMA
RNA-IP
environmental stress
flow cytometry
PCR
PCRs
reverse transcription quantitative PCR
bone marrow collection

Software Mentioned

R
ggplot2 R package
R Project ( R Development Core Team
GraphPad
Ensembl Biomart
Database for Annotation , Visualization and Integrated Discove...
FlowJo X Star
CellQuest Pro
R Development Core Team
Mix

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