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Regulation of neutrophil chemotaxis by toll-like receptor 9 is important for sepsis survival
Critical Care volume 14, Article number: P53 (2010)
Successful clearance of bacterial infection depends on efficient neutrophil migration to infected tissues . Chemotaxis is a crucial event for neutrophil migration to local infection and is controlled mainly through activation of G-protein-coupled receptors. Furthermore, the functionality of these receptors is regulated by G-protein-coupled receptor kinases (GRKs) . Impaired chemotactic responses in sepsis was correlated with dysregulated neutrophil toll-like receptor (TLR) signaling, TLR2 and TLR4, while TLR9 inhibition in dendritic cells was associated with reduction of mortality in polymicrobial sepsis . Despite the TLR9 expression, the role of this receptor in neutrophil chemotaxis has not been studied. Thus, the aim of the present study was to verify the importance of TLR9 activation on neutrophil migration during sepsis.
C57BL/6 wildtype (WT) and TLR9-/- mice were submitted to the cecal ligation and puncture (CLP) sepsis model and the survival rate was evaluated over 7 days. Also, neutrophil migration to the peritoneal cavity was measured 6 hours after CLP. Chemotaxis of blood neutrophils to CXCL2 in the Boyden camera, CXCR2 expression, and GRK2 induction on blood neutrophils, measured by flow cytometry and immunofluorescence, respectively, were performed 2 hours after CLP. All experiments were developed in accordance with the ethical guidelines of the School of Medicine of Ribeirão Preto, University of São Paulo (protocol number 150/2009).
TLR9-/- mice submitted to CLP had an enhanced survival rate when compared with WT mice (P = 0.096), and these knockout mice had increased the neutrophil migration to infectious focus (P = 0.0445). Investigating the mechanism by which the deficiency of TLR9 could recover neutrophil migration, it was observed that neutrophil derived from TLR9-/- CLP-treated mice had restored the ability to migrate in vitro (chemotact assay) toward MIP-2, CXCR2 ligand (P = 0.0133). Moreover, the recovery in neutrophil chemotaxis was associated with an enhancement in CXCR2 expression on the neutrophil surface and a reduction in GRK2 induction.
In sepsis, TLR9 activation, similar to that previously observed with TLR2 and TLR4, can also be harmful to control bacterial growth, because it impairs neutrophils from reaching the infection focus.
Alves-Filho JC, et al.: Regulation of chemokine receptor by toll-like receptor 2 is critical to neutrophil migration and resistance to polymicrobial sepsis. Proc Natl Acad Sci USA 2009, 106: 4018-4023. 10.1073/pnas.0900196106
Plitas G, et al.: Toll-like9 inhibition reduces mortality in polymicrobial sepsis. J Eexp Med 2008, 205: 1277-1283. 10.1084/jem.20080162
This presentation was supported by grants from the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), and Conselho Nacional de Pesquisa e Desenvolvimento Tecnológico (CNPq).
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Trevelin, S., Alves-Filho, J., Sônego, F. et al. Regulation of neutrophil chemotaxis by toll-like receptor 9 is important for sepsis survival. Crit Care 14, P53 (2010). https://doi.org/10.1186/cc9156
- TLR9 Expression
- CXCR2 Expression
- Neutrophil Migration
- TLR9 Activation
- Blood Neutrophil