A Leucine-Rich Repeat Motif of <i>Leishmania</i> Parasite Surface Antigen 2 Binds to Macrophages through the Complement Receptor 3

Kędzierski, Łukasz; Montgomery, Jacqui; Bullen, Denise V. R.; Curtis, Joan M.; Gardiner, Elizabeth E.; Jiménez-Ruı́z, Antonio; Handman, Emanuela

doi:10.4049/jimmunol.172.8.4902

Cited by 75 publications

(67 citation statements)

References 31 publications

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“…Of these, we cannot implicate FcgR for the changes brought about by Leishmania contact, because opsonized parasites were not used by us. The role of CR3 cannot be ruled out completely because L. major surface molecule PSA has been shown to bind with host monocyte CR3 receptor [37]. Signaling through MR has been extensively implicated in the subversion of macrophage proinflammatory responses in another important intracellular infection, M. tuberculosis [38].…”

Section: Discussionmentioning

confidence: 99%

Leishmania donovaniinfection down-regulates TLR2-stimulated IL-12p40 and activates IL-10 in cells of macrophage/monocytic lineage by modulating MAPK pathways through a contact-dependent mechanism

Chandra

Naik

2008

Clinical and Experimental Immunology

114

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SummaryThe failure of Leishmania, an intracellular pathogen, to stimulate a proinflammatory response following entry into macrophages has been well reported. This occurs in spite of the fact that ligands for the toll-like receptors (TLR) have been recently shown on the parasite surface and their role in disease protection well documented. The outcome of infection in leishmaniasis is determined by the Th1 versus Th2 nature of the effector response and the generation of IL-12 and IL-10 by the infected macrophages is important for this decision. We evaluated the effect of L. donovani infection of monocytes (cell line THP-1, and monocytes derived from human peripheral blood) on Pam3cys (TLR2 ligand) and lipopolysaccharide (TLR4 ligand) stimulated production of IL-12p40 and IL-10. L. donovani infection caused suppression of TLR2 and TLR4-stimulated IL-12p40, with an increase in IL-10 production. Parasites also modulated the TLR2-stimulated mitogen-activated protein kinase (MAPK) pathway by suppressing MAPK P 38 phosphorylation and activating extracellular regulated kinase (ERK)1/2 phosphorylation. These effects could be reversed either by using a MAPK P 38 activator, anisomycin, or ERK1/2 inhibitor, U0126. L. donovani caused modulation of TLR2-stimulated MAPK pathways in a contact-dependent mechanism. In addition parasite structural integrity but not viability was required for suppression of TLR2-stimulated IL-12p40 and activation of IL-10. These observations suggest that L. donovani has evolved survival strategies that subvert the proinflammatory response generated through TLRs.

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Section: Discussionmentioning

confidence: 99%

Leishmania donovaniinfection down-regulates TLR2-stimulated IL-12p40 and activates IL-10 in cells of macrophage/monocytic lineage by modulating MAPK pathways through a contact-dependent mechanism

Chandra

Naik

2008

Clinical and Experimental Immunology

114

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“…parasites with normal mouse serum is not necessary for inhibition (data not shown), suggesting that CR3 ligation is not mediating the interaction. However, MP are able to synthesize complement components (McPhaden and Whaley, 1993) that opsonize parasites even in serum-free conditions (Wozencraft et al, 1986) and parasite components have been suggested to bind CR3 directly (Russell and Wright, 1988;Talamas-Rohana et al, 1990;Kedzierski et al, 2004). Furthermore, the repetitive structure and glycan modifications associated with many Leishmania spp.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional Inhibition of Interleukin-12 Promoter Activity in Leishmania Spp.–Infected Macrophages

Jayakumar

Widenmaier

et al. 2008

Journal of Parasitology

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To establish and persist within a host, Leishmania spp. parasites delay the onset of cell-mediated immunity by suppressing interleukin-12 (IL-12) production from host macrophages. Although it is established that Leishmania spp.-infected macrophages have impaired IL-12 production, the mechanisms that account for this suppression remain to be completely elucidated. Using a luciferase reporter assay assessing IL-12 transcription, we report here that Leishmania major, Leishmania donovani, and Leishmania chagasi inhibit IL-12 transcription in response to interferon-gamma, lipopolysaccharide, and CD40 ligand and that Leishmania spp. lipophosphoglycan, phosphoglycans, and major surface protein are not necessary for inhibition. In addition, all the Leishmania spp. strains and life-cycle stages tested inhibited IL-12 promoter activity. Our data further reveal that autocrineacting host factors play no role in the inhibitory response and that phagocytosis signaling is necessary for inhibition of IL-12.The hallmark of an intracellular pathogen is its ability to survive within the intracellular niche. These organisms must be resistant to, or able to evade, the host cell's microbiocidal mechanisms. This dilemma is particularly relevant to Leishmania spp. because these organisms primarily reside within vertebrate macrophages (MP). These host cells become activated for microbial destruction and cytokine secretion by exposure to immune modulators, such as interferon-gamma (IFN-γ) and CD40 ligand (CD40L) found on activated T-cells. One strategy Leishmania spp. parasites use to avoid host cell activation is to interfere with the signaling pathways that induce MP to become microbicidal (Gregory and Olivier, 2005); another is inhibiting or delaying the production of activating cytokines (Belkaid et al., 2000).The most consistent dysfunction reported from Leishmania spp.-infected MP is the aberrant production of inflammatory cytokines, specifically an inhibition of interleukin-12 (IL-12) production (McDowell and Sacks, 1999). Being essential for T-helper 1 (Th1) cell differentiation, the inability of Leishmania spp.-infected MP to produce IL-12 allows Leishmania spp. to evade acquired resistance by postponing IL-12 production and the induction of IFN-γ, thereby allowing the establishment of the infection; both clinical and experimental studies indicate that the onset of Th1-mediated immunity and Leishmania spp. killing is indeed delayed (Melby, 1991). Inhibition of MP IL-12 production and resulting Th1 responses is not unique to Leishmania; viruses (Chehimi et al., 1994;Chougnet et al., 1996;Karp et 1996) and bacteria (Marth and Kelsall, 1997;Sutterwala et al., 1997;Matsunaga et al., 2003) also exploit this mechanism to avoid clearance.The general nature of impaired IL-12 production in Leishmania spp.-infected MP has extended to every IL-12 agonist that has been tested. Leishmania spp.-infected MP are unable to produce IL-12 even in response to strong inflammatory stimuli, including microbial stimuli, e.g., lipopolysacchar...

