Normal Host Defense during Systemic Candidiasis in Mannose Receptor-Deficient Mice

Abstract

Pathogen pattern recognition receptors (PRRs) recognize common structural and molecular motifs present on microbial surfaces and contribute to induction of innate immune responses. The mannose receptor (MR), a carbohydrate-binding receptor expressed on subsets of macrophages, is considered one such PRR. In vitro experiments have implicated the MR in phagocytosis of mannose-bearing microbes, including Candida albicans, and enhancement of antifungal response by macrophages. However, the significance of the MR's contribution to immune response during systemic C. albicans infection has never been directly demonstrated. Using MRdeficient mice in an in vivo infection experiment, we examined the role of the MR in immune response during disseminated candidiasis. MR ؊/؊ and wild-type control mice were challenged intraperitoneally with C. albicans, and the survival rates, tissue fungal burden, inflammatory cell recruitment, and specific antibody production after infection were evaluated. We found no significant difference in survival between the two mouse strains. MR ؊/؊ mice had higher average fungal burdens in some of the organs on days 7 and 21 but exhibited competence in inflammatory cell recruitment and antibody production. We also observed in vitro that MR ؊/؊ peritoneal cavity macrophages were equally capable of C. albicans uptake and that phagocytosis could be blocked with ␤-glucan. We conclude that the MR is not required for the normal host defense during disseminated candidiasis or for the phagocytosis of C. albicans and that a ␤-glucan receptor may be required for C. albicans phagocytosis.

Mannose-Containing Molecular Patterns Are Strong Inducers of Cyclooxygenase-2 Expression and Prostaglandin E2 Production in Human Macrophages

“…In fact, the function of the MR has currently been related to the capture, internalization, and presentation of mannosylated Ags (16) bypassing the oxidative burst in human macrophages (17) as well as to the activation of an anti-inflammatory and immunosuppressive program in monocyte-derived dendritic cells (18). This agrees with the finding of normal defense against Candida and Pneumocystis infection in animals with targeted disruption of the MR gene (19,20). Conversely, the synthesis of proinflammatory cytokines (21) and matrix metalloproteinase-9 (22) by engaging the MR has also been reported, and a recent study has described the ability of the MR to trigger activation of the transcription factor NF-B and the induction of IL-8, thus suggesting a central role for the MR in the defense by human alveolar macrophages against Pneumocytis infection (23) in the context of HIV infection (4).…”

Carbohydrate‐independent recognition of collagens by the macrophage mannose receptor

“…This cytokine induces a deactivated anti-inflammatory state in the Mu and is a key player in the control of inflammation in vivo [6] One of the hallmarks of alternatively activated and deactivated MU is increased expression of the mannose receptor (MR, CD206) [1,7]. The MR was originally described as an endocytic receptor for lysosomal enzymes [8] and studies in MR-deficient mice support the idea that MR is primarily a homeostatic clearance system with an additional role as a pathogen receptor [9][10][11][12].…”

“…It is intriguing that collagens II and IV can also be targeted by the acquired system since collagen II, a major component of cartilage, is an important autoantigen in rheumatoid arthritis patients [34], and collagen IV contains the antigen recognised by autoantibodies from Goodpasture syndrome patients [35]. The involvement of MR to Ag presentation is still unclear since no major contribution of MR to immunity against pathogens has been evident in experimental models of infection but rather a non-redundant role in homeostatic clearance of lysosomal enzymes has been demonstrated [9][10][11]. We have identified a novel MR-positive DC population in selected lymphoid organs that can bind MR ligands in vivo (E. McKenzie et al manuscript in preparation).…”

Lack of antigen-specific tissue remodeling in mice deficient in the macrophage galactose-type calcium-type lectin 1/CD301a

“…For example, mice deficient in macrophage mannose receptors exhibited decreased clearance of peptide hormones with sulfated N-acetylgalactosamine residues, although these mice showed similar susceptibility to the infections of Candida albicans and Pneumocystis carinii. [34][35][36][37] Galectin-3-deficient mice showed reduced recruitment of neutrophils into inflamed peritoneal cavities 38 ; macrophages from these mice showed suppressed spreading and phagocytic functions and the mice developed glomerulopathy under diabetic conditions. [39][40][41] MGL1 belongs to a large family of calcium-type lectins that include cell surface molecules such as type 2 transmembrane proteins, type 1 multilectins, selectins, humoral components such as collectins, 42 and extracellular matrix components such as aggrecan.…”