Posttranscriptional control of the neutrophil transcriptome by tristetraprolin promotes neutrophil apoptosis and compromises host antimicrobial defense

Posttranscriptional regulation of mRNA levels in neutrophils and its consequences for immune responses are unexplored. By employing profiling of the neutrophil transcriptome we show that the mRNA-destabilizing protein tristetraprolin (TTP) limits the expression of hundreds of genes, including genes negatively regulating apoptosis. Elicited TTP-deficient neutrophils exhibited reduced apoptosis and were increased in numbers. The anti-apoptotic protein Mcl-1 was elevated in TTP-deficient neutrophils and Mcl1 mRNA was bound and destabilized by TTP. Ablation of TTP in macrophages and neutrophils resulted in an improved defense and survival of mice during invasive infection with Streptococcus pyogenes. Mice lacking myeloid TTP prevented dissemination of bacteria and efficiently blunted systemic disease by massive but controlled neutrophil deployment. These data identify posttranscriptional control by TTP to restrict neutrophils and antimicrobial defense. Overall design: WT and TTPKO peritoneal neutrophils stimulated with LPS for 4 h. Each condition analyzed in three replicates

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