Lactate released by inflammatory bone marrow neutrophils induces their mobilization via endothelial GPR81 signaling.

Neutrophils provide first line of host defense against bacterial infections utilizing glycolysis for their effector functions. How glycolysis and its major byproduct lactate are triggered in bone marrow (BM) neutrophils and their contribution to neutrophil mobilization in acute inflammation is not clear. Here we report that bacterial lipopolysaccharides (LPS) or Salmonella Typhimurium triggers lactate release by increasing glycolysis, NADPH-oxidase-mediated reactive oxygen species and HIF-1α levels in BM neutrophils. Increased release of BM lactate preferentially promotes neutrophil mobilization by reducing endothelial VE-Cadherin expression, increasing BM vascular permeability via endothelial lactate-receptor GPR81 signaling. GPR81-/- mice mobilize reduced levels of neutrophils in response to LPS, unless rescued by VE-Cadherin disrupting antibodies. Lactate administration also induces release of the BM neutrophil mobilizers G-CSF, CXCL1 and CXCL2, indicating that this metabolite drives neutrophil mobilization via multiple pathways. Our study reveals a metabolic crosstalk between lactate-producing neutrophils and BM endothelium, which controls neutrophil mobilization under bacterial infection

Histological findings of autoimmune hepatitis

Histology of autoimmune hepatitis (AIH), chronic active hepatitis, is characterized by portal inflammation with interface hepatitis. Although the basic histology of AIH is similar to that of virus-related chronic hepatitis, hepatitic changes are usually prominent in AIH compared with chronic viral hepatitis. Clinicopathological diagnosis of AIH requires exclusion of other causes of liver disease, including hepatitis virus, alcohol, drugs, metabolic disorders, and other autoimmune diseases. At present, some criteria systems considering clinicopathological findings are proposed to categorize patients as having either definite or probably/atypical AIH. Among the pathological items of a simplified AIH scoring system of the International AIH Group, in addition to evident chronic hepatitis with interface hepatitis and hepatic rosette formation, emperipolesis, indicating the close immunological interaction of lymphocytes and hepatocytes, is noted but is sometimes difficult to evaluate. In addition to classical AIH, showing chronic active hepatitis, some AIH patients show a clinically acute hepatitis-like clinical course. These patients have mostly acute exacerbation from chronic active AIH, but acute-onset AIH cases, which histologically exhibit diffuse lobular hepatitis and/or confluent necrosis including perivenular zonal necrosis (zone 3 necrosis, centrizonal necrosis), are also encountered. © 2014 Springer Japan. All rights reserved.(Book Chapter

Anaerobic ammonium-oxidising bacteria: A biological source of the bacteriohopanetetrol stereoisomer in marine sediments

Bacterially-derived bacteriohopanepolyols (BHPs) are abundant, well preserved lipids in modern and paleo-environments. Bacteriohopanetetrol (BHT) is a ubiquitously produced BHP while its less common stereoisomer (BHT isomer) has previously been associated with anoxic environments; however, its biological source remained unknown. We investigated the occurrence of BHPs in Golfo Dulce, an anoxic marine fjord-like enclosure located in Costa Rica. The distribution of BHT isomer in four sediment cores and a surface sediment transect closely followed the distribution of ladderane fatty acids, unique biomarkers for bacteria performing anaerobic ammonium oxidation (anammox). This suggests that BHT isomer and ladderane lipids likely shared the same biological source in Golfo Dulce. This was supported by examining the BHP lipid compositions of two enrichment cultures of a marine anammox species ('. Candidatus Scalindua profunda'), which were found to contain both BHT and BHT isomer. Remarkably, the BHT isomer was present in higher relative abundance than BHT. However, a non-marine anammox enrichment contained only BHT, which explains the infrequence of BHT isomer observations in terrestrial settings, and indicates that marine anammox bacteria are likely responsible for at least part of the environmentally-observed marine BHT isomer occurrences. Given the substantially greater residence time of BHPs in sediments, compared to ladderanes, BHT isomer is a potential biomarker for past anammox activity

Primordial GATA6 macrophages function as extravascular platelets in sterile injury.

