Publications by authors named "Julia L Gregory"

13 Publications

  • Page 1 of 1

Molecular Signaling Interactions and Transport at the Osteochondral Interface: A Review.

Front Cell Dev Biol 2020 19;8:750. Epub 2020 Aug 19.

Department of Biomedical Engineering, University of Melbourne, Parkville, VIC, Australia.

Articular joints are comprised of different tissues, including cartilage and bone, with distinctive structural and mechanical properties. Joint homeostasis depends on mechanical and biological integrity of these components and signaling exchanges between them. Chondrocytes and osteocytes actively sense, integrate, and convert mechanical forces into biochemical signals in cartilage and bone, respectively. The osteochondral interface between the bone and cartilage allows these tissues to communicate with each other and exchange signaling and nutritional molecules, and by that ensure an integrated response to mechanical stimuli. It is currently not well known how molecules are transported between these tissues. Measuring molecular transport is highly desirable for tracking cartilage degeneration and osteoarthritis progression. Since transport of contrast agents, which are used for joint imaging, also depend on diffusion through the cartilage extracellular matrix, contrast agent enhanced imaging may provide a high resolution, non-invasive method for investigating molecular transport in the osteochondral unit. Only a few techniques have been developed to track molecular transport at the osteochondral interface, and there appear opportunities for development in this field. This review will describe current knowledge of the molecular interactions and transport in the osteochondral interface and discuss the potential of using contrast agents for investigating molecular transport and structural changes of the joint.
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http://dx.doi.org/10.3389/fcell.2020.00750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7466715PMC
August 2020

Local proliferation maintains a stable pool of tissue-resident memory T cells after antiviral recall responses.

Nat Immunol 2018 02 8;19(2):183-191. Epub 2018 Jan 8.

Department of Microbiology and Immunology, The University of Melbourne and The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia.

Although tissue-resident memory T cells (T cells) are critical in fighting infection, their fate after local pathogen re-encounter is unknown. Here we found that skin T cells engaged virus-infected cells, proliferated in situ in response to local antigen encounter and did not migrate out of the epidermis, where they exclusively reside. As a consequence, secondary T cells formed from pre-existing T cells, as well as from precursors recruited from the circulation. Newly recruited antigen-specific or bystander T cells were generated in the skin without displacement of the pre-existing T cell pool. Thus, pre-existing skin T cell populations are not displaced after subsequent infections, which enables multiple T cell specificities to be stably maintained within the tissue.
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http://dx.doi.org/10.1038/s41590-017-0027-5DOI Listing
February 2018

Genome-wide functional analysis reveals central signaling regulators of lymphatic endothelial cell migration and remodeling.

Sci Signal 2017 Oct 3;10(499). Epub 2017 Oct 3.

Tumour Angiogenesis and Microenvironment Program, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia.

Lymphatic vessels constitute a specialized vasculature that is involved in development, cancer, obesity, and immune regulation. The migration of lymphatic endothelial cells (LECs) is critical for vessel growth (lymphangiogenesis) and vessel remodeling, processes that modify the lymphatic network in response to developmental or pathological demands. Using the publicly accessible results of our genome-wide siRNA screen, we characterized the migratome of primary human LECs and identified individual genes and signaling pathways that regulate LEC migration. We compared our data set with mRNA differential expression data from endothelial and stromal cells derived from two in vivo models of lymphatic vessel remodeling, viral infection and contact hypersensitivity-induced inflammation, which identified genes selectively involved in regulating LEC migration and remodeling. We also characterized the top candidates in the LEC migratome in primary blood vascular endothelial cells to identify genes with functions common to lymphatic and blood vascular endothelium. On the basis of these analyses, we showed that , which encodes the glycan-binding protein Galectin-1, promoted lymphatic vascular growth in vitro and in vivo and contributed to maintenance of the lymphatic endothelial phenotype. Our results provide insight into the signaling networks that control lymphangiogenesis and lymphatic remodeling and potentially identify therapeutic targets and biomarkers in disease specific to lymphatic or blood vessels.
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http://dx.doi.org/10.1126/scisignal.aal2987DOI Listing
October 2017

Infection Programs Sustained Lymphoid Stromal Cell Responses and Shapes Lymph Node Remodeling upon Secondary Challenge.

