| 1. |
- Björnfot Holmström, Sofia, et al.
(författare)
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MMP-12 and S100s in saliva reflect different aspects of periodontal inflammation
- 2019
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Ingår i: Cytokine. - : Academic Press. - 1043-4666 .- 1096-0023. ; 113, s. 155-161
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Tidskriftsartikel (refereegranskat)abstract
- Matrix metalloproteinase (MMP)-12, S100A8/A9, and S100A12 are involved in innate immune responses. We addressed whether different aspects of oral health and non-disease-related covariates influence their levels in saliva. 436 participants were clinically examined, completed a health questionnaire, and provided stimulated saliva. Salivary levels of MMP-12, S100A8/A9, and S100A12 were determined by enzyme-linked immunosorbent assays. Lower MMP-12 levels were observed in individuals 40-64years old (yo) compared to < 40yo, and higher S100A8/A9 levels were found in individuals > 64yo compared to 40-64yo. Smokers exhibited lower MMP-12 and S100A12 levels compared to non-smokers. All three proteins were elevated in individuals with bleeding on probing (BOP)>20% compared to those with BOP/= 10% gingival pocket depths (PPD)>/=4mm compared to the ones with shallow pockets < 4mm. The extent of alveolar bone loss or presence of manifest caries did not alter any of the markers. MMP-12, S100A8/A9, and S100A12 levels were higher in participants with high periodontal inflammatory burden. All three proteins correlated positively to BOP, PPD, and to several inflammatory mediators. The explanatory variables for MMP-12 in saliva were age, smoking, presence of any tumor, and percentage of PPD>/=4mm. The determinant of salivary S100A8/A9 was percentage of BOP, while S100A12 levels were associated with percentage of BOP and presence of any tumor. Taken together, MMP-12 and the S100/calgranulin levels in saliva reflect different aspects of periodontal inflammation. Smoking and age should be taken into account in further investigation of these proteins as biomarker candidates of periodontal disease.
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| 2. |
- Björnfot Holmström, Sofia
(författare)
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The role of monocytes in chronic inflammatory diseases
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Monocytes and monocyte-derived cells are important players in the orchestration of inflammatory reactions in blood and peripheral tissues. However, little is known about the monocyte fate upon entry into human tissues, and current concepts are mainly based on animal models, with the addition of observational studies in humans that often do not allow determining causality. To provide additional understanding of the monocytes and the monocyte-derived cells in tissues, we developed three-dimensional (3D) co-culture models of epithelial tissues with monocytic cells implanted. These 3D tissue models in combination with clinical samples, including blood, saliva and tissue have been the platform for my thesis work on monocytes and monocytes-derived cells in chronic inflammatory diseases. In paper I, we identified increased mRNA expression of MMP12, COX2, TNF and DCSIGN, genes associated with inflammation and tissue remodeling, in gingival tissue from individuals with Periodontitis (PD). The increased production of MMP12 was confirmed at a protein level, and flow cytometry analysis identified CD68+CD64+CD14+ monocyte-derived cells as responsible for increased MMP12 production in tissue. In addition, monocyte-derived cells from PD gingival tissue had a relatively low surface expression of the co-inhibitory molecule CD200R. Similarly, using a multicellular 3D model of oral mucosa with induced inflammation showed increased MMP12 production and reduced CD200R surface expression by monocyte-derived cells. We identified CSF2 as a potent inducer of MMP12, and that treatment of CSF2-stimulated monocyte-derived cells with a CD200 ligand reduced MMP12 production. Thus, this study identified CD200/CD200R as a potential pathway to modulate aberrant inflammatory reactions in order to reduce the subsequent immunopathology and induce resolution of chronic inflammation. In a follow up study (paper II), a larger patient cohort (n=436) was investigated to assess the potential of MMP12, as well as the S100 proteins S100A8/A9 (calprotectin) and S100A12 as salivary biomarkers of PD. We found that MMP12 levels reflect destruction of periodontal structures, while the levels of the S100s reflect periodontal inflammation, and that smoking and age are important to take into consideration in future studies. The