@article{679,
  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.},
  author       = {Ebner, Florian and Sedlyarov, Vitaly and Tasciyan, Saren and Ivin, Masa and Kratochvill, Franz and Gratz, Nina and Kenner, Lukas and Villunger, Andreas and Sixt, Michael K and Kovarik, Pavel},
  issn         = {0021-9738},
  journal      = {The Journal of Clinical Investigation},
  number       = {6},
  pages        = {2051 -- 2065},
  publisher    = {American Society for Clinical Investigation},
  title        = {{The RNA-binding protein tristetraprolin schedules apoptosis of pathogen-engaged neutrophils during bacterial infection}},
  doi          = {10.1172/JCI80631},
  volume       = {127},
  year         = {2017},
}

@article{3943,
  abstract     = {Neutrophil granulocytes form the body's first line of antibacterial defense, but they also contribute to tissue injury and noninfectious, chronic inflammation. Proteinase 3 (PR3) and neutrophil elastase (NE) are 2 abundant neutrophil serine proteases implicated in antimicrobial defense with overlapping and potentially redundant substrate specificity. Here, we unraveled a cooperative role for PR3 and NE in neutrophil activation and noninfectious inflammation in vivo, which we believe to be novel. Mice lacking both PR3 and NE demonstrated strongly diminished immune complex-mediated (IC-mediated) neutrophil infiltration in vivo as well as reduced activation of isolated neutrophils by ICs in vitro. In contrast, in mice lacking just NE, neutrophil recruitment to ICs was only marginally impaired. The defects in mice lacking both PR3 and NE were directly linked to the accumulation of antiinflammatory progranulin (PGRN). Both PR3 and NE cleaved PGRN in vitro and during neutrophil activation and inflammation in vivo. Local administration of recombinant PGRN potently inhibited neutrophilic inflammation in vivo, demonstrating that PGRN represents a crucial inflammation-suppressing mediator. We conclude that PR3 and NE enhance neutrophil-dependent inflammation by eliminating the local antiinflammatory activity of PGRN. Our results support the use of serine protease inhibitors as antiinflammatory agents.},
  author       = {Kessenbrock, Kai and Fröhlich, Leopold and Sixt, Michael K and Lämmermann, Tim and Pfister, Heiko and Bateman, Andrew and Belaaouaj, Azzaq and Ring, Johannes and Ollert, Markus and Fässler, Reinhard and Jenne, Dieter},
  issn         = {1558-8238},
  journal      = {The Journal of Clinical Investigation},
  number       = {7},
  pages        = {2438 -- 2447},
  publisher    = {American Society for Clinical Investigation},
  title        = {{Proteinase 3 and neutrophil elastase enhance inflammation in mice by inactivating antiinflammatory progranulin}},
  doi          = {10.1172/JCI34694},
  volume       = {118},
  year         = {2008},
}