Toll-like receptor 9 activation in neutrophils impairs chemotaxis and reduces sepsis outcome.
OBJECTIVE
To investigate the role of toll-like receptor 9 on sepsis-induced failure of neutrophil recruitment to the site of infection.


METHODS
Prospective experimental study.


METHODS
University research laboratory.


METHODS
Model of polymicrobial sepsis induced by cecal ligation and puncture in wild-type and toll-like receptor 9-deficient mice.


RESULTS
Toll-like receptor 9-deficient mice with cecal ligation and puncture-induced severe sepsis did not demonstrate failure of neutrophil migration and consequently had a low systemic inflammatory response and a high survival rate. Upon investigating the mechanism by which toll-like receptor 9 deficiency prevents the failure of neutrophil migration, it was found that neutrophils derived from toll-like receptor 9--deficient mice with cecal ligation and puncture-induced severe sepsis expressed high levels of chemokine C-X-C motif receptor 2 (CXCR2) and had reduced induction of G-protein-coupled receptor kinase 2.


CONCLUSIONS
These findings suggest that the poor outcome of severe sepsis is associated with toll-like receptor 9 activation in neutrophils, which triggers G-protein-coupled receptor kinase 2 expression and CXCR2 downregulation. These events account for the reduction of neutrophil migration to the site of infection, with consequent spreading of the infection, onset of the systemic inflammatory response, and a decrease in survival.
Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil.
Silvia C
SC
Trevelin
José C
JC
Alves-Filho
Fabiane
F
Sônego
Walter
W
Turato
Daniele C
DC
Nascimento
Fabricio O
FO
Souto
Thiago M
TM
Cunha
Ricardo T
RT
Gazzinelli
Fernando Q
FQ
Cunha
D000818:Animals; D002470:Cell Survival; D002633:Chemotaxis / Q000502:physiology*; D004195:Disease Models, Animal; D005260:Female; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration / Q000502:physiology*; D011897:Random Allocation; D012016:Reference Values; D012680:Sensitivity and Specificity; D018805:Sepsis / Q000378:metabolism*; D018709:Statistics, Nonparametric; D051217:Toll-Like Receptor 9 / Q000378:metabolism*
D051217:Toll-Like Receptor 9; D054769:G-Protein-Coupled Receptor Kinase 2