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Dyslipidemia induces opposing effects on intrapulmonary and extrapulmonary host defense through divergent TLR response phenotypes.

ABSTRACT: Dyslipidemia influences innate immune responses in the bloodstream, but whether and how pulmonary innate immunity is sensitive to circulating lipoproteins is largely unknown. To define whether dyslipidemia impacts responses to bacteria in the airspace and, if so, whether differently from its effects in other tissues, airspace, bloodstream, and i.p. responses to LPS and Klebsiella pneumoniae were investigated using murine models of dyslipidemia. Dyslipidemia reduced neutrophil (PMN) recruitment to the airspace in response to LPS and K. pneumoniae by impairing both chemokine induction in the airspace and PMN chemotaxis, thereby compromising pulmonary bacterial clearance. Paradoxically, bacteria were cleared more effectively from the bloodstream during dyslipidemia. This enhanced systemic response was due, at least in part, to basal circulating neutrophilia and basal TLR4/MyD88-dependent serum cytokine induction and enhanced serum cytokine responses to systemically administered TLR ligands. Dyslipidemia did not globally impair PMN transvascular trafficking to, and host defense within all loci, because neutrophilia, cytokine induction, and bacterial clearance were enhanced within the infected peritoneum. Peritoneal macrophages from dyslipidemic animals were primed for more robust TLR responses, reflecting increased lipid rafts and increased TLR4 expression, whereas macrophages from the airspace, in which cholesterol was maintained constant during dyslipidemia, had normal responses and rafts. Dyslipidemia thus imparts opposing effects upon intra- and extrapulmonary host defense by inducing tissue-divergent TLR response phenotypes and dysregulating airspace/blood compartmental levels of PMNs and cytokines. We propose that the airspace is a "privileged" site, thereby uniquely sensitive to dyslipidemia.

SUBMITTER: Madenspacher JH

PROVIDER: S-EPMC3959792 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

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Dyslipidemia induces opposing effects on intrapulmonary and extrapulmonary host defense through divergent TLR response phenotypes.

Madenspacher Jennifer H JH Draper David W DW Smoak Kathleen A KA Li Haitao H Griffiths Gary L GL Suratt Benjamin T BT Wilson Martha D MD Rudel Lawrence L LL Fessler Michael B MB

Journal of immunology (Baltimore, Md. : 1950) 20100625 3

Dyslipidemia influences innate immune responses in the bloodstream, but whether and how pulmonary innate immunity is sensitive to circulating lipoproteins is largely unknown. To define whether dyslipidemia impacts responses to bacteria in the airspace and, if so, whether differently from its effects in other tissues, airspace, bloodstream, and i.p. responses to LPS and Klebsiella pneumoniae were investigated using murine models of dyslipidemia. Dyslipidemia reduced neutrophil (PMN) recruitment t ...[more]

PMID: 20581153

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Dataset Information

Dyslipidemia induces opposing effects on intrapulmonary and extrapulmonary host defense through divergent TLR response phenotypes.

Publications

Dyslipidemia induces opposing effects on intrapulmonary and extrapulmonary host defense through divergent TLR response phenotypes.

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