TOLL-LIKE RECEPTOR SIGNALING AND FAILURE OF NEUTROPHIL MIGRATION IN SEVERE SEPSIS

ALVES-FILHO J. C.(1)

(1)Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, São Paulo, Brazil.

Sepsis is a systemic inflammatory response that results from the inability of the immune system to limit bacterial spread during an ongoing infection. Neutrophils are critical effectors cells of the innate immune system that protect the host by migrating to inflammatory sites and killing pathogenic microbes. Studies from our laboratory have demonstrated that lethal sepsis, induced by cecal ligation and puncture (CLP) or bacterial inoculation models, is associated with impaired neutrophil migration to sites of infection. This impairment of neutrophil migration resulted in augmented number of bacteria in peritoneal cavity and blood which was associated with high mortality. Conversely, in sub-lethal sepsis, the neutrophil migration was not suppressed and the bacterial infection was restricted to the peritoneal cavity, consequently no significant mortality was observed. It seems that an early and inappropriate systemic inflammatory response, characterized by elevated levels of plasma cytokines, chemokines and nitric oxide released by immune cells after stimulation through bacteria and/or their products, mediates the neutrophil migration impairment. Moreover, although signaling through the TLRs has been implicated as an important element of host defense during an infection, recently, we showed that TLR2 and TLR4 signaling are crucial to the establishment of the impairment of neutrophil migration in lethal polymicrobial sepsis. It was observed that TLR2- and TLR4-deficient mice subjected to lethal polymicrobial sepsis induced by CLP did not present failure of neutrophil migration. As consequence, these animals presented low bacteremia and a high survival rate and did not display systemic inflammation determined by high levels of circulating cytokines and lung neutrophil sequestration. In conclusion, during lethal polimicrobial sepsis, a high concentration of cytokines/chemokines in the circulation with consequent production of nitric oxide induced by TLR2 and TLR4 signaling is a critical event that results in impaired neutrophil migration to the infectious focus, leading in turn to a failure of circumscription of the infection and high mortality.

KEY WORDS: Sepsis, neutrophil migration, TLRs, nitric oxide.

FINANCIAL SUPPORT: FAPESP, CNPq, PRONEX and FAEPA.

CORRESPONDENCE TO:

José Carlos Farias Alves Filho, Departamento de Farmacologia, FMRP, USP. Avenida dos Bandeirantes, 3.900, Monte Alegre, 14049-900, Ribeirão Preto, SP, Brasil, Fone: (16) 6023205 Fax: (16) 6332301. Email: fdqcunha@fmrp.usp.br