Cross-talk between CD14 and complement receptor 3 promotes phagocytosis of mycobacteria: Regulation by phosphatidylinositol 3-kinase and cytohesin-1

Khalid Sendide, Neil E. Reiner, Jimmy S.I. Lee, Sylvain Bourgoin, Amina Talal, Zakaria Hmama

Research output: Contribution to journalArticle

67 Scopus citations

Abstract

The glycosylphosphatidyl anchored molecule CD14 to the monocyte membrane plays a prominent role in innate immunity, and the paradigms for CD14 selective signaling are beginning to be elucidated. In this study, transfected human monocytic cell line THP-1 and Chinese hamster ovary (CHO) fibroblastic cells were used to examine phagocytosis of Mycobacterium bovis bacillus Calmette-Guérin (BCG). Flow cytometry was combined with molecular and biochemical approaches to demonstrate a dual mechanism for BCG internalization involving either CD14 alone or a CD14-regulated complement receptor (CR)3-dependent pathway. Phagocytosis by CD14-positive THP-1 cells was attenuated by phosphatidylinositol-3 inhibitors LY294002 and wortmannin and experiments using transfected CHO cells showed substantial accumalation of phosphatidylinositol-3,4,5-trisphosphate at the BCG attachment site in CHO cells expressing CD14 and TLR2 suggesting that bacteria bind to CD14 and use TLR2 to initiate a PI3K signaling pathway. Additional esperiments using blocking Abs showed that anti-TLR2 Abs inhibit phagocytosis of BCG by THP-1 cells. Furthermore, knockdown of cytohesin-1, a PI3K-regulated adaptor molecule for β2 integrin activation, specifically abrogated CD14-reguIated CR3 ingestion of BCG consistent with the observation of physical association between CM3 and cytohesin-1 in cells stimulated with mycobacterial surface components. These findings reveal that mycobacteria promote their aptake through a process of "inside-out" signaling involving CD14, TLR2, PI3K, and cytohesin-1. This converts low avidity CR3 into an active receptor leading to increased bacterial internalization.

Original languageEnglish (US)
Pages (from-to)4210-4219
Number of pages10
JournalJournal of Immunology
Volume174
Issue number7
DOIs
Publication statusPublished - Apr 1 2005
Externally publishedYes

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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