Most multicellular organisms have a major body cavity that harbors immune cells. In primordial species such as purple sea urchins, these cells perform phagocytic functions but are also crucial in repairing injuries. In mammals, the peritoneal cavity contains large numbers of resident GATA6+ macrophages, which may function similarly. However, it is unclear how cavity macrophages suspended in the fluid phase (peritoneal fluid) identify and migrate toward injuries. In this study, we used intravital microscopy to show that cavity macrophages in fluid rapidly form thrombus-like structures in response to injury by means of primordial scavenger receptor cysteine-rich domains. Aggregates of cavity macrophages physically sealed injuries and promoted rapid repair of focal lesions. In iatrogenic surgical situations, these cavity macrophages formed extensive aggregates that promoted the growth of intra-abdominal scar tissue known as peritoneal adhesions

FOXP3+ regulatory T cells in autoimmune hepatitis are fully functional and not reduced in frequency

BACKGROUND & AIMS: The pathogenesis of autoimmune hepatitis (AIH) is not understood, but it was suggested that AIH may be related to a numerical or functional impairment of CD4+CD25+FOXP3+ regulatory T cells (Treg), which are important mediators of immune tolerance to self-antigens. However, the role of Treg in AIH is not clear, since earlier studies reporting Treg impairment had used only CD25 as marker that cannot unambiguously distinguish Treg from activated effector T cells. METHODS: We assessed the frequency and suppressor function of Treg using current staining protocols that can distinguish Treg from activated effector T cells. RESULTS: The frequency of CD4+CD25(high)CD127(low)FOXP3+ Treg cells in blood of AIH patients was not reduced compared to healthy subjects, as shown by flow cytometry and confirmed by quantifying Treg-specific demethylation of the FOXP3 gene. Moreover, the suppressor function of Treg isolated from AIH patients was similar to that of Treg isolated from healthy subjects, indicating that Treg function was not impaired in AIH patients. However, we observed that the Treg frequency was significantly higher in those AIH patients with active disease than in those who were in a state of remission, suggesting that the Treg frequency may increase with the degree of inflammation. Indeed, analysis of FOXP3+ Treg in liver histology revealed that the intrahepatic Treg frequency was higher in AIH patients than in NASH patients and correlated with the inflammatory activity of the liver. CONCLUSIONS: The frequency and function of circulating Treg cells is not impaired in AIH

Reduced FOXP3(+) regulatory T cells in patients with primary sclerosing cholangitis are associated with IL2RA gene polymorphisms

Item does not contain fulltextBACKGROUND & AIMS: Recently, genome wide association studies in primary sclerosing cholangitis (PSC) revealed associations with gene polymorphisms that potentially could affect the function of regulatory T cells (Treg). The aim of this study was to investigate Treg in patients with PSC and to associate their numbers with relevant gene polymorphisms. METHODS: Treg frequency in blood was assessed by staining for CD4(+)CD25(high)FOXP3(+)CD127(low) lymphocytes and determination of Treg-specific FOXP3 gene locus demethylation. Single nucleotide polymorphisms (SNP) in the interleukin-2 receptor alpha (IL2RA), the interleukin-2 (IL2) and interleukin-21 (IL21) gene locus were analysed. Liver biopsies taken at the time of diagnosis were stained for FOXP3 and CD3. Treg function was assessed in a CFSE-based suppression assay. RESULTS: The frequency of Treg in peripheral blood of PSC patients was significantly decreased. We confirmed this finding by demonstrating a reduction of non-methylated DNA in the Treg-specific demethylated FOXP3 gene region of peripheral blood cells in PSC patients. Reduced peripheral Treg numbers were significantly associated with homozygosity for the major allele of the SNP "rs10905718" in the IL2RA gene. Intrahepatic FOXP3(+) cell numbers at the time of initial diagnosis were decreased in PSC as compared to PBC. In addition to reduced numbers, the suppressive capacity of Treg isolated from PSC patients seemed to be impaired as compared to healthy controls. CONCLUSIONS: Our findings indicate that Treg impairment may play a role in the immune dysregulation observed in PSC. Reduced Treg numbers in patients with PSC are associated with polymorphisms in the IL2RA gene