Abstract:SummaryMacrophages can fuse to form osteoclasts in bone or multinucleate giant cells (MGCs) as part of the immune response. We use a systems genetics approach in rat macrophages to unravel their genetic determinants of multinucleation and investigate their role in both bone homeostasis and inflammatory disease. We identify a trans-regulated gene network associated with macrophage multinucleation and Kcnn4 as being the most significantly trans-regulated gene in the network and induced at the onset of fusion. Kc… Show more
“…Median survival rates of the SK4 KO mice tend to result in a better outcome, but this tendency did not reach statistical significance. As SK4 channels are known to be important determinants in the activation of T and B cells (Begenisich et al ., 2004; Kang et al ., 2014; Xu et al ., 2014), decreased tumour formation in SK4 KO mice may be masked by the inability of the SK4‐deficient immune system to recognize and/or control tumorigenesis in breast cancer. To prove this hypothesis, we took a different approach and established an orthotopical transplantation model.…”
Oncogenic signalling via Ca2+‐activated K+ channels of intermediate conductance (SK4, also known as KCa3.1 or IK) has been implicated in different cancer entities including breast cancer. Yet, the role of endogenous SK4 channels for tumorigenesis is unclear. Herein, we generated SK4‐negative tumours by crossing SK4‐deficient (SK4 KO) mice to the polyoma middle T‐antigen (PyMT) and epidermal growth factor receptor 2 (cNeu) breast cancer models in which oncogene expression is driven by the retroviral promoter MMTV. Survival parameters and tumour progression were studied in cancer‐prone SK4 KO in comparison with wild‐type (WT) mice and in a syngeneic orthotopic mouse model following transplantation of SK4‐negative or WT tumour cells. SK4 activity was modulated by genetic or pharmacological means using the SK4 inhibitor TRAM‐34 in order to establish the role of breast tumour SK4 for cell growth, electrophysiological signalling, and [Ca2+]i oscillations. Ablation of SK4 and TRAM‐34 treatment reduced the SK4‐generated current fraction, growth factor‐dependent Ca2+ entry, cell cycle progression and the proliferation rate of MMTV‐PyMT tumour cells. In vivo, PyMT oncogene‐driven tumorigenesis was only marginally affected by the global lack of SK4, whereas tumour progression was significantly delayed after orthotopic implantation of MMTV‐PyMT SK4 KO breast tumour cells. However, overall survival and progression‐free survival time in the MMTV‐cNeu mouse model were significantly extended in the absence of SK4. Collectively, our data from murine breast cancer models indicate that SK4 activity is crucial for cell cycle control. Thus, the modulation of this channel should be further investigated towards a potential improvement of existing antitumour strategies in human breast cancer.
“…Median survival rates of the SK4 KO mice tend to result in a better outcome, but this tendency did not reach statistical significance. As SK4 channels are known to be important determinants in the activation of T and B cells (Begenisich et al ., 2004; Kang et al ., 2014; Xu et al ., 2014), decreased tumour formation in SK4 KO mice may be masked by the inability of the SK4‐deficient immune system to recognize and/or control tumorigenesis in breast cancer. To prove this hypothesis, we took a different approach and established an orthotopical transplantation model.…”
Oncogenic signalling via Ca2+‐activated K+ channels of intermediate conductance (SK4, also known as KCa3.1 or IK) has been implicated in different cancer entities including breast cancer. Yet, the role of endogenous SK4 channels for tumorigenesis is unclear. Herein, we generated SK4‐negative tumours by crossing SK4‐deficient (SK4 KO) mice to the polyoma middle T‐antigen (PyMT) and epidermal growth factor receptor 2 (cNeu) breast cancer models in which oncogene expression is driven by the retroviral promoter MMTV. Survival parameters and tumour progression were studied in cancer‐prone SK4 KO in comparison with wild‐type (WT) mice and in a syngeneic orthotopic mouse model following transplantation of SK4‐negative or WT tumour cells. SK4 activity was modulated by genetic or pharmacological means using the SK4 inhibitor TRAM‐34 in order to establish the role of breast tumour SK4 for cell growth, electrophysiological signalling, and [Ca2+]i oscillations. Ablation of SK4 and TRAM‐34 treatment reduced the SK4‐generated current fraction, growth factor‐dependent Ca2+ entry, cell cycle progression and the proliferation rate of MMTV‐PyMT tumour cells. In vivo, PyMT oncogene‐driven tumorigenesis was only marginally affected by the global lack of SK4, whereas tumour progression was significantly delayed after orthotopic implantation of MMTV‐PyMT SK4 KO breast tumour cells. However, overall survival and progression‐free survival time in the MMTV‐cNeu mouse model were significantly extended in the absence of SK4. Collectively, our data from murine breast cancer models indicate that SK4 activity is crucial for cell cycle control. Thus, the modulation of this channel should be further investigated towards a potential improvement of existing antitumour strategies in human breast cancer.
