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Malaria inhibits surface expression of complement receptor 1 in monocytes/macrophages, causing decreased immune complex internalization.

ABSTRACT: Complement receptor 1 (CR1) expressed on the surface of phagocytic cells binds complement-bound immune complexes (IC), playing an important role in the clearance of circulating IC. This receptor is critical to prevent accumulation of IC, which can contribute to inflammatory pathology. Accumulation of circulating IC is frequently observed during malaria, although the factors contributing to this accumulation are not clearly understood. We have observed that the surface expression of CR1 on monocytes/macrophages and B cells is strongly reduced in mice infected with Plasmodium yoelii, a rodent malaria model. Monocytes/macrophages from these infected mice present a specific inhibition of complement-mediated internalization of IC caused by the decreased CR1 expression. Accordingly, mice show accumulation of circulating IC and deposition of IC in the kidneys that inversely correlate with the decrease in CR1 surface expression. Our results indicate that malaria induces a significant decrease on surface CR1 expression in the monocyte/macrophage population that results in deficient internalization of IC by monocytes/macrophages. To determine whether this phenomenon is found in human malaria patients, we have analyzed 92 patients infected with either P. falciparum (22 patients) or P. vivax (70 patients) , the most prevalent human malaria parasites. The levels of surface CR1 on peripheral monocytes/macrophages and B cells of these patients show a significant decrease compared with uninfected control individuals in the same area. We propose that this decrease in CR1 plays an essential role in impaired IC clearance during malaria.

SUBMITTER: Fernandez-Arias C

PROVIDER: S-EPMC3673585 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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Malaria inhibits surface expression of complement receptor 1 in monocytes/macrophages, causing decreased immune complex internalization.

Fernandez-Arias Cristina C Lopez Jean Pierre JP Hernandez-Perez Jean Nikolae JN Bautista-Ojeda Maria Dolores MD Branch Oralee O Rodriguez Ana A

Journal of immunology (Baltimore, Md. : 1950) 20130225 7

Complement receptor 1 (CR1) expressed on the surface of phagocytic cells binds complement-bound immune complexes (IC), playing an important role in the clearance of circulating IC. This receptor is critical to prevent accumulation of IC, which can contribute to inflammatory pathology. Accumulation of circulating IC is frequently observed during malaria, although the factors contributing to this accumulation are not clearly understood. We have observed that the surface expression of CR1 on monocy ...[more]

PMID: 23440418

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Project description:ObjectiveSystemic lupus erythematosus (SLE) is an autoimmune disease with complex etiology that is not yet entirely understood. We aimed to elucidate the mechanisms and therapeutic potential of microRNAs (miRNAs) in SLE in a Tibetan population.MethodsPeripheral blood mononuclear cells from SLE patients (n = 5) and healthy controls (n = 5) were used for miRNA-mRNA co-sequencing to detect miRNAs related to immune abnormalities associated with SLE. Luciferase reporter assay was used to identify potential targets of candidate miRNA. The target genes were verified in miRNA-agomir/antagomir transfection assays with multiple cells lines and by expression analysis. The effects of candidate miRNA on monocyte and macrophage activation were evaluated by multiple cytokine profiling. Neutrophil extracellular traps (NETs) formation was analyzed in vitro by cell stimulation with supernatants of monocytes and macrophages transfected with candidate miRNA. The rodent MRL/lpr lupus model was used to evaluate the therapeutic effect of CXCL2Ab on SLE and the regulation effect of immune disorders.ResultsIntegrated miRNA and mRNA expression profiling identified miRNA-4512 as a candidate miRNA involved in the regulation of neutrophil activation and chemokine-related pathways. MiR-4512 expression was significantly reduced in monocytes and macrophages from SLE patients. MiR-4512 suppressed the TLR4 pathway by targeting TLR4 and CXCL2. Decreased monocyte and macrophage miR-4512 levels led to the expression of multiple proinflammatory cytokines in vitro. Supernatants of miR-4512 antagomir-transfected monocytes and macrophages significantly promoted NETs formation (P < 0.05). Blocking of CXCL2 alleviated various pathogenic manifestations in MRL/lpr mice, including kidney damage and expression of immunological markers of SLE.ConclusionsWe here demonstrated the role of miR-4512 in innate immunity regulation in SLE. The effect of miR-4512 involves the regulation of monocytes, macrophages, and NETs formation by direct targeting of TLR4 and CXCL2, indicating the miR-4512-TLR4-CXCL2 axis as a potential novel therapeutic target in SLE.

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Malaria inhibits surface expression of complement receptor 1 in monocytes/macrophages, causing decreased immune complex internalization.

Publications

Malaria inhibits surface expression of complement receptor 1 in monocytes/macrophages, causing decreased immune complex internalization.

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