The Yin and Yang of tyrosine kinase inhibition during experimental polymicrobial sepsis

Cassiano Felippe Gonçalves-de-Albuquerque, Ina Rohwedder, Adriana Ribeiro Silva, Alessandra Silveira Ferreira, Angela R.M. Kurz, Céline Cougoule, Sarah Klapproth, Tanja Eggersmann, Johnatas D. Silva, Gisele Pena de Oliveira, Vera Luiza Capelozzi, Gabriel Gutfilen Schlesinger, Edlaine Rijo Costa, Rita de Cassia Elias Estrela Marins, Attila Mócsai, Isabelle Maridonneau-Parini, Barbara Walzog, Patricia Rieken Macedo Rocco, Markus Sperandio, Hugo Caire de Castro-Faria-Neto

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5 Citations (Scopus)

Abstract

Neutrophils are the first cells of our immune system to arrive at the site of inflammation. They release cytokines, e.g., chemokines, to attract further immune cells, but also actively start to phagocytose and kill pathogens. In the case of sepsis, this tightly regulated host defense mechanism can become uncontrolled and hyperactive resulting in severe organ damage. Currently, no effective therapy is available to fight sepsis; therefore, novel treatment targets that could prevent excessive inflammatory responses are warranted. Src Family tyrosine Kinases (SFK), a group of tyrosine kinases, have been shown to play a major role in regulating immune cell recruitment and host defense. Leukocytes with SFK depletion display severe spreading and migration defects along with reduced cytokine production. Thus, we investigated the effects of dasatinib, a tyrosine kinase inhibitor, with a strong inhibitory capacity on SFKs during sterile inflammation and polymicrobial sepsis in mice. We found that dasatinib-treated mice displayed diminished leukocyte adhesion and extravasation in tumor necrosis factor-a-stimulated cremaster muscle venules in vivo. In polymicrobial sepsis, sepsis severity, organ damage, and clinical outcome improved in a dose-dependent fashion pointing toward an optimal therapeutic window for dasatinib dosage during polymicrobial sepsis. Dasatinib treatment may, therefore, provide a balanced immune response by preventing an overshooting inflammatory reaction on the one side and bacterial overgrowth on the other side.

Original languageEnglish
Article number901
JournalFrontiers in immunology
Volume9
Issue numberAPR
DOIs
Publication statusPublished - Apr 30 2018

Keywords

  • Dasatinib
  • Inflammation
  • Leukocyte trafficking
  • Sepsis
  • Src tyrosine kinase

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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  • Cite this

    Gonçalves-de-Albuquerque, C. F., Rohwedder, I., Silva, A. R., Ferreira, A. S., Kurz, A. R. M., Cougoule, C., Klapproth, S., Eggersmann, T., Silva, J. D., de Oliveira, G. P., Capelozzi, V. L., Schlesinger, G. G., Costa, E. R., Elias Estrela Marins, R. D. C., Mócsai, A., Maridonneau-Parini, I., Walzog, B., Rocco, P. R. M., Sperandio, M., & de Castro-Faria-Neto, H. C. (2018). The Yin and Yang of tyrosine kinase inhibition during experimental polymicrobial sepsis. Frontiers in immunology, 9(APR), [901]. https://doi.org/10.3389/fimmu.2018.00901