Inflammation-induced Migration Research Articles

A Novel Enolase-1 Antibody Targets Multiple Interacting Players in the Tumor Microenvironment of Advanced Prostate Cancer.

Prostate cancer is one of the most common causes of cancer death in men worldwide, and the treatment options are limited for patients with advanced stages of prostate cancer. Upon oncogenic or inflammatory stimulation, tumor cells or immune cells express cell surface enolase-1 (ENO1) as plasminogen receptor to facilitate their migration via plasmin activation. Little is known about the roles of ENO1 in prostate cancer, especially in the tumor microenvironment (TME). We hypothesized that targeting surface ENO1 with specific mAbs would exert multifactorial therapeutic potentials against prostate cancer. In vivo, we showed ENO1 mAb (HuL227) reduced the growth of subcutaneous PC-3 xenograft, monocytes recruitment, and intratumoral angiogenesis. In a PC-3 intratibial implantation model, HuL227 reduced tumor growth and osteoclast activation in the bone. To investigate the antitumor mechanism of ENO1 mAb, we found that blocking surface ENO1 significantly reduced VEGF-A-induced tube formation of endothelial cells in vitro. Furthermore, HuL227 inhibited inflammation-enhanced osteoclasts activity and the secretion of invasion-related cytokines CCL2 and TGFβ from osteoclasts. In addition, inflammation-induced migration and chemotaxis of androgen-independent prostate cancer cells were dose-dependently inhibited by HuL227. In summary, we showed that, ENO1 mAb targets multiple TME niches involved in prostate cancer progression and bone metastasis via a plasmin-related mechanism, which may provide a novel immunotherapy approach for men with advanced prostate cancer.

Atherosclerosis

For the past decade, cardiovascular disease (CVD) has been the leading cause of death and disability worldwide, and in most cases, atherosclerosis is the dominant underlying pathologic process. Atherosclerosis is characterized by subendothelial accumulation of lymphocytes, lipid-filled macrophages, and inflammation-induced migration of vascular smooth muscle cells slowly forming a fibroinflammatory lipid plaque. Over time, the plaque progressively weakens and occludes the vessel; however, with continued inflammation and hemodynamic changes, atheromas can dangerously manifest as ischemia (acute or chronic) or aneurysmal disease. This review discusses the economic impact, historical background, and pathogenesis of atherosclerosis, as well as normal arterial biology, risk factors, and screening. Tables outline physiologic properties of nitric oxide in native vessels, selected cellular and chemical mediators and their role in atherogenesis, current risk factors for peripheral arterial disease (PAD) development, and diagnosis criteria for diseases that confer increased PAD risk. Graphs demonstrate mortality due to PAD, PAD prevalence, and the economic impact of CVD. Illustrations depict normal vessel anatomy, blood flow with plaque at carotid bifurcation, the superficial femoral artery (SFA) with plaque, and the progression of atherosclerotic changes. A flow chart for atherogenesis, photograph of a human carotid endarterectomy specimen, and angiogram showing the classic occluding lesion of the SFA are also provided. This review contains 9 figures, 5 tables, and 91 references.

The role of meningeal lymphatics in viral meningitis

Abstract Discovery of the meningeal lymphatic vessels in the brain meninges (coverings of the brain) led to the hypothesis that they carry macromolecules and immune cells from cerebrospinal fluid (CSF) to cervical lymph nodes (cLN). Our new findings suggest that the lymphatic system controls immune responses through guiding antigen-presenting cells, such as dendritic cells (DC) from the meninges to draining lymph nodes. By using surgical and pharmacological methods to interfere with meningeal lymphatic vessels, we found lymphatics to serve as a major conduit by which DC leave the meninges, traffic to cLN and promote the generation of antigen-specific T cells. Inflammation-induced migration of DC is primarily regulated through a CC-chemokine receptor 7 (CCR7) dependent pathway. Co-injection of equal parts of differentially labeled CCR7-deficient and wild-type (WT) DCs into the CSF of the brain did allow translocation of CCR7-competent DC into the T cell zone of the draining lymph nodes but not CCR7−/− DC. Subsequently, antigenic stimulation by CCR7−/− DC did not induce a T cells response in the cLN, whereas WT DC enforced the majority of antigen-specific T cells to proliferate and increase their effective trafficking through integrin expression. To gain insights into how T cell responses are elicited when the meninges are infected with a virus, we currently set out to understand the lymphatics function in a mouse model of virus-induced meningitis. Injection of Lymphocytic choriomeningitis virus into the CSF induces rapid, uniform and fatal inflammation that is dependent on the generation of viral specific CD8+ T cells and potentially the exit of migratory DC through meningeal lymphatic vessels.

Pten regulates homeostasis and inflammation-induced migration of myelocytes in zebrafish

BackgroundLoss of the tumor suppressor phosphatase and tensin homolog (PTEN) is frequently observed in hematopoietic malignancies. Although PTEN has been implicated in maintaining the quiescence of hematopoietic stem cells (HSCs), its role in hematopoiesis during ontogeny remains largely unexplored.MethodsThe expression of hematopoietic marker genes was analyzed via whole mount in situ hybridization assay in ptena and ptenb double mutant zebrafish. The embryonic myelopoiesis was characterized by living imaging and whole mount in situ immunofluorescence with confocal microscopy, as well as cell-specific chemical staining for neutrophils and macrophages. Analyses of the involved signaling pathway were carried out by inhibitor treatment and mRNA injection.ResultsPten-deficient zebrafish embryos exhibited a strikingly increased number of myeloid cells, which were further characterized as being immune deficient. In accordance with this finding, the inhibition of phosphoinositide 3-kinase (PI3K) or the mechanistic target of rapamycin (mTOR) corrected the expansive myelopoiesis in the pten-deficient embryos. Further mechanistic studies revealed that the expression of cebpa, a critical transcription factor in myeloid precursor cells, was downregulated in the pten-deficient myeloid cells, whereas the injection of cebpa mRNA markedly ameliorated the dysmyelopoiesis induced by the loss of pten.ConclusionsOur data provide in vivo evidence that definitive myelopoiesis in zebrafish is critically regulated by pten via the elevation of cebpa expression.

