| 1. |
- Chakraborty, Paramita, et al.
(författare)
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Vesicular Location and Transport of S100A8 and S100A9 Proteins in Monocytoid Cells.
- 2015
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:12
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Tidskriftsartikel (refereegranskat)abstract
- We show here, by using surface biotinylation, followed by Western blotting or surface plasmon resonance analysis, that very low levels of S100A8 and/or S100A9 can be detected on the surface of THP-1 cells or freshly isolated human monocytes. This was supported by immune-electron microscopy where we observed membrane-associated expression of the proteins restricted to small patches. By using confocal microscopy we could determine that S100A8 and S100A9 protein in THP-1 cells or freshly isolated human monocytes was mostly present in vesicular structures. This finding was confirmed using immune-electron microscopy. Subcellular fractionation and confocal microscopy showed that these vesicular structures are mainly early endosomes and endolysosomes. Our subsequent studies showed that accumulation of S100A8 and S100A9 in the endolysosomal compartment is associated with induction of their release from the cells. Furthermore, an inhibitor of lysosomal activity could modulate the release of S100A8 and S100A9 in the extracellular milieu. Our current results suggest that the S100A8 and S100A9 proteins are primarily associated with certain kinds of cytosolic vesicles and may be secreted via an endolysosomal pathway.
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| 2. |
- Leanderson, Tomas, et al.
(författare)
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S100A9 as a pharmacological target molecule in inflammation and cancer.
- 2015
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Ingår i: Endocrine, Metabolic & Immune Disorders - Drug Targets. - 2212-3873. ; 15:2, s. 97-104
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Tidskriftsartikel (refereegranskat)abstract
- Upon tissue injury and infection both stressed and dying cells can release proteins that normally reside inside the cells. Some of the released proteins become ligands of various cell surface receptors expressed by local cells and such proteins are denoted damage associated molecular patterns (DAMPs). Binding of some DAMPs to certain cell surface receptors induces signals emanating in the production of pro-inflammatory cytokines, ultimately leading to an inflammatory response. Our laboratory is interested in the S100A9 protein, a bona fide DAMP protein. This protein normally resides inside monocytes and neutrophils and in these cells it forms heterodimers with the S100A8 protein. The S100A8/A9 heterodimer is released in large amounts during several types of inflammatory disease and is currently used clinically as a biomarker in some diseases. The fact that several different pro-inflammatory functions have been ascribed to this protein makes it a potential target for the development of small molecule inhibitors. We have developed several such inhibitors, some of which are already in phase III clinical development. This review describes our efforts to investigate the biological functions of the S100A9 protein as well as our ongoing efforts of developing second-generation, more specific, small molecule inhibitors of its pro-inflammatory functions.
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| 3. |
- Olsson, Anders, et al.
(författare)
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Tasquinimod triggers an early change in the polarization of tumor associated macrophages in the tumor microenvironment.
- 2015
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Ingår i: Journal for ImmunoTherapy of Cancer. - : BMJ. - 2051-1426. ; 3
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Tidskriftsartikel (refereegranskat)abstract
- Tasquinimod (a quinoline-3-carboxyamide) is a small molecule immunotherapy with demonstrated effects on the tumor microenvironment (TME) involving immunomodulation, anti-angiogenesis and inhibition of metastasis. A target molecule of tasquinimod is the inflammatory protein S100A9 which has been shown to affect the accumulation and function of suppressive myeloid cell subsets in tumors. Given the major impact of myeloid cells to the tumor microenvironment, manipulation of this cell compartment is a desirable goal in cancer therapeutics.
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| 4. |
- Stenström, Martin, et al.
(författare)
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Paquinimod reduces skin fibrosis in tight skin 1 mice, an experimental model of systemic sclerosis
- 2016
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Ingår i: Journal of Dermatological Science. - : Elsevier BV. - 0923-1811. ; 83:1, s. 52-59
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Tidskriftsartikel (refereegranskat)abstract
- Background: Systemic Sclerosis (SSc) is an autoimmune disease characterized by vascular and immune dysfunction. A hallmark of SSc is the excessive accumulation of extracellular matrix in the skin and in internal organs. There is a high and unmet medical need for novel therapies in this disease. The pathogenesis of SSc is complex and still poorly understood, but the innate immune system has emerged as an important factor in the disease. SSc patients show increased numbers of macrophages/monocytes in the blood and in the skin compared to healthy individuals and these cells are important sources of profibrotic cytokines and chemokines. Paquinimod belongs to a class of orally active quinoline-3-carboxamide (quinoline) derivatives with immunomodulatory properties and has shown effects in several models of autoimmune/inflammatory disorders. Paquinimod is currently in clinical development for treatment of SSc. The immunomodulatory effects of paquinimod is by targeting the myeloid cell compartment via the S100A9 protein. Objective: In this study we investigate whether targeting of myeloid cells by paquinimod can effect disease development in an experimental model of SSc, the tight skin 1 (Tsk-1) mouse model. Methods: Seven weeks old female B6.Cg-Fbn1Tsk/J (Tsk-1) mice were treated with vehicle or paquinimod at the dose of 5 or 25 mg/kg/day in the drinking water for 8 weeks. The effect of paquinimod on the level of skin fibrosis and on different subpopulations within the myeloid cell compartment in skin biopsies were evaluated by using histology, immunohistochemisty, a hydroxyproline assay and real-time PCR. Furthermore, the level of IgG in serum from treated animals was also analysed. The statistical analyses were performed using Mann-Whitney nonparametric two tailed rank test. Results: The results show that treatment with paquinimod reduces skin fibrosis measured as reduction of skin thickness and decreased number of myofibroblasts and total hydroxyproline content. The effect on fibrosis was associated with a polarization of macrophages in the skin from a pro-fibrotic M2 to a M1 phenotype. Paquinimod treatment also resulted in a reduced TGFβ-response in the skin and an abrogation of the increased auto-antibody production in this SSc model. Conclusions: Paquinimod reduces skin fibrosis in an experimental model of SSc, and this effect correlates with local and systemic effects on the immune system.
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