Rac1 signaling regulates platelet-dependent inflammation abdominal sepsis

Abstract: Sepsis is a systemic inflammatory response syndrome to a localized or systemic infection that leads to the over production of proinflammatory cytokines and the ultimate failure of multiple organ systems. However, little is known about the potential role of Rac1 in controlling sepsis-induced intracellular signaling pathways. We hypothesized that Rac1 might be involved in sepsis mediated signaling pathways leading to the activation of inflammatory cells. Paper (I), Rac1 signaling plays an important role in polymicrobial sepsis induced by cecal ligation and puncture (CLP). This study shows that Rac1 signaling regulates sepsis-induced inflammation in the lung by reducing chemokine production and Mac-1 expression on neutrophils. Rac1 inhibitor NSC23766 attenuates lung edema, tissue destruction and systemic pro-inflammatory cytokines in septic animals, suggesting that targeting Rac1 may be useful approach to protect against pulmonary injury in abdominal sepsis. Paper (II), in this study we showed that inhibition of Rac1 signaling protect sepsis-induced lung injury through two different mechanisms. First, Rac1 controls surface mobilization of CD40L on activated platelets and second, Rac1 regulates MMP-9 secretion from neutrophils. Our data indicate that inhibition of Rac1 signaling might be a useful target in order to control pathological secretion and shedding of CD40L into the systemic circulation in abdominal sepsis. Paper (III) This study indicates that Rac1 activity is increased in platelets and regulates platelet secretion of CCL5 in abdominal sepsis. Our findings show that CCL5 regulates neutrophil recruitment in septic lung injury via activation of alveolar macrophages leading to local secretion of CXCL2. Thus, our novel data not only elucidates complex mechanisms regulating pulmonary neutrophil trafficking in sepsis but also suggest that targeting Rac1 signaling and platelet-derived CCL5 might be a useful way to control pathological inflammation and tissue damage in the lung in abdominal sepsis. Paper (IV) Rac1 signaling is enhanced in platelets and regulates platelet secretion of CXCL4 in abdominal sepsis. This study indicates that CXCL4 controls neutrophil accumulation via secretion of CXCL2 from alveolar macrophages in septic lung injury. These findings not only delineate complex mechanisms of neutrophil trafficking in sepsis but also suggest that targeting platelet-derived CXCL4 might be an effective way to ameliorate inflammation and tissue damage in septic lung damage.