INTERACTIONS BETWEEN BIOLOGICAL SEX AND THE X-LINKED VARIANT IRAK1 HAPLOTYPE IN MODULATING CLINICAL OUTCOME AND CELLULAR PHENOTYPES AFTER TRAUMA.

Sex-related outcome differences in trauma remain controversial. The mechanisms causing sex-biased outcomes are likely to have hormonal and genetic components, in which X-linked genetic polymorphisms may play distinct roles because of X-linked inheritance, hemizygosity in males, and X chromosome mosaicism in females. The study aimed to elucidate the contribution of biological sex and the common X-linked IRAK1 haplotype to posttrauma clinical complications, inflammatory cytokine and chemokine production, and polymorphonuclear cell and monocyte activation.

Directional X Chromosome Skewing of White Blood Cells from Subjects with Heterozygous Mosaicism for the Variant IRAK1 Haplotype.

Random X chromosome (ChrX) inactivation and consequent cellular mosaicism for the active ChrXs in white blood cells (WBCs) is unique to females and may contribute to sex-biased modulation of the innate immune response. Polymorphic differences between the two parental ChrXs may result in ChrX skewing of circulating WBCs (ChrX inactivation-ratio (XCI) > 3) driven by differences in stem cell selection and activity in the bone marrow or WBC trafficking at the periphery. Independent of the mechanism, ChrX skewing may result in genotype-phenotype discrepancies.

X-Linked IRAK1 Polymorphism is Associated with Sex-Related Differences in Polymorphonuclear Granulocyte and Monocyte Activation and Response Variabilities.

Common X-linked genetic polymorphisms are expected to alter cellular responses affecting males and females differently through sex-linked inheritance pattern as well as X chromosome (ChrX) mosaicism and associated ChrX skewing, which is unique to females. We tested this hypothesis in ex vivo lipopolysaccharide and phorbol ester-stimulated polymorphonuclear granulocytes (PMNs) and monocytes from healthy volunteers (n = 51). Observations were analyzed after stratification by sex alone or the presence of variant IRAK1 haplotype a common X-linked polymorphism with previously demonstrated major clinical impacts.

Dopaminergic Control of Inflammation and Glycemia in Sepsis and Diabetes.

Most preclinical treatments for sepsis failed in clinical trials in part because the experimental models of sepsis were performed on healthy animals that do not mimic septic patients. Here, we report that experimental diabetes worsens glycemia, inflammation, and mortality in experimental sepsis. Diabetes increases hyperglycemia, systemic inflammation, and mortality in sepsis.

Inherent X-Linked Genetic Variability and Cellular Mosaicism Unique to Females Contribute to Sex-Related Differences in the Innate Immune Response.

Females have a longer lifespan and better general health than males. Considerable number of studies also demonstrated that, after trauma and sepsis, females present better outcomes as compared to males indicating sex-related differences in the innate immune response. The current notion is that differences in the immuno-modulatory effects of sex hormones are the underlying causative mechanism.

Trauma-Induced Acute X Chromosome Skewing in White Blood Cells Represents an Immuno-Modulatory Mechanism Unique to Females and a Likely Contributor to Sex-Based Outcome Differences.

Sex-related outcome disparities following severe trauma have been demonstrated in human and animal studies; however, sex hormone status could not fully account for the differences. This study tested whether X-linked cellular mosaicism, which is unique to females, could represent a genetically based mechanism contributing to sex-related immuno-modulation following trauma. Serial blood samples collected for routine laboratory tests were analyzed for ChrX inactivation (XCI) ratios in white blood cells.

Extracellular ATP protects against sepsis through macrophage P2X7 purinergic receptors by enhancing intracellular bacterial killing.

