Fabiano Pinheiro da Silva

CD16 promotes Escherichia coli sepsis through an FcR

Sepsis, a leading cause of death worldwide, involves proinflammatory responses and inefficient bacterial clearance. Phagocytic cells play a crucial part in the prevention of sepsis by clearing bacteria through host innate receptors. Here we show that the FcRγ adaptor, an immunoreceptor tyrosine-based activation motif (ITAM)-bearing signal transduction subunit of the Fc receptor family, has a deleterious effect on sepsis. FcRγ−/− mice show increased survival during peritonitis, owing to markedly increased E. coli phagocytosis and killing and to lower production of the proinflammatory cytokine tumor necrosis factor (TNF)-α. The FcRγ-associated receptor that inhibits E. coli phagocytosis is FcγRIII (also called CD16), and its absence protects mice from sepsis. FcγRIII binds E. coli, and this interaction induces FcRγ phosphorylation, recruitment of the tyrosine phosphatase SHP-1 and phosphatidylinositide-3 kinase (PI3K) dephosphorylation. Decreased PI3K activity inhibits E. coli phagocytosis and increases TNF-α production through Toll-like receptor 4. We identified the phagocytic receptor negatively regulated by FcRγ on macrophages as the class A scavenger receptor MARCO. E. coli-FcγRIII interaction induces the recruitment of SHP-1 to MARCO, thereby inhibiting E. coli phagocytosis. Thus, by binding FcγRIII, E. coli triggers an inhibitory FcRγ pathway that both impairs MARCO-mediated bacterial clearance and activates TNF-α secretion.

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Background The intestinal barrier is a layer that constitutes the most important barrier against the external environment. It can be partially disrupted in several frequent scenarios, leading to autoimmune and inflammatory diseases. Translocation of intestinal luminal contents into the intestinal mucosa may induce inflammatory disorders and therefore tissue injuries. Disruption of the intestinal barrier may induce local and systemic injuries and may play a role in inflammatory bowel disease, liver diseases, the aging process and in the systemic inflammatory response syndrome, including lung, heart and brain dysfunctions. Conclusion Here, we discuss how the maintenance of it selectively permeability is crucial to adequate absorption of nutrients, electrolytes and water while maintaining effective host defense properties in order to avoid intestinal injury, systemic inflammation and distant organ damage.

inhibitory pathway that prevents phagocytosis and facilitates inflammation

INTRODUCTION Hypocalcemia is a common and poorly understood finding in critically ill patients. The current study was designed to assess the association of ionized calcium, vitamin D, phosphorus and Parathyroid hormone levels in a cohort of patients with and without kidney dysfunction admitted for sepsis or non-infectious causes. METHODS Prospective cohort clinical and biochemical study. RESULTS We confirmed that hypocalcemia and hypovitaminosis D are a common finding in critically ill patients. Parathyroid hormone levels significantly rise in septic shock. In the recovery phase, however, despite persistent hypocalcemia, Parathyroid hormone levels abruptly decrease in patients with kidney dysfunction, but not in patients with normal renal function. CONCLUSIONS The systemic inflammatory response syndrome probably leads to inappropriately high Parathyroid hormone levels during septic shock. In the recovery phase, Parathyroid hormone levels decrease, but calcium levels remain low, displaying evidence that the parathyroid is not responding as expected. Since Parathyroid hormone receptors and calcium-sensing receptors have been described in immune cells and other cell types, we propose that these effects may have a plethora of other deleterious effects, with important implications to the pathogenesis of septic shock.

Intestinal Barrier Dysfunction in Human Pathology and Aging.

Abstract The objective of this randomized animal study and laboratory investigation was to investigate whether lipopolysaccharide tolerance redirects neutrophil migration between organs. Male BALB/c mice received subcutaneous injections of lipopolysaccharide (1 mg/kg) for 5 days, followed by cecal ligation and puncture (CLP). Cytokines and adhesion molecules were measured after tolerance and CLP challenge. Increased numbers of neutrophils were observed in the peritoneal cavity of tolerant mice, which was associated with increased levels of adhesion molecules and chemokines. In contrast, nontolerant mice accumulated higher numbers of neutrophils in the lungs compared with those in the peritoneal cavity. Neutrophil function accessed by hydrogen peroxide production from neutrophils recovered from peritoneal cavity showed that tolerance increased the capacity to produce hydrogen peroxide. Mortality was reduced in tolerant animals. This study demonstrated that tolerance reduces leukocyte accumulation in the lung after CLP by redirecting neutrophils to the site of infection.

