Minako Ito

SOCS, inflammation, and cancer.

Signal transduction pathways elicited by cytokines and hormones have been shown to regulate distinct stages of development. Suppressor of cytokine signaling (SOCS) proteins are negative feedback regulators of cytokine signaling mediated by the JAK-STAT signaling pathway. In particular, SOCS1 and SOCS3 are potent inhibitors of JAKs and can play pivotal roles in inflammation, as well as in the development and progression of cancers. Abnormal expression of SOCS1 and SOCS3 in cancer cells has been reported in human carcinoma associated with dysregulation of signals from cytokine receptors, Toll-like receptors (TLRs), and hormone receptors, resulting in malignancies. In this review, we focus on the role of SOCS1 and SOCS3 in cancer development. In addition, the potential of SOCS as a therapeutic target and diagnostic aid will be discussed.

Bruton’s tyrosine kinase is essential for NLRP3 inflammasome activation and contributes to ischaemic brain injury

In this contribution, I discuss an algebraic treatment of alpha-cluster nuclei based on the introduction of a spectrum generating algebra for the relative motion of the alpha-clusters. Particular attention is paid to the discrete symmetry of the geometric arrangement of the alpha-particles, and the consequences for the structure of the rotational bands in the 12C and 16O nuclei.Inflammasome activation has been implicated in various inflammatory diseases including post-ischaemic inflammation after stroke. Inflammasomes mediate activation of caspase-1, which subsequently induces secretion of pro-inflammatory cytokines such as IL-1β and IL-18, as well as a form of cell death called pyroptosis. In this study, we report that Brutons tyrosine kinase (BTK) is an essential component of the NLRP3 inflammasome, in which BTK physically interacts with ASC and NLRP3. Inhibition of BTK by pharmacological or genetic means severely impairs activation of the NLRP3 inflammasome. The FDA-approved BTK inhibitor ibrutinib (PCI-32765) efficiently suppresses infarct volume growth and neurological damage in a brain ischaemia/reperfusion model in mice. Ibrutinib inhibits maturation of IL-1β by suppressing caspase-1 activation in infiltrating macrophages and neutrophils in the infarcted area of ischaemic brain. Our study indicates that BTK is essential for NLRP3 inflammasome activation and could be a potent therapeutic target in ischaemic stroke.

Post-ischemic inflammation regulates neural damage and protection

Post-ischemic inflammation is important in ischemic stroke pathology. However, details of the inflammation process, its resolution after stroke and its effect on pathology and neural damage have not been clarified. Brain swelling, which is often fatal in ischemic stroke patients, occurs at an early stage of stroke due to endothelial cell injury and severe inflammation by infiltrated mononuclear cells including macrophages, neutrophils, and lymphocytes. At early stage of inflammation, macrophages are activated by molecules released from necrotic cells [danger-associated molecular patterns (DAMPs)], and inflammatory cytokines and mediators that increase ischemic brain damage by disruption of the blood–brain barrier are released. After post-ischemic inflammation, macrophages function as scavengers of necrotic cell and brain tissue debris. Such macrophages are also involved in tissue repair and neural cell regeneration by producing tropic factors. The mechanisms of inflammation resolution and conversion of inflammation to neuroprotection are largely unknown. In this review, we summarize information accumulated recently about DAMP-induced inflammation and the neuroprotective effects of inflammatory cells, and discuss next generation strategies to treat ischemic stroke.

Th17 Cells Carrying TCR Recognizing Epidermal Autoantigen Induce Psoriasis-like Skin Inflammation

Psoriasis is considered a Th17-type autoimmune skin inflammatory disease; however, involvement of an autoantigen-specific TCR has not been established. In this study, we show that psoriasis-like skin inflammation can be induced by autoreactive Th17 cells. We previously developed the desmoglein 3–specific TCR-transgenic (Dsg3H1) mouse, in which CD4+ T cells recognize physiological epidermal autoantigen. T cells from Dsg3H1 mice were polarized into Th17 cells in vitro and then adoptively transferred into Rag2−/− mice. Dsg3H1-Th17 cells induced severe psoriasis-like skin inflammation within 2 wk after transfer in the tissues in which desmoglein 3 is expressed. Such pathology was not observed when wild-type Th17 cells or Th1-skewed Dsg3H1 T cells were transferred, and it was strongly suppressed by anti–IL-12/23 and anti–IL-17 Abs. Although IFN-γ+/IL-17+ T cells accumulated in the skin lesions of mice that received Dsg3H1-Th17 cells, IFN-γ–deficient Dsg3H1-Th17 cells were fully pathogenic. These results demonstrate that cutaneous psoriasis-like immunopathology can be developed by epidermis-specific recognition of Th17 cells, which is strictly dependent on IL-17 but not IFN-γ.