Extracellular ATP binds to and signals through P2X7 receptors (P2X7Rs) to modulate immune function in both inflammasome-dependent and -independent manners. In this study, P2X7(-/-) mice, the pharmacological agonists ATP-magnesium salt (Mg-ATP; 100 mg/kg, EC50 ≈ 1.32 mM) and benzoylbenzoyl-ATP (Bz-ATP; 10 mg/kg, EC50 ≈ 285 μM), and antagonist oxidized ATP (oxi-ATP; 40 mg/kg, IC50 ≈ 100 μM) were used to show that P2X7R activation is crucial for the control of mortality, bacterial dissemination, and inflammation in cecal ligation and puncture-induced polymicrobial sepsis in mice.

Cellular mosaicism for X-linked polymorphisms and IRAK1 expression presents a distinct phenotype and improves survival following sepsis.

ChrX cellular mosaicism for X-linked genetic polymorphisms in females versus the single ChrX representation in males denotes a genetic difference, which may contribute to gender bias in the inflammatory response. This hypothesis was tested in female F1 offspring of consomic mice (BL6J-ChrX(A/J)/NaJ) that were homokaryotic or mosaic for the active BL6 and AJ ChrXs or for IRAK1 deficiency linked to the BL6 ChrX. Sepsis was initiated by CLP.

IRAK1-dependent signaling mediates mortality in polymicrobial sepsis.

Interleukin-1 receptor-associated kinase (IRAK1) is a key regulatory protein in TLR/IL1R-mediated cell activation during inflammatory response. Studies indicated that pending on the nature of the used inflammatory model, downregulation of IRAK1 may be beneficial or detrimental. However, the role of IRAK1 in affecting outcome in polymicrobial sepsis is unknown.

Ecto-5'-nucleotidase (CD73) decreases mortality and organ injury in sepsis.

The extracellular concentrations of adenosine are increased during sepsis, and adenosine receptors regulate the host's response to sepsis. In this study, we investigated the role of the adenosine-generating ectoenzyme, ecto-5'-nucleotidase (CD73), in regulating immune and organ function during sepsis. Polymicrobial sepsis was induced by subjecting CD73 knockout (KO) and wild type (WT) mice to cecal ligation and puncture.

Female X-chromosome mosaicism for NOX2 deficiency presents unique inflammatory phenotype and improves outcome in polymicrobial sepsis.

Cellular X-chromosome mosaicism, which is unique to females, may be advantageous during pathophysiological challenges compared with the single X-chromosome machinery of males, and it may contribute to gender dimorphism in the inflammatory response. We tested the hypothesis of whether cellular mosaicism for the X-linked gp91phox (NOX2) deficiency, the catalytic component of the superoxide anion-generating NADPH oxidase complex, is advantageous during polymicrobial sepsis. Deficient, wild-type (WT), and heterozygous/mosaic mice were compared following polymicrobial sepsis initiated by cecal ligation and puncture.

Intravenous injection of mesenteric lymph produced during hemorrhagic shock decreases RBC deformability in the rat.

Objective: To test the hypothesis that gut-derived factors carried in trauma-hemorrhagic shock (T/HS) lymph are sufficient to induce red blood cells (RBC) injury, to investigate their potential mechanisms of action, and to define the time post-T/HS that these factors appear in the lymph.

Methods: Mesenteric lymph collected from T/HS or trauma-sham shock (T/SS) rats over different time periods was injected intravenously into male rats at a rate of 1 mL/h for 3 hours. RBC deformability was measured using laser-assisted ektacytometer to calculate the elongation index.

Female X-chromosome mosaicism for gp91phox expression diversifies leukocyte responses during endotoxemia.

Objective: To test the hypothesis, using an animal model, whether female X-chromosome mosaicism for inflammatory gene expression could contribute to the gender dimorphic response during the host response. X-chromosome-linked genetic polymorphisms present a unique biological condition because females display heterozygous cellular mosaicism, due to the fact that either the maternal or the paternal X chromosomes are inactivated in each individual cell in females. This is in contrast with the conditions in males who carry exclusively the maternal X chromosome.

A2B adenosine receptors protect against sepsis-induced mortality by dampening excessive inflammation.

