Journal
JOURNAL OF LEUKOCYTE BIOLOGY
Volume 91, Issue 6, Pages 849-857Publisher
FEDERATION AMER SOC EXP BIOL
DOI: 10.1189/jlb.0311164
Keywords
apoplipoprotein E; cell death; foamy macrophages; host defense; hypercholesterolemi; low-density lipoprotein receptor; Mycobacterium tuberculosis
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Funding
- NIH [HL081149]
- Diabetes Endocrinology Research Center [DK32520]
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The prevalence of hypercholesterolemia is rising in industrialized and developing countries. We reported previously that host defense against Mtb was impaired by hypercholesterolemia in ApoE(-)(-/) mice, raising the possibility that people with HC could be more vulnerable to TB. The present study examined whether TB immunity was similarly impaired in a different hypercholesterolemic model, LDL-R-/- mice, which developed comparable elevation of total serum cholesterol as ApoE(-/-) mice when fed HC or LC diets. Like ApoE(-/-) mice, LDL-R-/- mice had an exaggerated lung inflammatory response to Mtb with increased tissue necrosis. Inflammation, foamy macrophage formation, and tissue necrosis in LDL-R-/- mice increased with the degree of hypercholesterolemia. Unlike ApoE(-/-) mice, LDL-R-/- mice fed a HC diet mounted a timely and protective adaptive immune response that restricted mycobacterial replication comparably with WT mice. Thus, ApoE(-/-) and LDL-R-/- mice share a cholesterol-dependent hyperinflammatory TB phenotype but do not share the impairment of adaptive immunity found in ApoE(-/-) mice. The impact of hypercholesterolemia on TB immunity is more complex than appreciated by total cholesterol alone, possibly reflecting the different functional effect of specific lipoprotein particles. J. Leukoc. Biol. 91: 849-857; 2012.
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