Bacterial Sensing, Cell Signaling, and Modulation of the Immune Response During Sepsis

Salomão, Reinaldo; Brunialti, Milena Karina Coló; Rapozo, Marjorie Marini; Baggio-Zappia, Giovana Lotici; Galanos, Chris; Freudenberg, Marina A.

doi:10.1097/shk.0b013e318262c4b0

Cited by 184 publications

(179 citation statements)

References 103 publications

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“…In addition, the timing and intensity of early immune activation of the body was associated with a range of factors, including the patients' physical status, virulence of pathogenic bacteria and other complicating factors (24). Among patients with refractory sepsis, due to the immunosuppression resulting from a deficiency in the inflammatory factors to activate the adaptive immune system, it is difficult for persistent infections to be controlled (25). The immunosuppression of patients with sepsis is predominantly characterized by the apoptosis of lymphocytes and dendritic cells, decreased expression levels of the cell-surface antigen-presenting complex and human leucocyte antigen-death receptor, and an increase in the expression level of inhibitory immune regulatory molecules, including programmed death 1 and cytotoxic T-lymphocyte-associated antigen 4.…”

Section: Discussionmentioning

confidence: 99%

Effects of bone marrow mesenchymal stem cells on the cardiac function and immune system of mice with endotoxemia

Zhou

et al. 2016

Molecular Medicine Reports

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Abstract. The present study aimed to investigate the effects of bone marrow mesenchymal stem cells (MSCs) on the cardiac function and immune system of mice with endotoxemia. The mice were divided into the following groups: Control group, endotoxemia group, lipopolysaccharide (LPS) treatment group, LPS and MSC treatment group (LPS + MSC group) and MSC group. Following treatment with LPS, the cardiac function of the mice was examined at after 2, 6 and 24 h, and on day 7. An enzyme-linked immunofluorescent assay was used to analyze the serum and the levels of cytokines in the myocardium, and western blotting was used to investigate any changes in the levels of signaling proteins associated with the myocardium. A 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay was used to investigate the growth rate of the splenic cells at after 24 h and on day 7, and the humoral immune function and phagocytosis of the macrophages in the mice were also examined. The cardiac function of the mice with endotoxemia declined, although this impairment was circumvented following treatment with MSCs. The levels of interleukin (IL)-1β, IL-6, tumor necrosis factor-α and IL-10 in the serum and the myocardium increased following stimulation by LPS, although these declined as a result of MSC treatment. The expression levels of Toll-like receptor 4, p65-nuclear factor-κB and phosphorylated p38 in the mouse myocardium were enhanced following stimulation by LPS, which subsequently decreased as a result of MSC treatment. Compared with the control group, the growth rate of the splenic cells, humoral immune function and the level of phagocytosis of macrophages were all increased, although these parameters declined following treatment with MSCs. Taken together, the present study revealed that the MSCs inhibited the inflammatory reaction in the mice with endotoxemia, and improved cardiac function. By contrast, the cellular and humoral immunity were depressed, and phagocytosis of the macrophages, which were enhanced following simulation with LPS, were decreased following treatment with MSCs. However, no overexpression of the anti-inflammatory factor, IL-10, was observed. The present study hypothesized that MSCs exert a bifunctional role in endotoxemia, by inhibiting inflammatory factors, including IL-1 and IL-6, and inhibiting the compensatory expression of IL-10 following LPS stimulation. This avoids the possibility of excessive inhibition of immunological function, as this results in immunosuppression, and a higher ratio of IL-10 to TNF-α is indicative of a poor prognosis in patients with sepsis.

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Section: Discussionmentioning

confidence: 99%

Effects of bone marrow mesenchymal stem cells on the cardiac function and immune system of mice with endotoxemia

Zhou

et al. 2016

Molecular Medicine Reports

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“…They can also be recruited from the circulation to sites of local injury. Tissue-resident MP are sentinels for disease, serving as first responders to tissue insult (145). The phenotypes of MP are heterogeneous and dependent on the microenvironment that they inhabit (15,44,62).…”

Section: The Mononuclear Phagocyte Systemmentioning

confidence: 99%

The Mononuclear Phagocyte System in Homeostasis and Disease: A Role for Heme Oxygenase-1

