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- Hoang, ATN, et al.
(author)
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Stromal cell-derived CXCL12 and CCL8 cooperate to support increased development of regulatory dendritic cells following Leishmania infection
- 2010
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In: Journal of immunology (Baltimore, Md. : 1950). - : The American Association of Immunologists. - 1550-6606 .- 0022-1767. ; 185:4, s. 2360-2371
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Journal article (peer-reviewed)abstract
- In the immune system, stromal cells provide specialized niches that control hematopoiesis by coordinating the production of chemokines, adhesion molecules, and growth factors. Stromal cells also have anti-inflammatory effects, including support for the differentiation of hematopoietic progenitors into dendritic cells (DCs) with immune regulatory properties. Together, these observations suggest that the alterations in hematopoiesis commonly seen in infectious disease models, such as experimental visceral leishmaniasis in mice, might result from altered stromal cell function. We report in this study that the stromal cell-derived chemokines CXCL12 and CCL8 cooperate to attract hematopoietic progenitors with the potential to differentiate into regulatory DCs. We also show that infection of murine bone marrow stromal cells by Leishmania donovani enhanced their capacity to support the development of regulatory DCs, as well as their capacity to produce CCL8. Likewise, in experimental visceral leishmaniasis, CCL8 production was induced in splenic stromal cells, leading to an enhanced capacity to attract hematopoietic progenitor cells. Thus, intracellular parasitism of stromal cells modifies their capacity to recruit and support hematopoietic progenitor differentiation into regulatory DCs, and aberrant expression of CCL8 by diseased stromal tissue may be involved in the switch from resolving to persistent infection.
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- Shambat, SM, et al.
(author)
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Modelling staphylococcal pneumonia in a human 3D lung tissue model system delineates toxin-mediated pathology
- 2015
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In: Disease models & mechanisms. - : The Company of Biologists. - 1754-8411 .- 1754-8403. ; 8:11, s. 1413-1425
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Journal article (peer-reviewed)abstract
- Staphylococcus aureus necrotizing pneumonia is recognized as a toxin-mediated disease, but yet the tissue destructive events remain elusive partly due to lack of mechanistic studies in human lung tissue. In this study, a 3D tissue model composed of human lung epithelial cells and fibroblasts was used to delineate the role of specific staphylococcal exotoxins in tissue pathology associated with severe pneumonia. To this end, the models were exposed to the mixture of exotoxins produced by S. aureus strains isolated from patients with varying severity of lung infection, namely necrotizing pneumonia or lung empyema, or to purified toxins. The necrotizing pneumonia strains secreted high levels of α-toxin and PVL, and triggered high cytotoxicity, inflammation, necrosis and loss of E-cadherin in the lung epithelium. In contrast, the lung empyema strain produced moderate levels of PVL, but negligible amounts of α-toxin, and triggered limited tissue damage. α-toxin had a direct damaging effect on the epithelium, as verified by toxin-deficient mutants and pure α-toxin. Moreover, PVL contributed to pathology through the lysis of neutrophils, and a combination of α-toxin and PVL resulted in the most severe epithelial injury. In addition, toxin-induced release of pro-inflammatory mediators from lung tissue models resulted in enhanced neutrophil migration. Using a collection of 31 strains from patients with staphylococcal pneumonia revealed that strains producing high levels of α-toxin and PVL were cytotoxic and associated with fatal outcome. Also, the strains that produced the highest toxin levels induced significantly greater epithelial disruption. Of importance, toxin-mediated lung epithelium destruction could be inhibited by polyspecific intravenous immunoglobulin containing antibodies against α-toxin and PVL. This study introduces a novel model system for studies of staphylococcal pneumonia in a human setting, and the results revealed that a combination and levels of α-toxin and PVL correlate with tissue pathology and clinical outcome associated with pneumonia.
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