Decreased Parathyroid Hormone Levels Despite Persistent Hypocalcemia in Patients with Kidney Failure Recovering from Septic Shock

Severe acute pancreatitis (AP) is a disease associated with high mortality and characterized by overwhelming systemic inflammation. Older people have a prolonged hospital stay and worst prognosis, when affected by this disease. Our group hypothesized, thus, that the systemic inflammatory response in the elderly would promote more organ damage when compared to the young. We sought to investigate the effect of systemic inflammation on the gene expression of cytokines, chemokines, and growth factors in the hearts of older and younger rats in an animal model of AP. AP was induced in all rats by injection of 0.5 mL of 2.5% taurocholate. There were two healthy age-matched control groups. An array of 79 cytokines, chemokines, and growth factors was measured in samples of cardiac tissue taken from the AP rats after 10 h, and from control rats. Older healthy rats had significantly higher levels of interleukin-10 (IL-10) and CCL1 gene expression than younger ones (P < 0.05), but all other measurements were similar among the study groups. This study indicates the systemic inflammation may show unique features for different organs in the body, but older animals with systemic inflammation are similar to the young regarding the cardiac inflammatory response.

Endotoxin tolerance drives neutrophil to infectious site.

Antimicrobial peptides are an ancient family of molecules that emerged millions of years ago and have been strongly conserved during the evolutionary process of living organisms. Recently, our group described that the human antimicrobial peptide LL-37 migrates to the nucleus, raising the possibility that LL-37 could directly modulate transcription under certain conditions. Here, we showed evidence that LL-37 binds to gene promoter regions, and LL-37 gene silencing changed the transcriptional program of melanoma A375 cells genes associated with histone, metabolism, cellular stress, ubiquitination and mitochondria.

Cytokine and chemokine levels in the heart tissue of aged rats following severe acute pancreatitis

Introduction. Inflammation is ubiquitous during sepsis and may be influenced by body mass index (BMI). We sought to evaluate if BMI was associated with serum levels of several cytokines measured at intensive care unit admission due to sepsis. Methods. 33 septic patients were included. An array of thirty-two cytokines and chemokines was measured using Milliplex technology. We assessed the association between cytokine levels and BMI by generalized additive model that also included illness severity (measured by SAPS 3 score); one model was built for each cytokine measured. Results. We found that levels of epidermal growth factor, vascular endothelial growth factor, and interleukins 4, 5, and 13 were associated with BMI in a complex, nonlinear way, independently of illness severity. Higher BMI was associated with higher levels of anti-inflammatory interleukins. Conclusion. BMI may influence host response to infection during critical illness. Larger studies should confirm these findings.

Antimicrobial peptide LL-37 participates in the transcriptional regulation of melanoma cells.

Sepsis is a complex condition that is initiated by infection. The incidence of sepsis and its severity are higher at an older age (mean age of approximately 65 years). Clinical manifestations of sepsis are derived from systemic inflammatory response syndrome. Age‐related defects in immunity are shown by changes in cellular and humoral immu‐ nity. Recent studies have shown significant changes in the innate response (e.g., changes in toll‐like receptor expression, abnormal activation of mitogen‐activated protein kinases, and production of reactive oxygen species) in older people. Transcriptomic analysis on a large scale has provided interesting information showing that specific groups of patients actually have singular profiles for inflammatory responses. Findings from our research group have identified major molecular pathways that are particularly affected in older people during sepsis. Oxidative phosphorylation pathways and mitochondrial dysfunc‐ tion are altered the most in older people with sepsis compared with younger patients with sepsis. These pathways might have a pivotal role in worsening clinical outcomes compared with younger people with sepsis. The mechanisms leading to specific dysfunc‐ tion of several signaling pathways in the immune response of older people are complex and appear to involve multiple factors, including environmental factors, microRNAs, and epigenetic changes.