Clusterin stimulates the chemotactic migration of macrophages through a pertussis toxin sensitive G-protein-coupled receptor and Gβγ-dependent pathways

Clusterin induces the expression of various chemotactic cytokines including tumor necrosis factor-α (TNF-α) in macrophages and is involved in the cell migration. According to the results of this study, clusterin induced the directional migration (chemotaxis) of macrophages based on a checkerboard analysis. The chemotactic activity of clusterin was prevented by pretreatment with pertussis toxin (PTX), indicating that the Gαi/o-protein coupled receptor (GPCR) was involved in the chemotactic response of clusterin. Clusterin-stimulated chemotaxis was abrogated in a dose-dependent manner by pretreatment with gallein (a Gβγ inhibitor), indicating the involvement of Gβγ released from the GPCR. In addition, inhibitors of phospholipase C (PLC, U73122) and phosphoinositide 3-kinase (PI3K, LY294002), the key targets of Gβγ binding and activation, suppressed chemotactic migration by clusterin. The phosphorylation of Akt induced by clusterin was blocked by pretreatment with gallein or LY294002 but not with U73122, indicating that Gβγ released from the PTX-sensitive Gi protein complex activated PLC and PI3K/Akt signaling pathways separately. The activation of cellular MAP kinases was essential in that their inhibitors blocked clusterin-induced chemotaxis, and Gβγ was required for the activation of MAP kinases because gallein reduced their phosphorylations induced by clusterin. In addition, the inflammation-induced migration of macrophages was greatly reduced in clusterin-deficient mice based on a thioglycollate-induced peritonitis model system. These results suggest that clusterin stimulates the chemotactic migration of macrophages through a PTX-sensitive GPCR and Gβγ-dependent pathways and describe a novel role of clusterin as a chemoattractant of monocytes/macrophages, suggesting that clusterin may serve as a molecular bridge between inflammation and its remodeling of related tissue by recruiting immune cells.

Autocrine/paracrine TGF-β1 inhibits Langerhans cell migration

Langerhans cells (LCs) are skin-resident dendritic cells (DC) located in the epidermis that migrate to skin-draining lymph nodes during the steady state and in response to inflammatory stimuli. TGF-β1 is a critical immune regulator that is highly expressed by LCs. The ability to test the functional importance of LC-derived TGF-β1 is complicated by the requirement of TGF-β1 for LC development and by the absence of LCs in mice with an LC-specific ablation of TGF-β1 or its receptor. To overcome these problems, we have engineered transgenic huLangerin-CreER(T2) mice that allow for inducible LC-specific excision. Highly efficient and LC-specific expression was confirmed in mice bred onto a YFP Cre reporter strain. We next generated huLangerin-CreER(T2) × TGF-βRII(fl) and huLangerin-CreER(T2) × TGF-β1(fl) mice. Excision of the TGFβRII or TGFβ1 genes induced mass migration of LCs to the regional lymph node. Expression of costimulatory markers and inflammatory cytokines was unaffected, consistent with homeostatic migration. In addition, levels of p-SMAD2/3 were decreased in LCs from wild-type mice before inflammation-induced migration. We conclude that TGF-β1 acts directly on LCs in an autocrine/paracrine manner to inhibit steady-state and inflammation-induced migration. This is a readily targetable pathway with potential therapeutic implications for skin disease.

Ibuprofen and hydrogel-released ibuprofen in the reduction of inflammation-induced migration in melanoma cells

There is growing evidence that inflammation may exacerbate cancer metastasis and several clinical studies show that taking nonsteroidal anti-inflammatory drugs appears to reduce metastases. The aims of this study were: (i) to examine the effects of ibuprofen on the major proinflammatory cytokine tumour necrosis factor (TNF)-alpha induction of migration of C8161 and HBL human melanoma cells; (ii) to develop ibuprofen-releasing hydrogels (Pluronics F127) for future topical use in reducing metastatic spread of primary melanoma; and (iii) to examine whether the actions of ibuprofen might be explained by induction of apoptosis. Melanoma cells were exposed to 300 U mL(-1) TNF-alpha for a 24-h period prior to making a scratch wound to which ibuprofen or ibuprofen-loaded hydrogels were then added. The effects of relevant concentrations of ibuprofen on cell viability and apoptosis were examined. Ibuprofen at 10(-3) mol L(-1) significantly reduced TNF-alpha-stimulated migration of both cell types to that of nonstimulated cells (P < 0.001). TNF-alpha-unstimulated cell migration was not significantly affected. Cells responded similarly to SS and SR forms of ibuprofen. Cells treated with ibuprofen sodium salt-loaded hydrogels showed a significant reduction in migration when compared with unloaded hydrogels. Ibuprofen induced apoptosis in HBL cells but had no effect on C8161 melanoma cells apoptosis at concentrations that reduced migration. These results demonstrate that TNF-alpha upregulated malignant melanoma migration in vitro and that this could be reduced by ibuprofen both in solution and delivered from a hydrogel. These effects of ibuprofen cannot be attributed simply to induction of apoptosis.