MAFB prevents excess inflammation after ischemic stroke by accelerating clearance of damage signals through MSR1

Damage-associated molecular patterns (DAMPs) trigger sterile inflammation after tissue injury, but the mechanisms underlying the resolution of inflammation remain unclear. In this study, we demonstrate that common DAMPs, such as high-mobility-group box 1 (HMGB1), peroxiredoxins (PRXs), and S100A8 and S100A9, were internalized through the class A scavenger receptors MSR1 and MARCO in vitro. In ischemic murine brain, DAMP internalization was largely mediated by MSR1. An elevation of MSR1 levels in infiltrating myeloid cells observed 3 d after experimental stroke was dependent on the transcription factor Mafb. Combined deficiency for Msr1 and Marco, or for Mafb alone, in infiltrating myeloid cells caused impaired clearance of DAMPs, more severe inflammation, and exacerbated neuronal injury in a murine model of ischemic stroke. The retinoic acid receptor (RAR) agonist Am80 increased the expression of Mafb, thereby enhancing MSR1 expression. Am80 exhibited therapeutic efficacy when administered, even at 24 h after the onset of experimental stroke. Our findings uncover cellular mechanisms contributing to DAMP clearance in resolution of the sterile inflammation triggered by tissue injury.

CDK inhibitors suppress Th17 and promote iTreg differentiation, and ameliorate experimental autoimmune encephalomyelitis in mice.

Th17 cells, which have been implicated in autoimmune diseases, require IL-6 and TGF-β for early differentiation. Several Smad-independent pathways including the JNK and the RhoA-ROCK pathways have been implicated in the induction of RORγt, the master regulator of Th17, however, molecular mechanisms underlying Smad-independent pathway remain largely unknown. To identify novel pathways involved in Th17 differentiation, we screened 285 chemical inhibitors for known signaling pathways. Among them, we found that Kenpaullone, a GSK3-β and CDK inhibitor, efficiently suppressed TGF-β-mediated RORγt induction and enhanced Foxp3 induction in primary T cells. Another CDK inhibitor, Roscovitine, but not other GSK3-β inhibitors, suppressed Th17 differentiation and enhanced iTreg development. Kenpaullone and Roscovitine suppressed experimental autoimmune encephalomyelitis (EAE), a typical Th17-mediated autoimmune disease model. These two compounds enhanced STAT5 phosphorylation and restored IL-2 production in the presence of TGF-β. These data suggest that CDK inhibitors modulate TGF-β-signaling pathways, which restore TGF-β-mediated suppression of IL-2 production, thereby modifying the Th17/iTreg balance.

Induction and maintenance of regulatory T cells by transcription factors and epigenetic modifications

Regulatory T cells (Tregs) are an essential cell subset for the maintenance of immune homeostasis. Foxp3 (Forkhead box P3) is the Treg master gene which is essential for immune suppressing activity. In addition, Tregs are characterized by a distinct pattern of gene expression, including upregulation of immune-suppressive genes and silencing of inflammatory genes. The molecular mechanisms of Treg development and maintenance have been intensively investigated. Tregs are characterized by expression of the transcription factor Foxp3. Several intronic enhancers and a promoter at the Foxp3 gene locus were shown to play important roles in Treg differentiation. The enhancers have been designated as conserved non-coding sequences (CNSs) 0, 1, 2, and 3. We showed that the transcription factors Nr4a and Smad2/3 are essential for the development of thymic Tregs and induced Tregs, respectively. Recently, Treg-specific DNA demethylation has been shown to play an important role in Treg stability. DNA demethylation of CNS2 has been implicated in Treg stability, and recent reports have revealed that the ten-eleven translocation (Tet) family of demethylation factor plays an important role in CpG demethylation at CNS2. This article reviews the recent progress on the roles of transcription factors and epigenetic modifications in the differentiation, maintenance, and function of Tregs.