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“…Another macrophage cell surface receptor that has acquired multiple, relatively low-affinity ligand binding activities is the CR3 complement receptor, which recognizes a range of ligands, including opsonized bacteria and viruses, Leishmania surface antigens, intracellular adhesion molecule-1, and fibrinogen, and can also mediate macrophage adhesion (117,118).…”

Section: Why So Many Receptors? Why So Many Ligands?mentioning

confidence: 99%

Thematic review series: The Immune System and Atherogenesis. Recent insights into the biology of macrophage scavenger receptors

Greaves

Gordon

2005

Journal of Lipid Research

188

115

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Scavenger receptors were originally defined by their ability to bind and internalize modified lipoproteins. Macrophages express at least six structurally different cell surface receptors for modified forms of LDL that contribute to foam cell formation in atherosclerosis. In addition to their role in the pathology of atherosclerosis, macrophage scavenger receptors, especially SR-A, play critical roles in innate immunity, apoptotic cell clearance, and tissue homeostasis. In this review, we highlight recent advances in understanding the biology of macrophage scavenger receptors as pattern recognition receptors for both infectious nonself (pathogens) and modified self (apoptotic cells and modified LDL). We critically evaluate the potential of scavenger receptors and their ligands as targets for therapeutic intervention in human disease. -Greaves, D. R., and S. Gordon. MACROPHAGE-DERIVED FOAM CELLSFatty streaks, which are the earliest forms of atherosclerotic lesion visible in the artery wall, consist almost entirely of macrophage-derived foam cells (1-3). Monocytes that have been recruited to the subendothelial space at sites of endothelial cell activation differentiate into macrophages and express a range of scavenger receptors, which mediate the endocytic uptake of modified forms of LDL (4). Brown, Goldstein, and colleagues (5, 6) coined the term "scavenger receptor" to distinguish the uptake of modified LDL by macrophages from LDL uptake via the classical LDL receptor, which is feedback inhibited by the accumulation of cholesterol within the cell. Molecular cloning and biochemical characterization of the cellular receptors that mediate the uptake of modified forms of LDL have revealed an unexpectedly large number of endocytic receptors (7, 8). These membrane proteins have widely different structures, and all the scavenger receptors characterized to date bind a number of ligands of biological importance other than modified LDL. Even more puzzling is the recently described scavenger receptor SR-PSOX (scavenger receptor that binds phosphatidylserine and oxidized lipoprotein), which can act both as a receptor [for oxidized LDL (OxLDL)] and as a ligand (the membranebound CXC chemokine, CXCL16).Their lack of feedback inhibition by intracellular cholesterol has made macrophage scavenger receptors scapegoats for the development of macrophage foam cell formation in the artery wall, but it is important to recognize that other metabolic pathways play an important role in the development of cholesteryl ester deposits in macrophage foam cells. Modified apolipoprotein B (apoB)-containing lipoproteins taken up via scavenger receptors are delivered to lysosomes and hydrolyzed to release free cholesterol and fatty acids. The conversion of free cholesterol into cholesteryl esters in macrophages is catalyzed by the enzyme ACAT, and free cholesterol can be converted by the mitochondrial enzyme Cyp27 into 27-hydroxycholesterol, one of several oxysterols that activate changes in macrophage foam cell transcription via the nuc...

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A Leucine-Rich Repeat Motif of Leishmania Parasite Surface Antigen 2 Binds to Macrophages through the Complement Receptor 3

Cited by 75 publications

References 31 publications

Leishmania donovaniinfection down-regulates TLR2-stimulated IL-12p40 and activates IL-10 in cells of macrophage/monocytic lineage by modulating MAPK pathways through a contact-dependent mechanism

Leishmania donovaniinfection down-regulates TLR2-stimulated IL-12p40 and activates IL-10 in cells of macrophage/monocytic lineage by modulating MAPK pathways through a contact-dependent mechanism

Transcriptional Inhibition of Interleukin-12 Promoter Activity in Leishmania Spp.–Infected Macrophages

Thematic review series: The Immune System and Atherogenesis. Recent insights into the biology of macrophage scavenger receptors

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