Critical role for serum opsonins and complement receptors CR3 (CD11b/CD18) and CR4 (CD11c/CD18) in phagocytosis of Francisella tularensis by human dendritic cells (DC)

Uptake of Francisella leads to activation of immature DC and intracellular survival of the bacteria

Abdelhakim Ben Nasr, Judith Haithcoat, Joseph E. Masterson, John S. Gunn, Tonyia Eaves-Pyles, Gary R. Klimpel

Research output: Contribution to journalArticle

83 Citations (Scopus)

Abstract

Francisella tularensis is one of the most infectious human pathogens known. Although much has been learned about the immune response of mice using an attenuated live vaccine strain (LVS) derived from F. tularensis subspecies holarctica (Type B), little is known about the responses of human monocyte-derived immature dendritic cells (DC). Here, we show that optimal phagocytosis of LVS by DC is dependent on serum opsonization. We demonstrate that complement factor C3-derived opsonins and the major complement receptors expressed by DC, the integrins CR3 (CD11b/CD18) and CR4 (CD11c/CD18), play a critical role in this adhesion-mediated phagocytosis. LVS induced proinflammatory cytokine production and up-regulation of costimulatory surface proteins (CD40, CD86, and MHC Class II) on DC but resisted killing. Once taken up, LVS grew intracellularly, resulting in DC death. DC maturation and cytokine production were induced by direct contact/phagocytosis of LVS or interaction with soluble products of the bacteria, and enhanced activation was seen when LVS was pretreated with serum. Sonicated LVS and supernatants from LVS cultures were potent activators of DC, but LVS LPS failed to activate DC maturation or cytokine production. Serum-treated LVS rapidly induced (within 6 h) a number of cytokines including IL-10, a potent suppressor of macrophage functions and down-regulator of Th1-like responses and the Th1 response inducer IL-12. These results suggest that the simultaneous production of an activating (IL-12, IL-1β, and TNF-α) and a suppressing (IL-10) cytokine profile could contribute to the immunopathogenesis of tularemia.

Original languageEnglish (US)
Pages (from-to)774-786
Number of pages13
JournalJournal of Leukocyte Biology
Volume80
Issue number4
DOIs
StatePublished - Oct 2006

Fingerprint

Francisella
Francisella tularensis
Complement Receptors
Phagocytosis
Dendritic Cells
Cell Survival
Vaccines
Bacteria
Serum
Cytokines
Interleukin-12
Interleukin-10
Opsonin Proteins
Tularemia
opsonin receptor
Attenuated Vaccines
Complement C3
Interleukin-1
Integrins
Monocytes

Keywords

  • Bacterial infection
  • Cytokines
  • Innate immunity
  • Lipopolysacchiride
  • LPS

ASJC Scopus subject areas

  • Cell Biology

Cite this

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title = "Critical role for serum opsonins and complement receptors CR3 (CD11b/CD18) and CR4 (CD11c/CD18) in phagocytosis of Francisella tularensis by human dendritic cells (DC): Uptake of Francisella leads to activation of immature DC and intracellular survival of the bacteria",
abstract = "Francisella tularensis is one of the most infectious human pathogens known. Although much has been learned about the immune response of mice using an attenuated live vaccine strain (LVS) derived from F. tularensis subspecies holarctica (Type B), little is known about the responses of human monocyte-derived immature dendritic cells (DC). Here, we show that optimal phagocytosis of LVS by DC is dependent on serum opsonization. We demonstrate that complement factor C3-derived opsonins and the major complement receptors expressed by DC, the integrins CR3 (CD11b/CD18) and CR4 (CD11c/CD18), play a critical role in this adhesion-mediated phagocytosis. LVS induced proinflammatory cytokine production and up-regulation of costimulatory surface proteins (CD40, CD86, and MHC Class II) on DC but resisted killing. Once taken up, LVS grew intracellularly, resulting in DC death. DC maturation and cytokine production were induced by direct contact/phagocytosis of LVS or interaction with soluble products of the bacteria, and enhanced activation was seen when LVS was pretreated with serum. Sonicated LVS and supernatants from LVS cultures were potent activators of DC, but LVS LPS failed to activate DC maturation or cytokine production. Serum-treated LVS rapidly induced (within 6 h) a number of cytokines including IL-10, a potent suppressor of macrophage functions and down-regulator of Th1-like responses and the Th1 response inducer IL-12. These results suggest that the simultaneous production of an activating (IL-12, IL-1β, and TNF-α) and a suppressing (IL-10) cytokine profile could contribute to the immunopathogenesis of tularemia.",
keywords = "Bacterial infection, Cytokines, Innate immunity, Lipopolysacchiride, LPS",
author = "Nasr, {Abdelhakim Ben} and Judith Haithcoat and Masterson, {Joseph E.} and Gunn, {John S.} and Tonyia Eaves-Pyles and Klimpel, {Gary R.}",
year = "2006",
month = "10",
doi = "10.1189/jlb.1205755",
language = "English (US)",
volume = "80",
pages = "774--786",
journal = "Journal of Leukocyte Biology",
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TY - JOUR