presence of other chronic inflammatory diseases did not influence MMP12 and S100 protein levels, however the presence of tumor was associated with an increase in the levels of MMP12 and S100A12. Paper III was a methodological study, where we further developed the 3D lung tissue model to establish protocols for live imaging analysis of monocytes-derived cell migratory behavior in inflamed tissue. Inflammation was induced by TLR ligand stimulation at the apical side of the lung tissue models, and the level of inflammation was evaluated by flow cytometry, gene expression analysis as well as cytokine secretion. An immunofluorescence live-imagine technique was established to study the migration of the monocyte-derived dendritic cells (DC) in 4D (time, x, y, z) in inflamed lung tissue models. In paper IV, we focused on IL-17A which is a cytokine associated with human chronic inflammatory diseases, and that has been linked to both PD and Langerhans cell histiocytosis (LCH). In LCH, DC-like cells have been described to produce IL-17A, and therefore, we investigated whether blood monocytes had IL-17A-producing capacity. These analyses led to the identification of IL-17A-producing monocytes in patients with LCH, particularly evident in patients with the highest disease activity. In contrast, IL-17A-producing monocytes could not be identified in patients with PD or healthy individuals. In summary, these studies have contributed to the establishment of new tools to study human monocytes in a tissue milieu, and identified new disease-associated mechanisms and pathways that can be further explored to develop new immunomodulatory treatments for chronic inflammatory diseases.
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| 3. |
- Lira-Junior, Ronaldo, et al.
(författare)
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S100A12 Expression Is Modulated During Monocyte Differentiation and Reflects Periodontitis Severity
- 2020
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Ingår i: Frontiers in Immunology. - : Frontiers Media S.A.. - 1664-3224. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- S100A12 is a calcium-binding protein of the S100 subfamily of myeloid-related proteins that acts as an alarmin to induce a pro-inflammatory innate immune response. It has been linked to several chronic inflammatory diseases, however its role in the common oral immunopathology periodontitis is largely unknown. Previous in vitro monoculture experiments indicate that S100A12 production decreases during monocyte differentiation stages, while the regulation within tissue is poorly defined. This study evaluated S100A12 expression in monocyte subsets, during monocyte-to-macrophage differentiation and following polarization, both in monoculture and in a tissue context, utilizing a three-dimensional co-culture oral tissue model. Further, we explored the involvement of S100A12 in periodontitis by analyzing its expression in peripheral circulation and gingival tissue, as well as in saliva. We found that S100A12 expression was higher in classical than in non-classical monocytes. S100A12 expression and protein secretion declined significantly during monocyte-to-macrophage differentiation, while polarization of monocyte-derived macrophages had no effect on either. Peripheral monocytes from periodontitis patients had higher S100A12 expression than monocytes from controls, a difference particularly observed in the intermediate and non-classical monocyte subsets. Further, monocytes from periodontitis patients displayed an increased secretion of S100A12 compared with monocytes from controls. In oral tissue cultures, monocyte differentiation resulted in increased S100A12 secretion over time, which further increased after inflammatory stimuli. Likewise, S100A12 expression was higher in gingival tissue from periodontitis patients where monocyte-derived cells exhibited higher expression of S100A12 in comparison to non-periodontitis tissue. In line with our findings, patients with severe periodontitis had significantly higher levels of S100A12 in saliva compared to non-periodontitis patients, and the levels correlated to clinical periodontal parameters. Taken together, S100A12 is predominantly secreted by monocytes rather than by monocyte-derived cells. Moreover, S100A12 is increased in inflamed tissue cultures, potentially as a result of enhanced production by monocyte-derived cells. This study implicates the involvement of S100A12 in periodontitis pathogenesis, as evidenced by increased S100A12 expression in inflamed gingival tissue, which may be due to altered circulatory monocytes in periodontitis.
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