Cell Rep 2017 01;18(2):406-418

Department of Microbiology and Immunology, The University of Melbourne, Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia; The Australian Research Council Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, VIC 3000, Australia. Electronic address:

Lymph nodes (LNs) are constructed of intricate networks of endothelial and mesenchymal stromal cells. How these lymphoid stromal cells (LSCs) regulate lymphoid tissue remodeling and contribute to immune responses remains poorly understood. We performed a comprehensive functional and transcriptional analysis of LSC responses to skin viral infection and found that LSC subsets responded robustly, with different kinetics for distinct pathogens. Recruitment of cells to inflamed LNs induced LSC expansion, while B cells sustained stromal responses in an antigen-independent manner. Infection induced rapid transcriptional responses in LSCs. This transcriptional program was transient, returning to homeostasis within 1 month of infection, yet expanded fibroblastic reticular cell networks persisted for more than 3 months after infection, and this altered LN composition reduced the magnitude of LSC responses to subsequent heterologous infection. Our results reveal the complexity of LSC responses during infection and suggest that amplified networks of LN stromal cells support successive immune responses.
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http://dx.doi.org/10.1016/j.celrep.2016.12.038DOI Listing
January 2017

CD8+ T cells from a novel T cell receptor transgenic mouse induce liver-stage immunity that can be boosted by blood-stage infection in rodent malaria.

PLoS Pathog 2014 May 22;10(5):e1004135. Epub 2014 May 22.

Department of Microbiology and Immunology, The Peter Doherty Institute, University of Melbourne, Parkville, Victoria, Australia; The ARC Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Parkville, Australia.

To follow the fate of CD8+ T cells responsive to Plasmodium berghei ANKA (PbA) infection, we generated an MHC I-restricted TCR transgenic mouse line against this pathogen. T cells from this line, termed PbT-I T cells, were able to respond to blood-stage infection by PbA and two other rodent malaria species, P. yoelii XNL and P. chabaudi AS. These PbT-I T cells were also able to respond to sporozoites and to protect mice from liver-stage infection. Examination of the requirements for priming after intravenous administration of irradiated sporozoites, an effective vaccination approach, showed that the spleen rather than the liver was the main site of priming and that responses depended on CD8α+ dendritic cells. Importantly, sequential exposure to irradiated sporozoites followed two days later by blood-stage infection led to augmented PbT-I T cell expansion. These findings indicate that PbT-I T cells are a highly versatile tool for studying multiple stages and species of rodent malaria and suggest that cross-stage reactive CD8+ T cells may be utilized in liver-stage vaccine design to enable boosting by blood-stage infections.
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http://dx.doi.org/10.1371/journal.ppat.1004135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4031232PMC
May 2014

Interstitial fluid drainage is impaired in ischemic stroke and Alzheimer's disease mouse models.

Acta Neuropathol 2013 Sep 2;126(3):353-64. Epub 2013 Jul 2.

Alzheimer Research Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, 114, 16th St., Charlestown, MA 02129, USA.

The interstitial fluid (ISF) drainage pathway has been hypothesized to underlie the clearance of solutes and metabolites from the brain. Previous work has implicated the perivascular spaces along arteries as the likely route for ISF clearance; however, it has never been demonstrated directly. The accumulation of amyloid β (Aβ) peptides in brain parenchyma is one of the pathological hallmarks of Alzheimer disease (AD), and it is likely related to an imbalance between production and clearance of the peptide. Aβ drainage along perivascular spaces has been postulated to be one of the mechanisms that mediate the peptide clearance from the brain. We therefore devised a novel method to visualize solute clearance in real time in the living mouse brain using laser guided bolus dye injections and multiphoton imaging. This methodology allows high spatial and temporal resolution and revealed the kinetics of ISF clearance. We found that the ISF drains along perivascular spaces of arteries and capillaries but not veins, and its clearance exhibits a bi-exponential profile. ISF drainage requires a functional vasculature, as solute clearance decreased when perfusion was impaired. In addition, reduced solute clearance was observed in transgenic mice with significant vascular amyloid deposition; we suggest the existence of a feed-forward mechanism, by which amyloid deposition promotes further amyloid deposition. This important finding provides a mechanistic link between cerebrovascular disease and Alzheimer disease and suggests that facilitation of Aβ clearance along the perivascular pathway should be considered as a new target for therapeutic approaches to Alzheimer disease and cerebral amyloid angiopathy.
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http://dx.doi.org/10.1007/s00401-013-1145-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3810119PMC
September 2013

Reducing available soluble β-amyloid prevents progression of cerebral amyloid angiopathy in transgenic mice.