T1 - Critical role for serum opsonins and complement receptors CR3 (CD11b/CD18) and CR4 (CD11c/CD18) in phagocytosis of Francisella tularensis by human dendritic cells (DC)

T2 - Uptake of Francisella leads to activation of immature DC and intracellular survival of the bacteria

AU - Nasr, Abdelhakim Ben

AU - Haithcoat, Judith

AU - Masterson, Joseph E.

AU - Gunn, John S.

AU - Eaves-Pyles, Tonyia

AU - Klimpel, Gary R.

PY - 2006/10

Y1 - 2006/10

N2 - Francisella tularensis is one of the most infectious human pathogens known. Although much has been learned about the immune response of mice using an attenuated live vaccine strain (LVS) derived from F. tularensis subspecies holarctica (Type B), little is known about the responses of human monocyte-derived immature dendritic cells (DC). Here, we show that optimal phagocytosis of LVS by DC is dependent on serum opsonization. We demonstrate that complement factor C3-derived opsonins and the major complement receptors expressed by DC, the integrins CR3 (CD11b/CD18) and CR4 (CD11c/CD18), play a critical role in this adhesion-mediated phagocytosis. LVS induced proinflammatory cytokine production and up-regulation of costimulatory surface proteins (CD40, CD86, and MHC Class II) on DC but resisted killing. Once taken up, LVS grew intracellularly, resulting in DC death. DC maturation and cytokine production were induced by direct contact/phagocytosis of LVS or interaction with soluble products of the bacteria, and enhanced activation was seen when LVS was pretreated with serum. Sonicated LVS and supernatants from LVS cultures were potent activators of DC, but LVS LPS failed to activate DC maturation or cytokine production. Serum-treated LVS rapidly induced (within 6 h) a number of cytokines including IL-10, a potent suppressor of macrophage functions and down-regulator of Th1-like responses and the Th1 response inducer IL-12. These results suggest that the simultaneous production of an activating (IL-12, IL-1β, and TNF-α) and a suppressing (IL-10) cytokine profile could contribute to the immunopathogenesis of tularemia.

AB - Francisella tularensis is one of the most infectious human pathogens known. Although much has been learned about the immune response of mice using an attenuated live vaccine strain (LVS) derived from F. tularensis subspecies holarctica (Type B), little is known about the responses of human monocyte-derived immature dendritic cells (DC). Here, we show that optimal phagocytosis of LVS by DC is dependent on serum opsonization. We demonstrate that complement factor C3-derived opsonins and the major complement receptors expressed by DC, the integrins CR3 (CD11b/CD18) and CR4 (CD11c/CD18), play a critical role in this adhesion-mediated phagocytosis. LVS induced proinflammatory cytokine production and up-regulation of costimulatory surface proteins (CD40, CD86, and MHC Class II) on DC but resisted killing. Once taken up, LVS grew intracellularly, resulting in DC death. DC maturation and cytokine production were induced by direct contact/phagocytosis of LVS or interaction with soluble products of the bacteria, and enhanced activation was seen when LVS was pretreated with serum. Sonicated LVS and supernatants from LVS cultures were potent activators of DC, but LVS LPS failed to activate DC maturation or cytokine production. Serum-treated LVS rapidly induced (within 6 h) a number of cytokines including IL-10, a potent suppressor of macrophage functions and down-regulator of Th1-like responses and the Th1 response inducer IL-12. These results suggest that the simultaneous production of an activating (IL-12, IL-1β, and TNF-α) and a suppressing (IL-10) cytokine profile could contribute to the immunopathogenesis of tularemia.

KW - Bacterial infection

KW - Cytokines

KW - Innate immunity

KW - Lipopolysacchiride

KW - LPS

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U2 - 10.1189/jlb.1205755

DO - 10.1189/jlb.1205755

M3 - Article

VL - 80

SP - 774

EP - 786

JO - Journal of Leukocyte Biology

JF - Journal of Leukocyte Biology

SN - 0741-5400

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ER -