| 1. |
- Agrawal, Smriti, et al.
(författare)
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Dystroglycan is selectively cleaved at the parenchymal basement membrane at sites of leukocyte extravasation in experimental autoimmune encephalomyelitis.
- 2006
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Ingår i: Journal of Experimental Medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 203:4, s. 1007-1019
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Tidskriftsartikel (refereegranskat)abstract
- The endothelial cell monolayer of cerebral vessels and its basement membrane (BM) are ensheathed by the astrocyte endfeet, the leptomeningeal cells, and their associated parenchymal BM, all of which contribute to establishment of the blood–brain barrier (BBB). As a consequence of this unique structure, leukocyte penetration of cerebral vessels is a multistep event. In mouse experimental autoimmune encephalomyelitis (EAE), a widely used central nervous system inflammatory model, leukocytes first penetrate the endothelial cell monolayer and underlying BM using integrin β1-mediated processes, but mechanisms used to penetrate the second barrier defined by the parenchymal BM and glia limitans remain uninvestigated. We show here that macrophage-derived gelatinase (matrix metalloproteinase [MMP]-2 and MMP-9) activity is crucial for leukocyte penetration of the parenchymal BM. Dystroglycan, a transmembrane receptor that anchors astrocyte endfeet to the parenchymal BM via high affinity interactions with laminins 1 and 2, perlecan and agrin, is identified as a specific substrate of MMP-2 and MMP-9. Ablation of both MMP-2 and MMP-9 in double knockout mice confers resistance to EAE by inhibiting dystroglycan cleavage and preventing leukocyte infiltration. This is the first description of selective in situ proteolytic damage of a BBB-specific molecule at sites of leukocyte infiltration.
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| 2. |
- Halin, Sofia, 1977-, et al.
(författare)
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Extratumoral macrophages promote tumor and vascular growth in an orthotopic rat prostate tumor model.
- 2009
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Ingår i: Neoplasia. - 1522-8002 .- 1476-5586. ; 11:2, s. 177-186
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Tidskriftsartikel (refereegranskat)abstract
- Tumor-associated macrophages are involved in angiogenesis and tumor progression, but their role and specific site of action in prostate cancer remain unknown. To explore this, Dunning R-3327 AT-1 rat prostate tumor cells were injected into the prostate of syngenic and immunocompetent Copenhagen rats and analyzed at different time points for vascular proliferation and macrophage density. Endothelial proliferation increased with tumor size both in the tumor and importantly also in the extratumoral normal prostate tissue. Macrophages accumulated in the tumor and in the extratumoral normal prostate tissue and were most abundant in the invasive zone. Moreover, only extratumoral macrophages showed strong positive associations with tumor size and extratumoral vascular proliferation. Treatment with clodronate-encapsulated liposomes reduced the monocyte/macrophage infiltration and resulted in a significant inhibition of tumor growth. This was accompanied by a suppressed proliferation in microvessels and in the extratumoral prostate tissue also in arterioles and venules. The AT-1 tumors produced, as examined by RT(2) Profiler PCR arrays, numerous factors promoting monocyte recruitment, angiogenesis, and tissue remodeling. Several, namely, chemokine (C-C) ligand 2, fibroblast growth factor 2, matrix metalloproteinase 9, interleukin 1beta, interferon gamma, and transforming growth factor beta, were highly upregulated by the tumor in vivo compared with tumor cells in vitro, suggesting macrophages as a plausible source. In conclusion, we here show the importance of extratumoral monocytes/macrophages for prostate tumor growth, angiogenesis, and extratumoral arteriogenesis. Our findings identify tumor-associated macrophages and several chemotactic and angiogenic factors as potential targets for prostate cancer therapy.
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| 3. |
- Larsson, Christer, 1975-, et al.
(författare)
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A novel animal model of Borrelia recurrentis louse-borne relapsing fever borreliosis using immunodeficient mice
- 2009
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Ingår i: PLoS Neglected Tropical Diseases. - : PLoS, Public Library of Science. - 1935-2727 .- 1935-2735. ; 3:9, s. e522-
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Tidskriftsartikel (refereegranskat)abstract
- Louse-borne relapsing fever (LBRF) borreliosis is caused by Borrelia recurrentis, and it is a deadly although treatable disease that is endemic in the Horn of Africa but has epidemic potential. Research on LBRF has been severely hampered because successful infection with B. recurrentis has been achieved only in primates (i.e., not in other laboratory or domestic animals). Here, we present the first non-primate animal model of LBRF, using SCID (-B, -T cells) and SCID BEIGE (-B, -T, -NK cells) immunocompromised mice. These animals were infected with B. recurrentis A11 or A17, or with B. duttonii 1120K3 as controls. B. recurrentis caused a relatively mild but persistent infection in SCID and SCID BEIGE mice, but did not proliferate in NUDE (-T) and BALB/c (wild-type) mice. B. duttonii was infectious but not lethal in all animals. These findings demonstrate that the immune response can limit relapsing fever even in the absence of humoral defense mechanisms. To study the significance of phagocytic cells in this context, we induced systemic depletion of such cells in the experimental mice by injecting them with clodronate liposomes, which resulted in uncontrolled B. duttonii growth and a one-hundred-fold increase in B. recurrentis titers in blood. This observation highlights the role of macrophages and other phagocytes in controlling relapsing fever infection. B. recurrentis evolved from B. duttonii to become a primate-specific pathogen that has lost the ability to infect immunocompetent rodents, probably through genetic degeneration. Here, we describe a novel animal model of B. recurrentis based on B- and T-cell-deficient mice, which we believe will be very valuable in future research on LBRF. Our study also reveals the importance of B-cells and phagocytes in controlling relapsing fever infection.
