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. 1997 Jun;91(2):289–296. doi: 10.1046/j.1365-2567.1997.00238.x

CR3-dependent phagocytosis by murine macrophages: different cytokines regulate ingestion of a defined CR3 ligand and complement-opsonized Cryptococcus neoformans.

C E Cross 1, H L Collins 1, G J Bancroft 1
PMCID: PMC1363860  PMID: 9227330

Abstract

Phagocytosis is a fundamental process in innate resistance to infection. We have used the pathogenic yeast Cryptococcus neoformans to study the interaction of this encapsulated organism with murine macrophages in vitro. In the absence of exogenous opsonins the encapsulated yeast is almost totally resistant to ingestion by murine macrophages. Owing to its ability to activate the alternative complement pathway, the anti-phagocytic properties of the polysaccharide capsule can be partially overcome following opsonization in vitro with non-immune mouse serum and subsequent phagocytosis via complement receptors. Here, we demonstrate the importance of the complement receptor type 3 (CR3) in in vitro phagocytosis of the yeast and in in vivo resistance to infection. In vitro, 70% of a population of resident murine macrophages are able to ingest C. neoformans and then only inefficiently (1-2 organisms per cell). Previously we have shown that tumour necrosis factor-alpha (TNF-alpha) and granulocyte-macrophage colony-stimulating factor (GM-CSF) efficiently enhance ingestion of serum-opsonized encapsulated C. neoformans, and we now show that the cytokines convert a population of resident macrophages to a state where all the cells are competent for ingestion of large numbers of yeasts (6-8 per cell). We also show that these cytokines have a direct effect on CR3, as enhanced levels of complement-opsonized sheep red blood cells (EIgMC) bind to macrophages activated in this way. However, cytokines that have previously been shown to enhance phagocytosis of EIgMC have no effect on ingestion of encapsulated C. neoformans. These results demonstrate that the cytokines regulating CR3-dependent ingestion of C. neoformans are different to those regulating ingestion of EIgMC and reinforce the importance of studying pathogens rather than inert ligands in understanding the regulation of phagocytosis.