Hull

Agarwal

George

2014

Antioxidants & Redox Signaling

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Significance: Heme oxygenase-1 (HO-1) is a potential therapeutic target in many diseases, especially those mediated by oxidative stress and inflammation. HO-1 expression appears to regulate the homeostatic activity and distribution of mononuclear phagocytes ( MP) in lymphoid tissue under physiological conditions. It also regulates the ability of MP to modulate the inflammatory response to tissue injury. Recent Advances: The induction of HO-1 within MP-particularly macrophages and dendritic cells-modulates the effector functions that they acquire after activation. These effector functions include cytokine production, surface receptor expression, maturation state, and polarization toward a pro-or anti-inflammatory phenotype. The importance of HO-1 in MP is emphasized by their expression of specific receptors that primarily function to ingest heme-containing substrate and deliver it to HO-1. Critical Issues: MP are the first immunological responders to tissue damage. They critically affect the outcome of injury to many organ systems, yet few therapies are currently available to specifically target MP during disease pathogenesis. Elucidation of the role of HO-1 expression in MP may help to direct broadly applicable therapies to clinical use that are based on the immunomodulatory capabilities of HO-1. Future Directions: Unraveling the complexities of HO-1 expression specifically within MP will more completely define how HO-1 provides cytoprotection in vivo. The use of models in which HO-1 expression is specifically modulated in bone marrow-derived cells will allow for a more complete characterization of its immunoregulatory properties.

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“…Coordination of the innate immune response during acute bacterial peritonitis is crucial to prevention of systemic dissemination and development of sepsis [44]. Here, we report novel insights into the roles of calpain proteases in mounting an effective innate immune response to bacterial infection in mice.…”

Section: Discussionmentioning

confidence: 97%

Calpains promote neutrophil recruitment and bacterial clearance in an acute bacterial peritonitis model

et al. 2013

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Activation of the innate immune system is critical for clearance of bacterial pathogens to limit systemic infections and host tissue damage. Here, we report a key role for calpain proteases in bacterial clearance in mice with acute peritonitis. Using transgenic mice expressing Cre recombinase primarily in innate immune cells (fes-Cre), we generated conditional capns1 knockout mice. Consistent with capns1 being essential for stability and function of the ubiquitous calpains (calpain-1, calpain-2), peritoneal cells from these mice had reduced levels of calpain-2/capns1, and reduced proteolysis of their substrate selenoprotein K. Using an acute bacterial peritonitis model, we observed impaired bacterial killing within the peritoneum and development of bacteremia in calpain knockout mice. These defects correlated with significant reductions in IL-1α release, neutrophil recruitment, and generation of reactive oxygen species in calpain knockout mice with acute bacterial peritonitis. Peritoneal macrophages from calpain knockout mice infected with enterobacteria ex vivo, were competent in phagocytosis of bacteria, but showed impaired clearance of intracellular bacteria compared with control macrophages. Together, these results implicate calpains as key mediators of effective innate immune responses to acute bacterial infections, to prevent systemic dissemination of bacteria that can lead to sepsis. Keywords: Bacterial infection r Calpains r Neutrophils r Phagocytosis r Reactive oxygen speciesAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionBacterial infection triggers pattern-recognition receptor (PRR) signaling within host cells designed to allow rapid bacterial clearance and avoid progression to systemic infection [1]. In bacterial Correspondence: Dr. Andrew W. B. Craig e-mail: andrew.craig@queensu.ca peritonitis, resident innate immune cells in the peritoneum (e.g. mast cells, macrophages) orchestrate the immune response via rapid release of preformed and de novo generated vasoactive mediators, cytokines, and chemokines [2][3][4]. This leads to recruitment of neutrophils and bacterial capture in neutrophil extracellular traps [5]. Bacterial clearance is facilitated by rapid degranulation, production of ROS and reactive nitrogen species, and phagocytosis by neutrophils and macrophages [6]. Balancing this potent immune response is critical to eliminate the pathogens prior to systemic dissemination and avoid tissue damage observed C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 832Vijay Kumar et al. Eur. J. Immunol. 2014. 44: 831-841 in severe sepsis [3]. Failure to tightly control production of proinflammatory cytokines such as IL-1, are also linked to the development of autoinflammatory disorders [7]. Thus, a better understanding of positive and negative regulation of PRR signaling may inform the development of more effective treatments for these diseases. Calpains are intracellular, calcium (Ca ++ )-dependent cysteine...

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Bacterial Sensing, Cell Signaling, and Modulation of the Immune Response During Sepsis

Cited by 184 publications

References 103 publications

Effects of bone marrow mesenchymal stem cells on the cardiac function and immune system of mice with endotoxemia

Effects of bone marrow mesenchymal stem cells on the cardiac function and immune system of mice with endotoxemia

The Mononuclear Phagocyte System in Homeostasis and Disease: A Role for Heme Oxygenase-1

Calpains promote neutrophil recruitment and bacterial clearance in an acute bacterial peritonitis model

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