Phagocytosis of leprosy bacilli is mediated by complement receptors CR1 and CR3 on human monocytes and complement component C3 in serum.

Schlesinger, Larry S.; Horwitz, Marcus A.

doi:10.1172/jci114568

Cited by 119 publications

(113 citation statements)

References 48 publications

(31 reference statements)

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“…We confirmed these results using siRNA; when downregulation of CD11b blocked the phagocytosis of opsonized particles while silencing CD11c had no effect on their uptake (Sándor et al, 2013 leprae (Schlesinger & Horwitz, 1990), similarly to neutrophils in the case of Francisella tularensis (Schwartz et al, 2012). In our present study we show that in the phagocytosis of the extracellular S. aureus opsonized by iC3b, CR3 plays a dominant role over CR4 by both monocytes and neutrophils.…”

Section: Discussionsupporting

confidence: 70%

The role of CR3 (CD11b/CD18) and CR4 (CD11c/CD18) in complement-mediated phagocytosis and podosome formation by human phagocytes

et al. 2017

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CR3 and CR4 belong to the family of β 2 -integrins and play an important role in phagocytosis, cellular adherence and migration. CR3 and CR4 are generally expected to mediate similar functions due to their structural homology, overlapping ligand specificity and parallel expression on human phagocytes. Although the different signalling pathways of these receptors suggest distinct functions, possible differences are just being revealed.Previously we proved that CR3 plays a key role in the uptake of iC3b-opsonized particles by human dendritic cells. Now, besides measuring the overall phagocytic capacity of cells including the assessment of surface bound as well as internalized particles, we extended our investigations and studied the digestion of the iC3b opsonized antigen by various human phagocytes. The participation of CR3 and CR4 was compared in the process of binding, internalization and digestion of iC3b opsonized Staphylococcus aureus by monocytes, monocyte derived macrophages (MDMs), monocyte derived dendritic cells (MDDCs), and neutrophils. Comparing the activity of the two β 2 -integrin type complement receptors we found that CR3 plays a dominant role in the phagocytosis of iC3b opsonized S. aureus by all of these cell types. Studying another important integrin-mediated function we demonstrated earlier thatCR4 is dominant in the adhesion of monocytes, MDMs and MDDCs to fibrinogen. Here we studied the participation of CR3 and CR4 in podosome formation by human phagocytes, since these structures are known to play an essential role in cell migration. Our confocal microscopy analysis revealed that both CD11b and CD11c concentrate in the podosome adhesion ring. In summary our data highlight differences in the function of human CR3 and CR4 in the process of uptake and digestion of complement opsonized antigen, while in the process of podosome formation, connected to cellular motility, both receptors equally take part. Keywordsphagocytosis, podosomes, human phagocytes, β 2 integrins, CR3 (CD11b/CD18), CR4 (CD11c/CD18) Highlights -CR3 is the dominant receptor mediating the phagocytosis of iC3b opsonized S. aureus -surface bound and digested bacteria should be distinguished -MDDCs have a unique podosome pattern compared to monocytes, MDMs and neutrophils -both CR3 and CR4 are located in the adhesion ring of podosomes

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Section: Discussionsupporting

confidence: 70%

The role of CR3 (CD11b/CD18) and CR4 (CD11c/CD18) in complement-mediated phagocytosis and podosome formation by human phagocytes

et al. 2017

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“…In the absence of complement opsonization, the O-antigen mutants are internalized by a looping phagocytosis process that resembles that of the parental LVS, and in the presence of complement, they are internalized by tightly adherent and often redundant pseudopod loops. In both cases, they are internalized by a process that differs markedly from the conventional zipper-like phagocytosis that we have observed for other bacteria, such as E. coli, Mycobacterium tuberculosis, and Mycobacterium leprae (8,16,32,33), indicating that factors other than the O antigen are important in the altered phagocytic process. The uptake of the complement-opsonized, O-antigendeficient LVS by relatively tight asymmetric loops or by multiple layers of tightly juxtaposed pseudopods resembles a process that has been called "overlapping phagocytosis" by Rittig et al in their description of the uptake of Leishmania promastigotes and of the spirochete Borrelia burgdorferi (27,28).…”

Section: Discussionmentioning

confidence: 55%

O-Antigen-Deficient Francisella tularensis Live Vaccine Strain Mutants Are Ingested via an Aberrant Form of Looping Phagocytosis and Show Altered Kinetics of Intracellular Trafficking in Human Macrophages