J Neuropathol Exp Neurol 2012 Nov;71(11):1009-17

Department of Neurology/Alzheimer Research Unit, Massachusetts General Hospital, Charlestown, MA, USA.

Cerebral amyloid angiopathy (CAA), the accumulation of β-amyloid (Aβ) in the walls of leptomeningeal and cortical blood vessels of the brain, is a major cause of intracerebral hemorrhage and cognitive impairment and is commonly associated with Alzheimer disease. The progression of CAA, as measured in transgenic mice by longitudinal imaging with multiphoton microscopy, occurs in a predictable linear manner. The dynamics of Aβ deposition in and clearance from vascular walls and their relationship to the concentration of Aβ in the brain are poorly understood. We manipulated Aβ levels in the brain using 2 approaches: peripheral clearance via administration of the amyloid binding "peripheral sink" protein gelsolin and direct inhibition of its formation via administration of LY-411575, a small-molecule γ-secretase inhibitor. We found that gelsolin and LY-411575 both reduced the rate of CAA progression in Tg2576 mice from untreated rates of 0.58% ± 0.15% and 0.52% ± 0.09% to 0.11% ± 0.18% (p = 0.04) and -0.17% ± 0.09% (p < 0.001) of affected vessel per day, respectively, in the absence of an immune response. The progression of CAA was also halted when gelsolin was combined with LY-411575 (-0.004% ± 0.10%, p < 0.003). These data suggest that CAA progression can be prevented with non-immune approaches that may reduce the availability of soluble Aβ but without evidence of substantial amyloid clearance from vessels.
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http://dx.doi.org/10.1097/NEN.0b013e3182729845DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3491571PMC
November 2012

Macrophage migration inhibitory factor and CD74 regulate macrophage chemotactic responses via MAPK and Rho GTPase.

J Immunol 2011 Apr 16;186(8):4915-24. Epub 2011 Mar 16.

Department of Medicine, Centre for Inflammatory Diseases, Monash University, Monash Medical Centre, Clayton, Victoria 3168, Australia.

Macrophage migration inhibitory factor (MIF) promotes leukocyte recruitment to sites of inflammation. However, whether this stems from a direct effect on leukocyte migration is unknown. Furthermore, the role of the MIF-binding protein CD74 in this response has not been investigated. Therefore, the aim of this study was to examine the contributions of MIF and CD74 to chemokine-induced macrophage recruitment. Intravital microscopy studies demonstrated that CCL2-induced leukocyte adhesion and transmigration were reduced in MIF(-/-) and CD74(-/-) mice. MIF(-/-) and CD74(-/-) macrophages also exhibited reduced chemotaxis in vitro, although CD74(-/-) macrophages showed increased chemokinesis. Reduced CCL2-induced migration was associated with attenuated MAPK phosphorylation, RhoA GTPase activity, and actin polymerization in MIF(-/-) and CD74(-/-) macrophages. Furthermore, in MIF(-/-) macrophages, MAPK phosphatase-1 was expressed at elevated levels, providing a potential mechanism for the reduction in MAPK phosphorylation in MIF-deficient cells. No increase in MAPK phosphatase-1 expression was observed in CD74(-/-) macrophages. In in vivo experiments assessing the link between MIF and CD74, combined administration of MIF and CCL2 increased leukocyte adhesion in both MIF(-/-) and CD74(-/-) mice, showing that CD74 was not required for this MIF-induced response. Additionally, although leukocyte recruitment induced by administration of MIF alone was reduced in CD74(-/-) mice, consistent with a role for CD74 in leukocyte recruitment induced by MIF, MIF-treated CD74(-/-) mice displayed residual leukocyte recruitment. These data demonstrate that MIF and CD74 play previously unappreciated roles in CCL2-induced macrophage adhesion and migration, and they indicate that MIF and CD74 mediate this effect via both common and independent mechanisms.
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http://dx.doi.org/10.4049/jimmunol.1003713DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3388798PMC
April 2011

Independent roles of macrophage migration inhibitory factor and endogenous, but not exogenous glucocorticoids in regulating leukocyte trafficking.

Microcirculation 2009 Nov;16(8):735-48

Monash University Department of Medicine, Monash Medical Center, Clayton, Victoria, Australia.

Objectives: Macrophage migration inhibitory factor (MIF) promotes leukocyte recruitment and antagonizes the anti-inflammatory effects of glucocorticoids (GC). The aim of this study was to examine whether interaction between MIF and GC underlies the ability of MIF to promote leukocyte-endothelial cell (EC) interactions.

