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The Duffy antigen modifies systemic and local tissue chemokine responses following lipopolysaccharide stimulation.

ABSTRACT: The Duffy blood group Ag (dfy) binds selective CXC and CC chemokines at high affinity and is expressed on erythrocytes and endothelial cells. However, it does not transmit a signal via G proteins, as occurs with other seven-transmembrane receptors. We hypothesized that dfy functions as a chemokine reservoir and regulates inflammation by altering soluble chemokine concentrations in the blood and tissue compartments. We determined whether Duffy Ag "loss-of-function" phenotypes (human and murine) are associated with alterations in plasma chemokine concentrations during the innate inflammatory response to LPS. Plasma CXCL8 and CCL2 concentrations from humans homozygous for the GATA-1 box polymorphism, a dfy polymorphism that abrogates erythrocyte chemokine binding, were higher than in heterozygotes following LPS stimulation of their whole blood in vitro. Similarly, dfy(-/-) mice showed higher plasma MIP-2 concentrations than dfy(+/+) mice following LPS stimulation of whole blood in vitro. We then determined the relative contributions of erythrocyte and endothelial Duffy Ag in modifying chemokine concentrations and neutrophil recruitment in the lungs following intratracheal LPS administration in dfy(-/-) and dfy(+/+) mice reconstituted with dfy(-/-) or dfy(+/+) marrow. Mice lacking endothelial dfy expression had higher MIP-2 and keratinocyte chemoattractant concentrations in the airspaces. Mice lacking erythrocyte dfy had higher MIP-2 and keratinocyte chemoattractant concentrations in the lung tissue vascular space, but lower plasma chemokine concentrations associated with attenuated neutrophil recruitment into the airspaces. These data indicate that dfy alters soluble chemokine concentrations in blood and local tissue compartments and enhances systemic bioavailability of chemokines produced during local tissue inflammation.

SUBMITTER: Lee JS

PROVIDER: S-EPMC2665269 | biostudies-literature | 2006 Dec

REPOSITORIES: biostudies-literature

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The Duffy antigen modifies systemic and local tissue chemokine responses following lipopolysaccharide stimulation.

Lee Janet S JS Wurfel Mark M MM Matute-Bello Gustavo G Frevert Charles W CW Rosengart Matthew R MR Ranganathan Mrunalini M Wong Venus W VW Holden Tarah T Sutlief Steve S Richmond Ann A Peiper Stephen S Martin Thomas R TR

Journal of immunology (Baltimore, Md. : 1950) 20061201 11

The Duffy blood group Ag (dfy) binds selective CXC and CC chemokines at high affinity and is expressed on erythrocytes and endothelial cells. However, it does not transmit a signal via G proteins, as occurs with other seven-transmembrane receptors. We hypothesized that dfy functions as a chemokine reservoir and regulates inflammation by altering soluble chemokine concentrations in the blood and tissue compartments. We determined whether Duffy Ag "loss-of-function" phenotypes (human and murine) a ...[more]

PMID: 17114483

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Project description:BACKGROUND:The epithelium is the first line of defense against pathogens. Notably the epithelial cells lining the respiratory track are crucial in sensing airborne microbes and mounting an effective immune response via the expression of target genes such as cytokines and chemokines. Gene expression regulation following microbial recognition is partly regulated by chromatin re-organization and has been described in immune cells but data from epithelial cells is not as detailed. Here, we report genome-wide changes of the H3K27ac mark, characteristic of activated enhancers and promoters, after stimulation of nasopharyngeal epithelial cells with the bacterial endotoxin Lipopolysaccharide (LPS). RESULTS:In this study, we have identified 626 regions where the H3K27ac mark showed reproducible increase following LPS induction in epithelial cells. This indicated that sensing of LPS led to opening of the chromatin in our system. Moreover, this phenomenon seemed to happen extensively at enhancers regions and we could observe instances of Super-enhancer formation. As expected, LPS-increased H3K27ac regions were found in the vicinity of genes relevant for LPS response and these changes correlated with up-regulation of their expression. In addition, we found the induction of H3K27ac mark to overlap with the binding of one of the NF-kB members and key regulator of the innate immune response, RELA, following LPS sensing. Indeed, inhibiting the NF-kB pathway abolished the deposition of H3K27ac at the TNF locus, a target of RELA, suggesting that these two phenomena are associated. CONCLUSIONS:Enhancers' selection and activation following microbial or inflammatory stimuli has been described previously and shown to be mediated via the NF-kB pathway. Here, we demonstrate that this is also likely to occur in the case of LPS-sensing by nasopharyngeal epithelial cells as well. In addition to validating previous findings, we generated a valuable data set relevant to the host immune response to epithelial cell colonizing or infecting pathogens.

Project description:Background: Microglial activation after systemic infection has been suggested to mediate sepsis-associated delirium. A systematic review of animal studies suggested distinct differences between microglial activation after systemic challenge with live bacteria and lipopolysaccharide (LPS). Here, we describe a mouse model of microglial activation after systemic challenge with live Escherichia coli (E. coli) and compare results with systemic challenge with LPS. Methods: Sixty mice were intraperitoneally injected with E. coli (1 × 104 colony-forming units) and sacrificed at 12, 20, 48, and 72 h after inoculation. For 48 and 72 h time points, mice were treated with ceftriaxone. Thirty mice were intraperitoneally injected with LPS (5 mg/kg) and sacrificed 3 and 48 h after inoculation; 48 control mice were intraperitoneally injected with isotonic saline. Microglial response was monitored by immunohistochemical staining with Iba-1 antibody and flow cytometry; and inflammatory response by mRNA expression of pro- and anti-inflammatory mediators. Results: Mice infected with live E. coli showed microglial activation 72 h post-inoculation, with increased cell number in cortex (p = 0.0002), hippocampus (p = 0.003), and thalamus (p = 0.0001), but not in the caudate nucleus/putamen (p = 0.33), as compared to controls. At 72 h, flow cytometry of microglia from E. coli infected mice showed increased cell size (p = 0.03) and CD45 expression (p = 0.03), but no increase in CD11b expression, and no differences in brain mRNA expression of inflammatory mediators as compared to controls. In mice with systemic LPS stimulation, microglial cells were morphologically activated at the 48 h time point with increased cell numbers in cortex (p = 0.002), hippocampus (p = 0.0003), thalamus (p = 0.007), and caudate nucleus/putamen (p < 0.0001), as compared to controls. At 48 h, flow cytometry of microglia from LPS stimulated mice showed increased cell size (p = 0.03), CD45 (p = 0.03), and CD11b (p = 0.04) expression. Brain mRNA expression of TNF-α (p = 0.02), IL-1β (p = 0.02), and MCP-1 (p = 0.03) were increased as compared to controls. Interpretation: Systemic challenge with live E. coli causes a neuro-inflammatory response, but this response occurs at a later time point and is less vigorous as compared to LPS stimulation.The E. coli model mimics the clinical situation of infection associated delirium more closely than stimulation with supra-natural LPS.

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The Duffy antigen modifies systemic and local tissue chemokine responses following lipopolysaccharide stimulation.

Publications

The Duffy antigen modifies systemic and local tissue chemokine responses following lipopolysaccharide stimulation.

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