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-α-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.
Highlights
Sepsis is a life-threatening systemic inflammatory condition which results in shock, multiple organ dysfunction, and eventually death [1, 2]
We set out to evaluate the effect of dasatinib on leukocyte recruitment in an in vivo model of tumor necrosis factor (TNF)-α (2 h) induced inflammation of the mouse cremaster muscle using Lyz2GFP mice
Observation of leukocyte rolling in cremaster muscle venules revealed a signi ficant increase in the number of rolling leukocytes in the presence of dasatinib (Figure 2A)
Summary
Sepsis is a life-threatening systemic inflammatory condition which results in shock, multiple organ dysfunction, and eventually death [1, 2] It is characterized by a cytokine storm released from myeloid cells during an inadequate antimicrobial response to invading pathogens [3]. Various studies using knockout mice or inhibitors demonstrated the importance of SFKs in host defense and inflammation [15,16,17,18,19], including adhesion and transmigration during leukocyte recruitment [20] Because of these findings, tyrosine kinase inhibitors, originally designed for cancer therapy, have been studied for their role as immune-modulating drugs. In a model of polymicrobial sepsis, dasatinib treatment improved survival and sepsis severity in mice and reduced organ damage in a dose-dependent manner with an optimal dose for survival
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