Methods: Intravital microscopy was used to assess leukocyte-EC interactions in wild-type and MIF(-/-) mice following treatment with lipopolysaccharide (LPS), the GC dexamethasone, and inhibition of endogenous GC, using the GC-receptor antagonist, RU486.

Results: Dexamethasone reduced LPS-induced leukocyte interactions in wild-type mice to levels similar to those observed in MIF(-/-) mice not treated with dexamethasone, whereas in MIF(-/-) mice, leukocyte interactions were not further inhibited by dexamethasone. RU486 increased LPS-induced leukocyte adhesion and emigration to a similar extent in both wild-type and MIF(-/-) mice, indicating that endogenous GC exert a similar inhibitory effect on leukocyte trafficking in wild-type and MIF(-/-) mice. Both MIF deficiency and RU486 treatment reduced VCAM-1 expression, while neither treatment modulated expression of ICAM-1 or chemokines CCL2, KC, and MIP-2.

Conclusions: These results suggest that endogenous MIF and GC regulate leukocyte-EC interactions in vivo reciprocally but through predominantly independent mechanisms, and that the anti-inflammatory effect of MIF deficiency is comparable to that of exogenous GC.
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http://dx.doi.org/10.3109/10739680903210421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3070174PMC
November 2009

The cytoplasmic domain of tissue factor in macrophages augments cutaneous delayed-type hypersensitivity.

J Leukoc Biol 2008 Apr 7;83(4):902-11. Epub 2008 Jan 7.

Centre for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, Victoria, Australia.

In addition to its procoagulant role, tissue factor (TF) has important coagulation-independent roles, including in inflammation. The cytoplasmic domain of TF has been implicated in some of these coagulation-independent roles, particularly cell signaling. To assess the contribution of the cytoplasmic domain of TF to cell-mediated adaptive immunity, the development of cutaneous delayed-type hypersensitivity (DTH) was studied in mice lacking the cytoplasmic domain of TF (TF(deltaCT/deltaCT) mice). DTH responses in sensitized mice were significantly attenuated in TF(deltaCT/deltaCT) mice, and leukocyte-endothelial cell interactions, assessed by intravital microscopy, were impaired significantly. Studies in chimeric mice, created by bone marrow transplantation, showed that the absence of the cytoplasmic domain of TF in leukocytes rather than endothelial cells was responsible for reduced DTH and leukocyte recruitment. DTH responses to OVA could be induced in wild-type mice but not in TF(deltaCT/deltaCT) mice by transfer of activated CD4(+) OVA-specific TCR transgenic T cells, demonstrating that the defective DTH response in TF(deltaCT/deltaCT) mice was independent of any defect in T cell activation. Macrophage and neutrophil accumulation and expression of TNF-alpha mRNA and phospho-p38-MAPK were reduced significantly in TF(deltaCT/deltaCT) mice, and their macrophages had reduced P-selectin-binding capacity and reduced in vivo emigration in response to MCP-1. These results indicate that leukocyte expression of the cytoplasmic domain of TF contributes to antigen-specific cellular adaptive immune responses via effects on leukocyte recruitment and activation.
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http://dx.doi.org/10.1189/jlb.0607353DOI Listing
April 2008

MIF is a noncognate ligand of CXC chemokine receptors in inflammatory and atherogenic cell recruitment.

Nat Med 2007 May 15;13(5):587-96. Epub 2007 Apr 15.

Department of Biochemistry and Molecular Cell Biology, Institute of Biochemistry, University Hospital Aachen, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, D-52074 Aachen, Germany.

The cytokine macrophage migration inhibitory factor (MIF) plays a critical role in inflammatory diseases and atherogenesis. We identify the chemokine receptors CXCR2 and CXCR4 as functional receptors for MIF. MIF triggered G(alphai)- and integrin-dependent arrest and chemotaxis of monocytes and T cells, rapid integrin activation and calcium influx through CXCR2 or CXCR4. MIF competed with cognate ligands for CXCR4 and CXCR2 binding, and directly bound to CXCR2. CXCR2 and CD74 formed a receptor complex, and monocyte arrest elicited by MIF in inflamed or atherosclerotic arteries involved both CXCR2 and CD74. In vivo, Mif deficiency impaired monocyte adhesion to the arterial wall in atherosclerosis-prone mice, and MIF-induced leukocyte recruitment required Il8rb (which encodes Cxcr2). Blockade of Mif but not of canonical ligands of Cxcr2 or Cxcr4 in mice with advanced atherosclerosis led to plaque regression and reduced monocyte and T-cell content in plaques. By activating both CXCR2 and CXCR4, MIF displays chemokine-like functions and acts as a major regulator of inflammatory cell recruitment and atherogenesis. Targeting MIF in individuals with manifest atherosclerosis can potentially be used to treat this condition.
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http://dx.doi.org/10.1038/nm1567DOI Listing
May 2007

Macrophage migration inhibitory factor induces macrophage recruitment via CC chemokine ligand 2.