Construction of HEMS in Japanese cold district for reduction of carbon dioxide emissions

Increasing carbon dioxide emissions have given rise to global warming. Therefore, the need to reduce these emissions is being widely discussed. Decreasing energy consumption by efficient energy use is required to directly influence carbon dioxide emissions. Recently, energy consumption in the civilian sector is rising in Japan. To address this problem, the introduction of a Home Energy Management System (HEMS) is effective because it enables the control of power consumption and an economical energy use. Controlled heating, ventilation, and air conditioning (HVAC) is an essential function to be implemented in HEMS. HVAC control systems are now commercial and several HEMS experiments with HVAC control have been conducted in Japan. However, only few experiments have been conducted in cold districts because peak energy consumption predominantly occurs in summer. Nevertheless, from a carbon dioxide emissions reduction viewpoint, in such districts, the use of kerosene fan heaters, which are popular, becomes a dominant source of emissions around the year, but particularly in winter. In this study, we constructed a HEMS at 16 houses in a cold district, with the collecting function of environmental conditions, heating appliances status, the amount electric/oil energy consumption, and with the control function of HVAC systems. In particular, specially designed fully-controlled and monitored kerosene fan heaters are introduced. To confirm the effectiveness of the proposed HEMS, an energy saving experiment was conducted in which the use of kerosene fan heaters was controlled on the basis of the acquired environmental information, without degrading the room comfort. A reduction in carbon dioxide emissions was monitored along with the comfort level. This is the first experiment which integrates kerosene fan heaters into HEMS. This study demonstrated the ability of autonomous heater control to reduce the burden of residents and the usefulness of HEMS in Japans cold district.

Proposal for home energy management system to survey individual thermal comfort range for HVAC control with little contribution from users

Heating, ventilation, and air conditioning (HVAC) control is used to effectively reduce energy consumption in a home energy management system (HEMS). For the HVAC control, it is necessary to evaluate the indoor comfort level because the HVAC operation is significantly related to indoor environmental conditions. Although there are some indices for indoor comfort, individuals have different comfort ranges. A questionnaire is one way to gather data on individual comfort ranges. However, it requires contributions from users. Therefore, we proposed a new survey method that varied the intervals of the questions addressed to users to reduce the number of responses needed. Additionally, a comfort estimation method was proposed that did not require a questionnaire. This method analyzes the users operation of the HVAC system, such as touching its on/off switch. An HEMS with the capability of utilizing these two methods was installed in a laboratory and 16 houses in Miyagi prefecture, Japan. An experiment using this HEMS was conducted, and it was able to reduce the number of feedbacks needed to maintain each persons comfort by an average of 32.2%. The HEMS provided the same accuracy as hourly questionnaires. Namely, it confirmed that the estimation based on the air conditioner operations was almost the same as that based on an hourly questionnaire.

A practical case study of HVAC control with MET measuring in HEMS environment

As a peak-cut or peak leveling control, heating, ventilation, and air conditioning (HVAC) are essential method for controlling the demand of electric power consumption. However, it is important to consider environmental amenity when designing control systems because the control may cause the deterioration of the amenity. In existing methods, metabolic equivalent (MET) values are not considered. Measurement and processing of MET values can be costly, requiring special infrastructure to both measure the values and communicate these values with a home energy management system (HEMS) or building energy management system (BEMS). This paper proposes a HVAC control method that considers the tradeoff between environmental amenity and energy conservation using the Keio University network oriented intelligent and versatile energy management system (KNIVES). The proposed method uses an iPod touch or iPhone application to obtain accurate measurements of both the MET value and the predicted mean vote (PMV). The accuracy of the PMV values after incorporation of MET estimates was confirmed experimentally. A HEMS experiment was conducted and a reduction in energy consumption was observed, demonstrating the usefulness of both the application and the proposed HVAC control method.