Abnormal trafficking and degradation of TLR4 underlie the elevated inflammatory response in cystic fibrosis

Emanuela M. Bruscia, Ping Xia Zhang, Ayano Satoh, Christina Caputo, Ruslan Medzhitov, Ambika Shenoy, Marie E. Egan, Diane S. Krause

Research output: Contribution to journalArticle

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Abstract

Morbidity and mortality in cystic fibrosis (CF) are due not only to abnormal epithelial cell function, but also to an abnormal immune response. We have shown previously that macrophages lacking CF transmembrane conductance regulator (CFTR), the gene mutated in CF, contribute significantly to the hyperinflammatory response observed in CF. In this study, we show that lack of functional CFTR in murine macrophages causes abnormal TLR4 subcellular localization. Upon LPS stimulation, CFTR macrophages have prolonged TLR4 retention in the early endosome and reduced translocation into the lysosomal compartment. This abnormal TLR4 trafficking leads to increased LPS-induced activation of the NF-κB, MAPK, and IFN regulatory factor-3 pathways and decreased TLR4 degradation, which affects downregulation of the proinflammatory state. In addition to primary murine cells, mononuclear cells isolated from CF patients demonstrate similar defects in response to LPS. Moreover, specific inhibition of CFTR function induces abnormal TLR4 trafficking and enhances the inflammatory response of wild-type murine cells to LPS. Thus, functional CFTR in macrophages influences TLR4 spatial and temporal localization and perturbs LPS-mediated signaling in both murine CF models and patients with CF.

Original languageEnglish
Pages (from-to)6990-6998
Number of pages9
JournalJournal of Immunology
Volume186
Issue number12
DOIs
Publication statusPublished - Jun 15 2011

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Cystic Fibrosis
Macrophages
Interferon Regulatory Factor-3
Cystic Fibrosis Transmembrane Conductance Regulator
Endosomes
Regulator Genes
Down-Regulation
Epithelial Cells
Morbidity
Mortality

ASJC Scopus subject areas

  • Immunology

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Abnormal trafficking and degradation of TLR4 underlie the elevated inflammatory response in cystic fibrosis. / Bruscia, Emanuela M.; Zhang, Ping Xia; Satoh, Ayano; Caputo, Christina; Medzhitov, Ruslan; Shenoy, Ambika; Egan, Marie E.; Krause, Diane S.

In: Journal of Immunology, Vol. 186, No. 12, 15.06.2011, p. 6990-6998.

Research output: Contribution to journalArticle

Bruscia, EM, Zhang, PX, Satoh, A, Caputo, C, Medzhitov, R, Shenoy, A, Egan, ME & Krause, DS 2011, 'Abnormal trafficking and degradation of TLR4 underlie the elevated inflammatory response in cystic fibrosis', Journal of Immunology, vol. 186, no. 12, pp. 6990-6998. https://doi.org/10.4049/jimmunol.1100396
Bruscia, Emanuela M. ; Zhang, Ping Xia ; Satoh, Ayano ; Caputo, Christina ; Medzhitov, Ruslan ; Shenoy, Ambika ; Egan, Marie E. ; Krause, Diane S. / Abnormal trafficking and degradation of TLR4 underlie the elevated inflammatory response in cystic fibrosis. In: Journal of Immunology. 2011 ; Vol. 186, No. 12. pp. 6990-6998.
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