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| 4. |
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| 5. |
- Reyes, Jose L., et al.
(författare)
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Splenic B Cells from Hymenolepis diminuta-Infected Mice Ameliorate Colitis Independent of T Cells and via Cooperation with Macrophages
- 2015
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Ingår i: Journal of Immunology. - : American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 194:1, s. 364-378
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Tidskriftsartikel (refereegranskat)abstract
- Helminth parasites provoke multicellular immune responses in their hosts that can suppress concomitant disease. The gut lumen-dwelling tapeworm Hymenolepis diminuta, unlike other parasites assessed as helminth therapy, causes no host tissue damage while potently suppressing murine colitis. With the goal of harnessing the immunomodulatory capacity of infection with H. diminuta, we assessed the putative generation of anti-colitic regulatory B cells following H. diminuta infection. Splenic CD19(+) B cells isolated from mice infected 7 [HdBc(7(d))] and 14(d) (but not 3(d)) previously with H. diminuta and transferred to naive mice significantly reduced the severity of dinitrobenzene sulfonic acid (DNBS)-, oxazolone-, and dextran-sodium sulfate-induced colitis. Mechanistic studies with the DNBS model, revealed the anti-colitic HdBc(7(d)) was within the follicular B cell population and its phenotype was not dependent on IL-4 or IL-10. The HdBc(7(d)) were not characterized by increased expression of CD1d, CD5, CD23, or IL-10 production, but did spontaneously, and upon LPS plus anti-CD40 stimulation, produce more TGF-beta than CD19(+) B cells from controls. DNBS-induced colitis in RAG1(-/-) mice was inhibited by administration of HdBc(7(d)), indicating a lack of a requirement for T and B cells in the recipient; however, depletion of macrophages in recipient mice abrogated the anti-colitic effect of HdBc(7(d)). Thus, in response to H. diminuta, a putatively unique splenic CD19(+) B cell with a functional immunoregulatory program is generated that promotes the suppression of colitis dominated by TH1, TH2, or TH1-plus-TH2 events, and may do so via the synthesis of TGF-beta and the generation of, or cooperation with, a regulatory macrophage.
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| 6. |
- Schiopu, Alexandru, et al.
(författare)
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Inflammatory Ly-6C(hi) monocytes play an important role in the development of severe transplant arteriosclerosis in hyperlipidemic recipients
- 2012
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Ingår i: Atherosclerosis. - : Elsevier BV. - 1879-1484 .- 0021-9150. ; 223:2, s. 291-298
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Transplant arteriosclerosis (TA) restricts long-term survival of heart transplant recipients. Although the role of monocyte/macrophages is well established in native atherosclerosis, it has been studied to a much lesser extent in TA. Plasma cholesterol is the most important non-immunologic risk factor for development of TA but the underlying mechanisms are largely unknown. We hypothesized that monocyte/macrophages might play an important role in the pathogenesis of TA under hyperlipidemic conditions. Methods: We studied TA in fully mismatched arterial allografts transplanted into hyperlipidemic ApoE(-/-) recipients compared to wild-type controls. The recruitment of distinct monocyte populations into the grafts was tracked by in vivo labelling with fluorescent microspheres. We used antibody-mediated depletion protocols to dissect the relative contribution of T lymphocytes and monocytes to disease development. Results: In the hyperlipidemic environment the progression of TA was highly exacerbated and the inflammatory CD11b(+)CD115(+)Ly-6C(hi) monocytes were preferentially recruited into the neointima. The number of macrophage-derived foam cells present in the grafts strongly correlated with plasma cholesterol and disease severity. Depletion of Ly-6C(hi) monocytes and neutrophils significantly inhibited macrophage accumulation and disease progression. The accelerated monocyte recruitment occurs through a T cell-independent mechanism, as T cell depletion did not influence macrophage accumulation into the grafts. Conclusions: Our study identifies for the first time the involvement of inflammatory Ly-6C(hi) monocytes into the pathogenesis of TA, particularly in conditions of hyperlipidemia. Targeted therapies modulating the recruitment and activation of these cells could potentially delay coronary allograft vasculopathy and improve long-term survival of heart transplant recipients. (C) 2012 Elsevier Ireland Ltd. All rights reserved.
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| 7. |
- Wang, Hui, et al.
(författare)
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Lack of CD47 on nonhematopoietic cells induces split macrophage tolerance to CD47null cells
- 2007
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : National academy of sciences. - 0027-8424 .- 1091-6490. ; 104:34, s. 13744-13749
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Tidskriftsartikel (refereegranskat)abstract
- Macrophages recognize CD47 as a marker of "self" and phagocytose CD47null hematopoietic cells. Using CD47 chimera models, here, we show that the phagocytic activity of macrophages against CD47null hematopoietic cells is conferred by CD47 expression on nonhematopoietic cells, and this "education" process is hematopoietic cell-independent. Macrophages in the chimeras where nonhematopoietic cells express CD47 phagocytose CD47null cells, whereas those in the chimeras lacking CD47 on nonhematopoietic cells are tolerant to CD47null cells. However, macrophages in the latter chimeras retain phagocytic activity against CD47null RBCs, demonstrating a split macrophage tolerance to CD47null hematopoietic cells. The findings highlight the potential importance of nonhematopoietic cells in the regulation of macrophage function, and suggest a previously uncharacterized mechanism of macrophage tolerance.
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