CR3 (CD11b/CD18) and CR4 (CD11c/CD18) Are Involved in Complement-Independent Antibody-Mediated Phagocytosis of Cryptococcus neoformans

Taborda, Carlos Pelleschi; Casadevall, Arturo

doi:10.1016/s1074-7613(02)00328-x

Cited by 162 publications

(176 citation statements)

References 40 publications

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“…␣ M ␤ 2 and ␣ X ␤ 2 bind to heparin and not chondroitin sulfate (39), and to the glucuronic acid derivative glucuronoxylomannan (40). In agreement, we found inhibition by heparin and not chondroitin sulfate of I domain binding to Fg (Fig.…”

Section: Neutrophil Adhesion To Protease-digested Fgsupporting

confidence: 86%

Exposure of acidic residues as a danger signal for recognition of fibrinogen and other macromolecules by integrin α_Xβ₂

Vorup-Jensen

Carman

Shimaoka

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

117

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The structural integrity of tissue proteins is damaged in processes ranging from remodeling of the extracellular matrix to destruction by microbial pathogens. Leukocytes play a prominent role in tissue surveillance and repair. However, it remains enigmatic what features of structurally decayed proteins prompt recognition by leukocyte cell-surface receptors. Here, we report that adhesion of human neutrophil granulocytes to fibrinogen is greatly increased by plasmin digestion in a mode where ␣X␤2 dominates the integrindependent binding. The bacterial protease subtilisin also enhances binding by ␣X␤2. The ␣X ligand binding domain has an unusually high affinity for carboxyl groups, with KD at Ϸ100 M. Our findings implicate enhanced accessibility of negatively charged residues in structurally decayed proteins as a pattern recognition motif for ␣ X ␤ 2 integrin. Comparisons among integrins show relevance of these findings to the large number of ligands recognized by ␣M␤2 and ␣X␤2 but not ␣L␤2. The observations suggest that the pericellular proteolysis at the leading edge of neutrophils not only facilitates passage through the extracellular matrix but also manufactures binding sites for ␣X␤2.plasmin ͉ scavenger receptor T he detrimental influence of unfolded or denatured proteins and the importance of regulating removal are underscored for the intracellular environment in eukaryotes by the high elaboration of the ubiquitination pathway. By contrast, little is known about how damaged proteins are recognized in the extracellular compartment, particularly given the broad range of cleavages catalyzed by the vast array of proteolytic enzymes to which the extracellular environment is exposed. Infectious agents, inflammatory cells, and processes including coagulation, wound healing, angiogenesis, and tissue remodeling in development engender structural decay of proteins. Evidence from murine leukocytes implicates so-called macrophage scavenger receptors in binding denatured collagen (1). However, the best characterized scavenger receptor ligands are a diverse range of polyanionic species such as modified low-density lipoprotein and lipopolysaccharides (2). Myeloid leukocytes bind to an exceedingly large number of protein ligands as well as denatured protein (3) through the structurally and functionally similar ␣ X ␤ 2 (p150,95, CD18͞CD11c) and ␣ M ␤ 2 (Mac-1, CD18͞CD11b) integrins, but the molecular basis for recognition of multiple ligands and selectivity for denatured proteins remains obscure.Fibrinogen (Fg) is one of the best studied ligands of ␣ M ␤ 2 and ␣ X ␤ 2 (4, 5). Plasma Fg, derived from hepatic synthesis, assembles after cleavage by thrombin into fibrin in hemostasis. However, it has recently been established that Fg is also secreted by epithelial cells in inflammation and is assembled together with fibronectin independently of thrombin into fibrils in the extracellular matrix during wound repair (6, 7). The receptor for urokinase-type plasminogen activator closely associates with both ␣ X ␤ 2 and ␣ M ␤ 2 in the c...

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Section: Neutrophil Adhesion To Protease-digested Fgsupporting

confidence: 86%

Exposure of acidic residues as a danger signal for recognition of fibrinogen and other macromolecules by integrin α_Xβ₂

Vorup-Jensen

Carman

Shimaoka

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

117

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“…Indeed, recent experiments have demonstrated that mAbs of the IgM isotype directed against the KEX1 protein of P. carinii were able to control growth of P. carinii when injected intranasally into SCID mice (19). Additionally, it has been shown that IgM Abs can mediate clearance of another fungal pathogen, Cryptococcus neoformans (35). However, our data using CD40KO mice (Figs.…”