“…Therefore, KCa3.1 is an attractive pharmacological target for use in immunotherapy. [9][10][11] KCa3.1 gating is voltage independent and only requires a small increase in intracellular calcium. Intracellular calcium binds to calmodulin molecules that are constitutively associated with the channel protein and induce channel opening, which results in K + efflux that maintains a negative membrane potential.…”
Objective-Emerging evidence indicates that proinflammatory macrophage polarization imbalance plays a key role in atherosclerotic plaque progression and instability. The calcium-activated potassium channel KCa3.1 is critically involved in macrophage activation and function. However, the role of KCa3.1 in macrophage polarization is unknown. This study investigates the potential role of KCa3.1 in transcriptional regulation in macrophage polarization and its relationship to plaque instability. Approach and Results-Human monocytes were differentiated into macrophages using macrophage colony-stimulating factor. Macrophages were then polarized into proinflammatory M1 cells by interferon-γ and lipopolysaccharide and into alternative M2 macrophages by interleukin-4. A model for plaque instability was induced by combined partial ligation of the left renal artery and left common carotid artery in apolipoprotein E knockout mice. Significant upregulation of KCa3.1 expression was observed during the differentiation of human monocytes into macrophages. Blocking KCa3.1 significantly reduced the expression of proinflammatory genes during macrophages polarization. Further mechanistic studies indicated that blocking KCa3.1 inhibited macrophage differentiation toward the M1 phenotype by downregulating signal transducer and activator of transcription-1 phosphorylation. In animal models, KCa3.1 blockade therapy strikingly reduced the incidence of plaque rupture and luminal thrombus in carotid arteries, decreased the expression of markers associated with M1 macrophage polarization, and enhanced the expression of M2 markers within atherosclerotic lesions. opening, which results in K + efflux that maintains a negative membrane potential. Thus, the initial influx of Ca 2+ feeds forward, thereby, preserving the negative V m (membrane voltage) required for sustained Ca 2+ influx. 12 The Ca 2+ influx leads to an increase in cytosolic Ca 2+ concentration, which is necessary for the translocation of nuclear factors to the nucleus and the initiation of new transcription.
Conclusions-TheseParticularly, in macrophages, KCa3.1 has been shown to be involved in activation, migration, proliferation, and respiratory bursting, indicating that KCa3.1 suppression might be helpful in some macrophage-related disorders, such as asthma, multiple sclerosis, stroke, and so forth. [13][14][15] Previous evidence has demonstrated a role for KCa3.1 in atherosclerosis. In mouse models, pharmacological inhibition of KCa3.1 by the selective blocker TRAM-34 attenuates atherosclerotic lesion formation and may provide a novel approach for the prevention and treatment of atherosclerosis. 16 However, in advanced atherosclerotic lesions, the role of KCa3.1 in the pathogenesis of plaque instability and its underlying mechanisms are unknown. A recent study reported that IL-4 stimulation increases KCa3.1 current in microglia, 17 which suggests that KCa3.1 may be involved in the polarization of macrophages and atherosclerotic plaque disruption. In this study, we pharmacologic...
“…Dissecting the genetic regulation of gene networks inferred in a target tissue can uncover genetic control points of processes that are deregulated in the context of disease, which might then be used to design new drugs for therapeutic interventions. Gene networks can be linked to the genome by individual eQTL mapping of the genes in the network, which can point to a common regulatory locus in the genome (Kang et al, 2014). It is also feasible to map the variability of the whole network to the genome, and thereby define a ‘network-QTL’.…”
Section: Data Modeling Strategies Used In System Geneticsmentioning
confidence: 99%
“…4). Although we focus on the two main systems genetics studies carried out so far in the rat system (Heinig et al, 2010; Kang et al, 2014), we will also comment on related systems genetics investigations carried out in other species (humans in particular). Fig.…”
Section: Landmark Systems Genetics Studies In the Ratmentioning
confidence: 99%
“…Left: trans -eQTL networks were associated with cellular-level traits driving whole-body phenotypes in rodents (i.e. bone homeostasis and inflammatory disease) (Kang et al, 2014). Right: trans -eQTL networks identified in the rat were conserved to humans and enriched for GWAS variants, therefore linking the networks to a whole-body disease phenotype (i.e.…”
Section: Landmark Systems Genetics Studies In the Ratmentioning
Complementary to traditional gene mapping approaches used to identify the hereditary components of complex diseases, integrative genomics and systems genetics have emerged as powerful strategies to decipher the key genetic drivers of molecular pathways that underlie disease. Broadly speaking, integrative genomics aims to link cellular-level traits (such as mRNA expression) to the genome to identify their genetic determinants. With the characterization of several cellular-level traits within the same system, the integrative genomics approach evolved into a more comprehensive study design, called systems genetics, which aims to unravel the complex biological networks and pathways involved in disease, and in turn map their genetic control points. The first fully integrated systems genetics study was carried out in rats, and the results, which revealed conserved trans-acting genetic regulation of a pro-inflammatory network relevant to type 1 diabetes, were translated to humans. Many studies using different organisms subsequently stemmed from this example. The aim of this Review is to describe the most recent advances in the fields of integrative genomics and systems genetics applied in the rat, with a focus on studies of complex diseases ranging from inflammatory to cardiometabolic disorders. We aim to provide the genetics community with a comprehensive insight into how the systems genetics approach came to life, starting from the first integrative genomics strategies [such as expression quantitative trait loci (eQTLs) mapping] and concluding with the most sophisticated gene network-based analyses in multiple systems and disease states. Although not limited to studies that have been directly translated to humans, we will focus particularly on the successful investigations in the rat that have led to primary discoveries of genes and pathways relevant to human disease.
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