2012

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We examined the uptake and intracellular trafficking of F. tularensis Live Vaccine Strain (LVS) and LVS with disruptions of wbt-DEF and wbtI genes essential for synthesis of the O antigen of lipopolysaccharide. Unlike parental bacteria, O-antigen-deficient LVS is efficiently killed by serum with intact complement but not by serum lacking terminal complement components. Opsonization of O-antigen-deficient LVS in serum lacking terminal complement components allows efficient uptake of these live bacteria by macrophages. In the presence of complement, whereas parental F. tularensis LVS is internalized within spacious pseudopod loops, mutant LVS is internalized within tightly juxtaposed multiple onion-like layers of pseudopodia. Without complement, both parental and mutant LVSs are internalized within spacious pseudopod loops. Thus, molecules other than O antigen are important in triggering dramatic pseudopod extensions and uptake by spacious pseudopod loops. Following uptake, both parental and mutant LVSs enter compartments that show limited staining for the lysosomal membrane glycoprotein CD63 and little fusion with secondary lysosomes. Subsequently, both parental and mutant LVSs lose their CD63 staining. Whereas the majority of parental LVS escapes into the cytosol by 6 h after uptake, mutant LVS shows a marked lag but does escape by 1 day after uptake. Despite the altered kinetics of phagosome escape, both mutant and parental strains grow to high levels within human macrophages. Thus, the O antigen plays a role in the morphology of uptake in the presence of complement and the kinetics of intracellular growth but is not essential for escape, survival, altered membrane trafficking, or intramacrophage growth.

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“…29 and 30). For example, Leishmania major (31,32), Legionella pneumophilia (33), Mycobacterium leprae (34), and Mycobacterium tuberculosis (35) all activate complement and become coated with C3b or its derivatives, and then enter host macrophages via CR1 or CR3. Other pathogens express surface ligands that bind directly to complement control proteins, such as the Dr-like Ags of Escherichia coli that adhere to decay-accelerating factor (36), and measles virus hemagglutinin that binds to CD46 (37).…”

Section: Discussionmentioning

confidence: 99%

Mapping of the Region of Complement Receptor (CR) 1 Required forPlasmodium falciparumRosetting and Demonstration of the Importance of CR1 in Rosetting in Field Isolates

Rowe

Rogerson

Raza

et al. 2000

The Journal of Immunology

104

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The malaria parasite Plasmodium falciparum induces a number of novel adhesion properties in the erythrocytes that it infects. One of these properties, the ability of infected erythrocytes to bind uninfected erythrocytes to form rosettes, is associated with severe malaria and may play a direct role in the pathogenesis of disease. Previous work has shown that erythrocytes deficient in complement receptor (CR) 1 (CR1, CD35; C3b/C4b receptor) have greatly reduced rosetting capacity, indicating an essential role for CR1 in rosette formation. Using deletion mutants and mAbs, we have localized the region of CR1 required for the formation of P. falciparum rosettes to the area of long homologous repeat regions B and C that also acts as the binding site for the activated complement component C3b. This result raises the possibility that C3b could be an intermediary in rosetting, bridging between the infected erythrocyte and CR1. We were able to exclude this hypothesis, however, as parasites grown in C3-deficient human serum formed rosettes normally. We have also shown in this report that rosettes can be reversed by mAb J3B11 that recognizes the C3b binding site of CR1. This rosette-reversing activity was demonstrated in a range of laboratory-adapted parasite strains and field isolates from Kenya and Malawi. Thus, we have mapped the region of CR1 required for rosetting and demonstrated that the CR1-dependent rosetting mechanism occurs commonly in P. falciparum isolates, and could therefore be a potential target for future therapeutic interventions to treat severe malaria.

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Phagocytosis of leprosy bacilli is mediated by complement receptors CR1 and CR3 on human monocytes and complement component C3 in serum.

Cited by 119 publications

References 48 publications

The role of CR3 (CD11b/CD18) and CR4 (CD11c/CD18) in complement-mediated phagocytosis and podosome formation by human phagocytes

The role of CR3 (CD11b/CD18) and CR4 (CD11c/CD18) in complement-mediated phagocytosis and podosome formation by human phagocytes

O-Antigen-Deficient Francisella tularensis Live Vaccine Strain Mutants Are Ingested via an Aberrant Form of Looping Phagocytosis and Show Altered Kinetics of Intracellular Trafficking in Human Macrophages

Mapping of the Region of Complement Receptor (CR) 1 Required forPlasmodium falciparumRosetting and Demonstration of the Importance of CR1 in Rosetting in Field Isolates

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