Section: Discussioncontrasting

confidence: 56%

Clearance ofPneumocystis cariniiin Mice Is Dependent on B Cells But Not onP. carinii-Specific Antibody

Lund

Schuer

Hollifield

et al. 2003

The Journal of Immunology

107

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Both CD4+ T cells and B cells are critical for defense against Pneumocystis carinii infection; however, the mechanism by which B cells mediate protection is unknown. We show that P. carinii-specific IgM is not sufficient to mediate clearance of P. carinii from the lungs since CD40-deficient mice produced normal levels of specific IgM, but were unable to clear the organisms. Using chimeric mice in which the B cells were deficient in CD40 (CD40KO chimeras) we found that clearance of P. carinii infection is delayed compared with wild-type controls. These CD40KO chimeric mice produced normal levels of P. carinii-specific IgM, but did not produce class-switched IgG or IgA. Similarly, clearance of P. carinii was delayed in mice deficient in FcγRI and III (FcγRKO), indicating that P. carinii-specific IgG partially mediates opsonization and clearance of P. carinii. Opsonization of organisms by complement did not compensate for the lack of specific IgG or FcγR, since C3-deficient and C3-depleted FcγRKO mice were still able to clear P. carinii. Finally, μMT and CD40KO chimeric mice had reduced numbers of activated CD4+ T cells in the lungs and lymph nodes compared with wild-type mice, suggesting that B cells are important for activation of T cells in response to P. carinii. Together these data indicate that P. carinii-specific IgG plays an important, but not critical, role in defense against P. carinii. Moreover, these data suggest that B cells also mediate host defense against P. carinii by facilitating CD4+ T cell activation or expansion.

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“…In fact, direct evidence for a requirement for TLR2 in phagocytosis of mycobacteria was demonstrated using transfected CHO cells. Such transfectants are considered valid and highly useful models to study macrophage functions including phagocytosis (19,51) and wild type CHO cells express a nonfunctional TLR2 (52). Coexpression of both CD14 and TLR2 (CHO/ CD14/TLR2) markedly enhanced uptake of BCG consistent with the finding that blocking anti-TLR2 but not anti-TLR4 mAbs significantly inhibited phagocytosis of BCG by THP-1wt.…”

Section: Discussionmentioning

confidence: 99%

Cross-Talk between CD14 and Complement Receptor 3 Promotes Phagocytosis of Mycobacteria: Regulation by Phosphatidylinositol 3-Kinase and Cytohesin-1

Sendide

Reiner

Lee

et al. 2005

The Journal of Immunology

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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 accumulation 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 experiments 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-regulated CR3 ingestion of BCG consistent with the observation of physical association between CR3 and cytohesin-1 in cells stimulated with mycobacterial surface components. These findings reveal that mycobacteria promote their uptake 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.

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CR3 (CD11b/CD18) and CR4 (CD11c/CD18) Are Involved in Complement-Independent Antibody-Mediated Phagocytosis of Cryptococcus neoformans

Cited by 162 publications

References 40 publications

Exposure of acidic residues as a danger signal for recognition of fibrinogen and other macromolecules by integrin α_Xβ₂

Exposure of acidic residues as a danger signal for recognition of fibrinogen and other macromolecules by integrin α_Xβ₂

Clearance ofPneumocystis cariniiin Mice Is Dependent on B Cells But Not onP. carinii-Specific Antibody

Cross-Talk between CD14 and Complement Receptor 3 Promotes Phagocytosis of Mycobacteria: Regulation by Phosphatidylinositol 3-Kinase and Cytohesin-1

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CR3 (CD11b/CD18) and CR4 (CD11c/CD18) Are Involved in Complement-Independent Antibody-Mediated Phagocytosis of Cryptococcus neoformans

Cited by 162 publications

References 40 publications

Exposure of acidic residues as a danger signal for recognition of fibrinogen and other macromolecules by integrin αXβ2

Exposure of acidic residues as a danger signal for recognition of fibrinogen and other macromolecules by integrin αXβ2

Clearance ofPneumocystis cariniiin Mice Is Dependent on B Cells But Not onP. carinii-Specific Antibody

Cross-Talk between CD14 and Complement Receptor 3 Promotes Phagocytosis of Mycobacteria: Regulation by Phosphatidylinositol 3-Kinase and Cytohesin-1

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Product

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Exposure of acidic residues as a danger signal for recognition of fibrinogen and other macromolecules by integrin α_Xβ₂

Exposure of acidic residues as a danger signal for recognition of fibrinogen and other macromolecules by integrin α_Xβ₂