Despite intensive research, efforts to reduce the mortality of septic patients have failed. Adenosine is a potent extracellular signaling molecule, and its levels are elevated in sepsis. Adenosine signals through G-protein-coupled receptors and can regulate the host's response to sepsis.

CB2 cannabinoid receptors contribute to bacterial invasion and mortality in polymicrobial sepsis.

Background: Sepsis is a major healthcare problem and current estimates suggest that the incidence of sepsis is approximately 750,000 annually. Sepsis is caused by an inability of the immune system to eliminate invading pathogens. It was recently proposed that endogenous mediators produced during sepsis can contribute to the immune dysfunction that is observed in sepsis.

Trauma-hemorrhagic shock-induced red blood cell damage leads to decreased microcirculatory blood flow.

Objective: To test the hypothesis that trauma-hemorrhagic shock (T/HS)-induced changes in red blood cells (RBC) contribute to the reduction of blood flow in distant organs.

Design: Laboratory study.

Setting: Academic medical center laboratory.

Adenosine A2A receptor activation inhibits T helper 1 and T helper 2 cell development and effector function.

Adenosine is an immunosuppressive nucleoside, and adenosine A(2A) receptors inhibit T-cell activation. We investigated the role of A(2A) receptors in regulating T helper (Th)1- and Th2-cell development and effector function. A(2A)-receptor stimulation suppressed the development of T-cell receptor (TCR) -stimulated naive T cells into both Th1 and Th2 cells, as indicated by decreased IFN-gamma production by cells developed under Th1-skewing conditions and decreased interleukin (IL) -4, IL-5, and IL-10 production by cells developed under Th2-skewing conditions.

Endotoxemia down-regulates bone marrow lymphopoiesis but stimulates myelopoiesis: the effect of G6PD deficiency.

Bone marrow (BM) dysfunction is an important component of immunomodulation. This study investigated alterations in cell content, apoptotic responses, and cell proliferation in BM, blood, and spleen in endotoxemic mice (LPS from Escherichia coli). As the decreased antioxidant status associated with glucose-6-phosphate dehydrogenase (G6PD) deficiency has been shown to modulate the innate immune response, we also tested whether a G6PD mutation (80% decrease in cellular enzyme activity) alters BM responses during endotoxemia.

Sphingosine 1-phosphate has dual functions in the regulation of endothelial cell permeability and Ca2+ metabolism.

Ca2+ signaling plays an important role in endothelial cell (EC) functions including the regulation of barrier integrity. Recently, the endogenous lipid derivative, sphingosine-1-phosphate (S1P), has emerged as an important modulator of EC barrier function. We investigated the role of endogenously generated S1P in Ca2+ metabolism and barrier function in human umbilical endothelial cells (HUVECs) stimulated by thrombin, histamine, or other agonists.

The X-files of inflammation: cellular mosaicism of X-linked polymorphic genes and the female advantage in the host response to injury and infection.

Females as compared with males display better general health status, longevity, and improved clinical course after injury and infection. It is generally believed that the female advantage is associated with the effects of sex hormones. This review argues that the sex benefit of females during the host response is associated with polymorphism of X-linked genes and cellular mosaicism for X-linked parental alleles.

Augmented erythrocyte band-3 phosphorylation in septic mice.

Infection-induced RBC dysfunction has been shown to play a role in the modulation of host response to injury and infection. The underlying biochemical mechanisms are not known. This study investigated alterations in RBC band-3 phosphorylation status and its relationship to anion exchange activity in vitro as well as under in vivo septic conditions induced by cecal ligation and puncture (CLP) in mice.

Glucose-6-phosphate dehydrogenase deficiency and the inflammatory response to endotoxin and polymicrobial sepsis.

Objective: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a common human genetic polymorphism. The deficiency protects against malaria but was shown to worsen the clinical course after severe trauma. This study tested whether the deficiency is associated with altered cytokine responses in vitro and in vivo and affects survival after endotoxemia or polymicrobial sepsis (cecal ligation and puncture).