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TLR Signaling Rescues Fungicidal Activity in Syk-Deficient Neutrophils
Adam L Viens1, Kyle D Timmer2, Natalie J Alexander2
1Division of Infectious Diseases, Massachusetts General Hospital, Boston, MA; mkmansour@mgh.harvard.edu aviens1@mgh.harvard.edu.
Abstract:
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 used an established system of conditionally immortalized mouse neutrophil progenitors to investigate the ability to augment Syk-deficient neutrophil function against Candida albicans with 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 demonstrates partial rescue of fungicidal activity, including phagocytosis, degranulation, and neutrophil swarming, but not reactive oxygen species production against C. albicans, in part due to c-Fos activation. Similarly, LPS priming of human neutrophils rescues fungicidal activity in the presence of pharmacologic inhibition of Syk and Bruton's tyrosine kinase (Btk), both critical kinases in the innate immune response to fungi. In vivo, neutropenic mice were reconstituted with wild-type or Syk-deficient neutrophils and challenged i.p. with C. albicans. In this model, LPS improved wild-type neutrophil homing to the fungal challenge, although 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.
Insights
Toll-like receptor (TLR) agonist signaling can partially restore neutrophil function against Candida infections, even when key kinases like spleen tyrosine kinase (Syk) are deficient. This offers a potential therapeutic avenue for patients with impaired immune responses.
Area of Science:
- Immunology
- Infectious Diseases
- Cell Biology
Background:
- Impaired neutrophil function increases susceptibility to life-threatening fungal infections.
- Iatrogenic immune modulators can cause neutrophil dysfunction by inhibiting critical kinases, such as spleen tyrosine kinase (Syk).
Purpose of the Study:
- To investigate if Toll-like receptor (TLR) agonist signaling can augment the function of Syk-deficient neutrophils against Candida albicans.
- To explore the potential of TLR agonists as an alternative pathway to restore neutrophil effector functions in the context of kinase inhibition.
Main Methods:
- Utilized conditionally immortalized mouse neutrophil progenitors and primary human neutrophils.
- Investigated the effects of lipopolysaccharide (LPS), a TLR agonist, on Syk-deficient neutrophils and neutrophils with pharmacologic Syk/Bruton's tyrosine kinase (Btk) inhibition.
- Assessed neutrophil functions including phagocytosis, degranulation, reactive oxygen species (ROS) production, and neutrophil swarming.
- Conducted in vivo studies using neutropenic mice reconstituted with wild-type or Syk-deficient neutrophils challenged with C. albicans.
Main Results:
- LPS priming partially rescued fungicidal activity, phagocytosis, degranulation, and swarming in Syk-deficient mouse neutrophils against C. albicans, but not ROS production.
- LPS priming restored fungicidal activity in human neutrophils with pharmacologic inhibition of Syk and Btk.
- In vivo, LPS enhanced wild-type neutrophil homing to fungal infection sites, but Syk-deficient neutrophils showed poor in vivo persistence.
Conclusions:
- TLR signaling represents an alternative activation pathway capable of partially restoring neutrophil effector functions against Candida, independent of Syk.
- While TLR agonists can enhance certain neutrophil functions, Syk remains crucial for neutrophil persistence in vivo during fungal infections.
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