hiv protease inhibitor In conclusion the current study of S

In conclusion, the current study of S. aureus re-infection in planarians unveils a role of neoblasts in the establishment of immune resistance to re-infection to S. aureus and defines the critical function of neoblasts in controlling the heightened expression of Smed-PGRP-2 and Smed-setd8-1 during re-infection. Collectively, this work supports the use of planarians as a model organism for the study of innate immune memory of bacterial infection and reveals an unexpected role of neoblasts as a central regulator of immune memory and master regulator of animal resistance to S. aureus infection.
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Introduction Sepsis is a life-threatening condition that results from a harmful host response to infection. Sepsis-associated multiple organ dysfunction syndrome (MODS) is the predominant cause of mortality among seriously ill patients (Deitch, 1992). Despite improvements in laboratory testing and clinical therapy, the mortality rate of severe sepsis remains at approximately 30% and hospital admissions for severe sepsis have increased (Opal et al., 2013) (Caironi et al., 2014) (Lagu et al., 2012). Because around 750,000 patients are diagnosed with severe sepsis in the United States each year (Angus et al., 2001), improvements in care for severe sepsis remain a priority. Mitochondria regulate many aspects of cellular signaling and metabolic pathways through the fatty hiv protease inhibitor oxidation (FAO), the tricarboxylic acid cycle and the electron transport chain. Several lines of evidence suggest that mitochondrial dysfunction is associated with poor outcomes in patients with sepsis and MODS (Brealey et al., 2002) (Brealey et al., 2004) (Duvigneau et al., 2008). While the causality is not yet confirmed, it does nevertheless suggest a new route for therapeutic intervention focused on either mitochondrial protection or acceleration of the recovery process during sepsis (Singer, 2014). Endotoxin/lipopolysaccharide (LPS), a component of the outer membrane of Gram-negative bacteria, has been widely used in sepsis research. Expressed at the cell surface, toll like receptor (TLR) 4 detects LPS from Gram-negative bacteria. Interaction of TLR4 with LPS induces several intracellular signaling molecules, leading to the expression of nuclear factor-κB (NF-κB)-dependent pro-inflammatory cytokines or interferon regulatory factor-dependent type I interferons (IFNs) (Kawai and Akira, 2010). The inflammatory response is orchestrated by proinflammatory cytokines such as tumor necrosis factor (TNF), interleukin (IL)-1, and IL-6. IL-6 is a pleiotropic cytokine that plays a major role in host defense by regulating immune and inflammatory responses. During infection and chronic inflammation, IL-6 is produced by various types of cells, such as fibroblasts, macrophages, dendritic cells, T-cells, B-cells, keratinocytes, endothelial cells, mesangial cells, adipocytes and some tumor cells. Importantly, fibroblasts like other immune cells are a major source of IL-6. In chronic inflammation, fibroblasts are recognized as important regulators of inflammation through the production of IL-6 (Bernardo and Fibbe, 2013). In spite of the presence of several negative feedback mechanisms, constitutive overproduction of IL-6 is responsible for the pathogenesis of various inflammatory diseases, such as rheumatoid arthritis, systemic juvenile arthritis, and Crohn\'s disease (Kishimoto, 2010). Therefore, IL-6 signaling blockade with the humanized anti-IL-6 receptor antibody, tocilizumab, is a novel therapeutic strategy for various autoimmune and inflammatory diseases (Kishimoto, 2010). Moreover, several studies have investigated the validity of using IL-6 for early sepsis diagnosis and predicting mortality (Viallon et al., 2000) (Gardlund et al., 1995) (Pettila et al., 2002). IL-6 has also been used as a prognostic marker for outcomes in septic patients, but it is still unknown whether sepsis-induced mitochondria dysfunction is associated with the production of IL-6.