Journal
JOURNAL OF IMMUNOLOGY
Volume 189, Issue 3, Pages 1459-1466Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1200484
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Funding
- National Institutes of Health [DK074727, DK082427, AI089700]
- Clinical Nutrition Research Center at Harvard [P30 DK040561]
- Inflammatory Bowel Disease [DK43351]
- Boston Area Diabetes and Endocrinology Research Center [DK57521]
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Autophagy is an important mechanism used by macrophages to kill intracellular pathogens. The results reported in this study demonstrate that autophagy is also involved in the macrophage killing of the extracellular enteropathogen Citrobacter rodentium after phagocytosis. The process was significantly impaired in macrophages isolated from mice chronically infected with the helminth parasite Heligmosomoides polygyrus. The H. polygyrus-mediated inhibition of autophagy was Th2 dependent because it was not observed in macrophages isolated from helminth-infected STAT6-deficient mice. Moreover, autophagy of Citrobacter was inhibited by treating macrophages with IL-4 and IL-13. The effect of H. polygyrus on autophagy was associated with decreased expression and processing of L chain protein 3 (LC3), a key component of the autophagic machinery. The helminth-induced inhibition of LC3 expression and processing was STAT6 dependent and could be recapitulated by treatment of macrophages with IL-4 and IL-13. Knockdown of LC3 significantly inhibited autophagic killing of Citrobacter, attesting to the functional importance of the H. polygyrus-mediated downregulation of this process. These observations reveal a new aspect of the immunosuppressive effects of helminth infection and provide mechanistic insights into our earlier finding that H. polygyrus significantly worsens the in vivo course of Citrobacter infection. The Journal of Immunology, 2012, 189: 1459-1466.
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