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Selected References

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  1. Berger M., Wetzler E. M., Wallis R. S. Tumor necrosis factor is the major monocyte product that increases complement receptor expression on mature human neutrophils. Blood. 1988 Jan;71(1):151–158. [PubMed] [Google Scholar]
  2. Blom M., Tool A. T., Kok P. T., Koenderman L., Roos D., Verhoeven A. J. Granulocyte-macrophage colony-stimulating factor, interleukin-3 (IL-3), and IL-5 greatly enhance the interaction of human eosinophils with opsonized particles by changing the affinity of complement receptor type 3. Blood. 1994 May 15;83(10):2978–2984. [PubMed] [Google Scholar]
  3. Brown E. J. Complement receptors and phagocytosis. Curr Opin Immunol. 1991 Feb;3(1):76–82. doi: 10.1016/0952-7915(91)90081-b. [DOI] [PubMed] [Google Scholar]
  4. Cooper D., Butcher C. M., Berndt M. C., Vadas M. A. P-selectin interacts with a beta 2-integrin to enhance phagocytosis. J Immunol. 1994 Oct 1;153(7):3199–3209. [PubMed] [Google Scholar]
  5. Cross C. E., Bancroft G. J. Ingestion of acapsular Cryptococcus neoformans occurs via mannose and beta-glucan receptors, resulting in cytokine production and increased phagocytosis of the encapsulated form. Infect Immun. 1995 Jul;63(7):2604–2611. doi: 10.1128/iai.63.7.2604-2611.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Detmers P. A., Zhou D., Powell D. E. Different signaling pathways for CD18-mediated adhesion and Fc-mediated phagocytosis. Response of neutrophils to LPS. J Immunol. 1994 Sep 1;153(5):2137–2145. [PubMed] [Google Scholar]
  7. Diamond M. S., Staunton D. E., Marlin S. D., Springer T. A. Binding of the integrin Mac-1 (CD11b/CD18) to the third immunoglobulin-like domain of ICAM-1 (CD54) and its regulation by glycosylation. Cell. 1991 Jun 14;65(6):961–971. doi: 10.1016/0092-8674(91)90548-d. [DOI] [PubMed] [Google Scholar]
  8. Drevets D. A., Campbell P. A. Roles of complement and complement receptor type 3 in phagocytosis of Listeria monocytogenes by inflammatory mouse peritoneal macrophages. Infect Immun. 1991 Aug;59(8):2645–2652. doi: 10.1128/iai.59.8.2645-2652.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Graham I. L., Gresham H. D., Brown E. J. An immobile subset of plasma membrane CD11b/CD18 (Mac-1) is involved in phagocytosis of targets recognized by multiple receptors. J Immunol. 1989 Apr 1;142(7):2352–2358. [PubMed] [Google Scholar]
  10. Granger D. L., Hibbs J. B., Jr, Perfect J. R., Durack D. T. Specific amino acid (L-arginine) requirement for the microbiostatic activity of murine macrophages. J Clin Invest. 1988 Apr;81(4):1129–1136. doi: 10.1172/JCI113427. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Hazenbos W. L., van den Berg B. M., van Furth R. Very late antigen-5 and complement receptor type 3 cooperatively mediate the interaction between Bordetella pertussis and human monocytes. J Immunol. 1993 Dec 1;151(11):6274–6282. [PubMed] [Google Scholar]
  12. Kozel T. R., Pfrommer G. S., Guerlain A. S., Highison B. A., Highison G. J. Strain variation in phagocytosis of Cryptococcus neoformans: dissociation of susceptibility to phagocytosis from activation and binding of opsonic fragments of C3. Infect Immun. 1988 Nov;56(11):2794–2800. doi: 10.1128/iai.56.11.2794-2800.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Levitz S. M., Tabuni A. Binding of Cryptococcus neoformans by human cultured macrophages. Requirements for multiple complement receptors and actin. J Clin Invest. 1991 Feb;87(2):528–535. doi: 10.1172/JCI115027. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Loenen W. A., De Vries E., Gravestein L. A., Hintzen R. Q., Van Lier R. A., Borst J. The CD27 membrane receptor, a lymphocyte-specific member of the nerve growth factor receptor family, gives rise to a soluble form by protein processing that does not involve receptor endocytosis. Eur J Immunol. 1992 Feb;22(2):447–455. doi: 10.1002/eji.1830220224. [DOI] [PubMed] [Google Scholar]
  15. Mosser D. M., Springer T. A., Diamond M. S. Leishmania promastigotes require opsonic complement to bind to the human leukocyte integrin Mac-1 (CD11b/CD18). J Cell Biol. 1992 Jan;116(2):511–520. doi: 10.1083/jcb.116.2.511. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Neuman E., Huleatt J. W., Jack R. M. Granulocyte-macrophage colony-stimulating factor increases synthesis and expression of CR1 and CR3 by human peripheral blood neutrophils. J Immunol. 1990 Nov 15;145(10):3325–3332. [PubMed] [Google Scholar]
  17. Newman S. L., Mikus L. K., Tucci M. A. Differential requirements for cellular cytoskeleton in human macrophage complement receptor- and Fc receptor-mediated phagocytosis. J Immunol. 1991 Feb 1;146(3):967–974. [PubMed] [Google Scholar]
  18. Rabb H., Michishita M., Sharma C. P., Brown D., Arnaout M. A. Cytoplasmic tails of human complement receptor type 3 (CR3, CD11b/CD18) regulate ligand avidity and the internalization of occupied receptors. J Immunol. 1993 Jul 15;151(2):990–1002. [PubMed] [Google Scholar]
  19. Rosen H., Gordon S. Monoclonal antibody to the murine type 3 complement receptor inhibits adhesion of myelomonocytic cells in vitro and inflammatory cell recruitment in vivo. J Exp Med. 1987 Dec 1;166(6):1685–1701. doi: 10.1084/jem.166.6.1685. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Rosen H., Gordon S., North R. J. Exacerbation of murine listeriosis by a monoclonal antibody specific for the type 3 complement receptor of myelomonocytic cells. Absence of monocytes at infective foci allows Listeria to multiply in nonphagocytic cells. J Exp Med. 1989 Jul 1;170(1):27–37. doi: 10.1084/jem.170.1.27. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Ross G. D., Cain J. A., Lachmann P. J. Membrane complement receptor type three (CR3) has lectin-like properties analogous to bovine conglutinin as functions as a receptor for zymosan and rabbit erythrocytes as well as a receptor for iC3b. J Immunol. 1985 May;134(5):3307–3315. [PubMed] [Google Scholar]
  22. Sampson L. L., Heuser J., Brown E. J. Cytokine regulation of complement receptor-mediated ingestion by mouse peritoneal macrophages. M-CSF and IL-4 activate phagocytosis by a common mechanism requiring autostimulation by IFN-beta. J Immunol. 1991 Feb 1;146(3):1005–1013. [PubMed] [Google Scholar]
  23. Schelenz S., Malhotra R., Sim R. B., Holmskov U., Bancroft G. J. Binding of host collectins to the pathogenic yeast Cryptococcus neoformans: human surfactant protein D acts as an agglutinin for acapsular yeast cells. Infect Immun. 1995 Sep;63(9):3360–3366. doi: 10.1128/iai.63.9.3360-3366.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Schlesinger L. S., Horwitz M. A. Phagocytosis of Mycobacterium leprae by human monocyte-derived macrophages is mediated by complement receptors CR1 (CD35), CR3 (CD11b/CD18), and CR4 (CD11c/CD18) and IFN-gamma activation inhibits complement receptor function and phagocytosis of this bacterium. J Immunol. 1991 Sep 15;147(6):1983–1994. [PubMed] [Google Scholar]
  25. Schlesinger L. S. Macrophage phagocytosis of virulent but not attenuated strains of Mycobacterium tuberculosis is mediated by mannose receptors in addition to complement receptors. J Immunol. 1993 Apr 1;150(7):2920–2930. [PubMed] [Google Scholar]
  26. Stahl P. D. The mannose receptor and other macrophage lectins. Curr Opin Immunol. 1992 Feb;4(1):49–52. doi: 10.1016/0952-7915(92)90123-v. [DOI] [PubMed] [Google Scholar]
  27. Van Strijp J. A., Russell D. G., Tuomanen E., Brown E. J., Wright S. D. Ligand specificity of purified complement receptor type three (CD11b/CD18, alpha m beta 2, Mac-1). Indirect effects of an Arg-Gly-Asp (RGD) sequence. J Immunol. 1993 Sep 15;151(6):3324–3336. [PubMed] [Google Scholar]
  28. Wilson M. E., Pearson R. D. Roles of CR3 and mannose receptors in the attachment and ingestion of Leishmania donovani by human mononuclear phagocytes. Infect Immun. 1988 Feb;56(2):363–369. doi: 10.1128/iai.56.2.363-369.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Wright S. D., Meyer B. C. Phorbol esters cause sequential activation and deactivation of complement receptors on polymorphonuclear leukocytes. J Immunol. 1986 Mar 1;136(5):1759–1764. [PubMed] [Google Scholar]

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