| Autor: |
Viens, Adam L., Timmer, Kyle D., Alexander, Natalie J., Barghout, Rana, Milosevic, Jelena, Hopke, Alex, Atallah, Natalie J., Scherer, Allison K., Sykes, David B., Irimia, Daniel, Mansour, Michael K. |
| Jazyk: |
angličtina |
| Rok vydání: |
2022 |
| Předmět: |
|
| Zdroj: |
J Immunol |
| Popis: |
An impaired neutrophil response to pathogenic fungi puts patients at risk for fungal infections with a high risk of morbidity and mortality. Acquired neutrophil dysfunction in the setting of iatrogenic immune modulators can include the inhibition of critical kinases such as spleen tyrosine kinase (Syk). In this study, we utilized an established system of conditionally immortalized mouse neutrophil progenitors to investigate the ability to augment Syk-deficient neutrophil function against Candida albicans with Toll-Like Receptor (TLR) agonist signaling. LPS, a known immunomodulatory molecule derived from gram negative bacteria, was capable of rescuing effector functions of Syk-deficient neutrophils, which are known to have poor fungicidal activity against Candida species. LPS priming of Syk-deficient mouse neutrophils demonstrate partial rescue of fungicidal activity including phagocytosis, degranulation and neutrophil swarming, but not reactive oxygen species (ROS) production against C. albicans, in part, due to c-Fos activation. Similarly, LPS priming of human neutrophil rescues fungicidal activity in the presence of pharmacologic inhibition of Syk and Bruton’s tyrosine kinase (Btk), both critical kinases innate immune response to fungi. In vivo, neutropenic mice were reconstituted with WT or Syk deficient neutrophils and challenged with intraperitoneal C. albicans. In this model, LPS improved WT neutrophil homing to the fungal challenge, while Syk deficient neutrophils did not persist in vivo, speaking to its crucial role on in vivo persistence. Taken together, we identify TLR signaling as an alternate activation pathway capable of partially restoring neutrophil effector function against Candida in a Syk-independent manner. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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