J Immunol 2006 Dec;177(11):8072-9

Centre for Inflammatory Diseases, Department of Medicine, Monash Institute of Medical Research, Monash University, 246 Clayton Road, Clayton, Victoria 3168, Australia.

Macrophage migration inhibitory factor (MIF) was originally identified for its ability to inhibit the random migration of macrophages in vitro. MIF is now recognized as an important mediator in a range of inflammatory disorders. We recently observed that the absence of MIF is associated with a reduction in leukocyte-endothelial cell interactions induced by a range of inflammatory mediators, suggesting that one mechanism whereby MIF acts during inflammatory responses is by promoting leukocyte recruitment. However, it is unknown whether MIF is capable of inducing leukocyte recruitment independently of additional inflammatory stimuli. In this study, we report that MIF is capable of inducing leukocyte adhesion and transmigration in postcapillary venules in vivo. Moreover, leukocytes recruited in response to MIF were predominantly CD68(+) cells of the monocyte/macrophage lineage. Abs against the monocyte-selective chemokine CCL2 (JE/MCP-1) and its receptor CCR2, but not CCL3 and CXCL2, significantly inhibited MIF-induced monocyte adhesion and transmigration. CCL2(-/-) mice displayed a similar reduction in MIF-induced recruitment indicating a critical role of CCL2 in the MIF-induced response. This hypothesis was supported by findings that MIF induced CCL2 release from primary microvascular endothelial cells. These data demonstrate a previously unrecognized function of this pleiotropic cytokine: induction of monocyte migration into tissues. This function may be critical to the ability of MIF to promote diseases such as atherosclerosis and rheumatoid arthritis, in which macrophages are key participants.
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http://dx.doi.org/10.4049/jimmunol.177.11.8072DOI Listing
December 2006

Reduced leukocyte-endothelial cell interactions in the inflamed microcirculation of macrophage migration inhibitory factor-deficient mice.

Arthritis Rheum 2004 Sep;50(9):3023-34

Centre for Inflammatory Diseases, Monash University, Victoria, Australia.

Objective: Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine with established roles in a range of inflammatory conditions. However, it is not known whether MIF influences inflammation via the direct promotion of leukocyte-endothelial cell interactions. Therefore, the aim of these experiments was to investigate the ability of MIF to regulate leukocyte-endothelial cell interactions in the inflamed microvasculature.

Methods: Intravital microscopy was used to examine postcapillary venules in the cremaster muscle and synovium of wild-type and MIF(-/-) mice. Leukocyte-endothelial cell interactions (rolling, adhesion, emigration) were compared under a range of inflammatory conditions.

Results: In cremasteric postcapillary venules of MIF(-/-) mice, lipopolysaccharide (LPS)-induced leukocyte rolling, adhesion, and emigration were significantly reduced relative to that in wild-type mice. Similar responses were observed in response to tumor necrosis factor alpha and histamine. Examination of the synovial microvasculature following exposure to carrageenan revealed that leukocyte rolling and adhesion in synovial postcapillary venules and leukocyte entry into the joint space were also reduced significantly in MIF(-/-) mice. In each of these models, the level of P-selectin-dependent rolling was reduced in MIF(-/-) mice. Despite this, no difference in P-selectin expression was observed following LPS treatment. However, microvascular shear forces were elevated in MIF(-/-) mice, raising a possible mechanism to explain the reduced interactions in these animals.

Conclusion: MIF(-/-) mice consistently displayed a reduction in P-selectin-dependent rolling, suggesting that MIF exerts proinflammatory effects, in part, via the promotion of P-selectin-mediated rolling. Together, these data indicate that MIF promotes interactions between leukocytes and endothelial cells, thereby enhancing the entry of leukocytes into sites of inflammation.
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http://dx.doi.org/10.1002/art.20470DOI Listing
September 2004