| Autor: |
Hirako, Isabella C., Gallego-Marin, Carolina, Ataide, Marco A., Andrade, Warrison A., Gravina, Humberto, Rocha, Bruno C., de Oliveira, Rosane B., Pereira, Dhelio B., Vinetz, Joseph, Diamond, Betty, Ram, Sanjay, Golenbock, Douglas T., Gazzinelli, Ricardo T. |
| Zdroj: |
mBio; October 2015, Vol. 6 Issue: 6 |
| Abstrakt: |
ABSTRACTHigh levels of circulating immunocomplexes (ICs) are found in patients with either infectious or sterile inflammation. We report that patients with either Plasmodium falciparumor Plasmodium vivaxmalaria have increased levels of circulating anti-DNA antibodies and ICs containing parasite DNA. Upon stimulation with malaria-induced ICs, monocytes express an NF-κB transcriptional signature. The main source of IC-induced proinflammatory cytokines (i.e., tumor necrosis factor alpha [TNF-α] and interleukin-1β [IL-1β])in peripheral blood mononuclear cells from acute malaria patients was found to be a CD14+CD16 (FcγRIIIA)+CD64 (FcγRI)highCD32 (FcγRIIB)lowmonocyte subset. Monocytes from convalescent patients were predominantly of the classical phenotype (CD14+CD16−) that produces high levels of IL-10 and lower levels of TNF-α and IL-1β in response to ICs. Finally, we report a novel role for the proinflammatory activity of ICs by demonstrating their ability to induce inflammasome assembly and caspase-1 activation in human monocytes. These findings illuminate our understanding of the pathogenic role of ICs and monocyte subsets and may be relevant for future development of immunity-based interventions with broad applications to systemic inflammatory diseases.IMPORTANCEEvery year, there are approximately 200 million cases of Plasmodium falciparumand P. vivaxmalaria, resulting in nearly 1 million deaths, most of which are children. Decades of research on malaria pathogenesis have established that the clinical manifestations are often a consequence of the systemic inflammation elicited by the parasite. Recent studies indicate that parasite DNA is a main proinflammatory component during infection with different Plasmodiumspecies. This finding resembles the mechanism of disease in systemic lupus erythematosus, where host DNA plays a central role in stimulating an inflammatory process and self-damaging reactions. In this study, we disclose the mechanism by which ICs containing PlasmodiumDNA activate innate immune cells and consequently stimulate systemic inflammation during acute episodes of malaria. Our results further suggest that Toll-like receptors and inflammasomes have a central role in malaria pathogenesis and provide new insights toward developing novel therapeutic interventions for this devastating disease. |
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