Aberrant actin depolymerization triggers the pyrin inflammasome and autoinflammatory disease that is dependent on IL-18, not IL-1β

Gain-of-function mutations that activate the innate immune system can cause systemic autoinflammatory diseases associated with increased IL-1β production. This cytokine is activated identically to IL-18 by an intracellular protein complex known as the inflammasome; however, IL-18 has not yet been specifically implicated in the pathogenesis of hereditary autoinflammatory disorders. We have now identified an autoinflammatory disease in mice driven by IL-18, but not IL-1β, resulting from an inactivating mutation of the actin-depolymerizing cofactor Wdr1. This perturbation of actin polymerization leads to systemic autoinflammation that is reduced when IL-18 is deleted but not when IL-1 signaling is removed. Remarkably, inflammasome activation in mature macrophages is unaltered, but IL-18 production from monocytes is greatly exaggerated, and depletion of monocytes in vivo prevents the disease. Small-molecule inhibition of actin polymerization can remove potential danger signals from the system and prevents monocyte IL-18 production. Finally, we show that the inflammasome sensor of actin dynamics in this system requires caspase-1, apoptosis-associated speck-like protein containing a caspase recruitment domain, and the innate immune receptor pyrin. Previously, perturbation of actin polymerization by pathogens was shown to activate the pyrin inflammasome, so our data now extend this guard hypothesis to host-regulated actin-dependent processes and autoinflammatory disease.Autoinflammatory syndromes are caused by dysregulation of the innate immune system, frequently affecting the inflammasome or other pathogen recognition pathways and leading to the overproduction of active IL-1β and IL-18 (Masters et al., 2009). To date, there are at least 12 known genetic causes of autoinflammatory disease, including familial Mediterranean fever (FMF), hyper-IgD syndrome, and cryopyrin-associated periodic syndrome. Therapeutic options for these diseases include nonsteroidal antiinflammatory drugs, corticosteroids, colchicine (for FMF), anti-TNF, and direct blockade of IL-1, which can be highly efficacious (Masters et al., 2009; Caso et al., 2013). IL-18 and IL-1β are produced in many cells, including monocytes and macrophages (Okamura et al., 1995; Ushio et al., 1996). IL-18 and IL-1β are produced as precursors and do not have a signal peptide to facilitate their secretion; instead, they are activated and released extracellularly as mature proteins after cleavage by caspase-1 (Li et al., 1995; Ghayur et al., 1997; Gu et al., 1997). Despite these similarities, there is no known hereditary autoinflammatory disease where the pathology is caused exclusively by IL-18.The inflammasome is an intracellular molecular platform that forms in response to pathogen- or danger-associated molecular patterns (DAMPs), leading to recruitment and activation of caspase-1 (Martinon et al., 2002; Schroder and Tschopp, 2010). A growing number of inflammasomes have been reported, each nucleated by a different innate immune receptor, such as NLRP1 (Martinon et al., 2000; Boyden and Dietrich, 2006), NLRP3 (Agostini et al., 2004), NLRC4 (Franchi et al., 2006), pyrin (Chae et al., 2011), and AIM2 (Hornung et al., 2009). Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is a key adaptor used by most of these innate immune receptors to interact with and recruit caspase-1 (Srinivasula et al., 2002). Activating mutations in NLRP3 result in increased IL-1β and IL-18 production, which can be prevented in mice by deleting caspase-1 or ASC. Furthermore, deleting either the IL-18R or the IL-1R can both independently protect mice from this NLRP3-mediated autoinflammatory disease (Brydges et al., 2013). For the FMF protein, pyrin, activating mutations induce ASC-dependent but NLRP3-independent IL-1β activation and cause severe autoinflammation in mice (Chae et al., 2011). Interestingly, pyrin interacts with ASC, microtubules, and actin filaments (Mansfield et al., 2001; Richards et al., 2001; Waite et al., 2009), and it has recently been shown that modification of RhoGTPases by bacterial toxins can trigger the pyrin inflammasome, perhaps via modulation of actin dynamics (Xu et al., 2014). This raises the fascinating prospect of a link between perturbations in the actin cytoskeleton and autoinflammatory disease.Wdr1 is required for disassembly of actin filaments in conjunction with the actin-depolymerizing factor/cofilin family of proteins. Mice homozygous for a hypomorphic allele of Wdr1 (Wdr1^rd/rd) exhibit spontaneous autoinflammatory disease and thrombocytopenia (Kile et al., 2007). Both defects have been suggested to result from a disruption in actin dynamics. Thrombocytopenia results from defects in megakaryocytes, a cell type that is entirely dependent on a functional cytoskeleton to shed platelets (Patel et al., 2005). Wdr1 mutant mice also exhibit neutrophilia; however, the critical inflammatory mediators and cell types important for the development of inflammation in this genetic condition are unclear (Kile et al., 2007). Intriguingly, Wdr1 was found to be secreted after caspase-1 activation (Keller et al., 2008).We examined the role of key inflammatory mediators that drive autoinflammation in Wdr1^rd/rd mice and demonstrated that this disease is IL-18 dependent, but IL-1 independent. As expected, this IL-18 is produced by the inflammasome; however, it is not produced from neutrophils or macrophages, but instead only from monocytes. Finally, we found that the autoinflammatory disease was mediated by pyrin, providing evidence that this innate immune receptor recognizes alterations in the actin polymerization pathway.     

Color temperature’s impact on task performance and brainwaves of school-age children

[Purpose] This study investigated color temperature’s impact on task performance. It presents a scientific analysis of brainwave and task performance time changes, and the results of a self-report type survey. [Subjects] Twenty-four elementary school fifth-grade boys and girls with no visual problems participated in the experiment. [Methods] Physiological reaction times of task performance were measured in a laboratory that could fix and maintain color temperature. Brainwave changes and the task performance times were measured, and a self-report questionnaire was conducted in order to measure of emotional reactions. [Results] Regarding the brainwave changes associated with color temperature, alpha waves were emitted in the O2 area when puzzle tasks were illuminated by orange light and low and high beta waves were emitted in the F3 area under white light. Five items (Brilliant, Soft, Lively, Relaxed, Open) were reported predominantly in responses to orange light in the self-report questionnaire. [Conclusion] The results of this study show that relaxation and stability are not assured when the color temperature is low, and that concentration and cognitive activity are not necessarily easier when the color temperature is high. The color temperature change when performing tasks promoted emotional factors more than brainwave, a biological change.Key words: Physical environment, Brainwave, Color temperature     

The impact of the pelvic floor muscles on dynamic ventilation maneuvers

[Purpose] The aim of the present study was to examine the impact of the pelvic floor muscles (PFM) on dynamic ventilation maneuvers. [Subjects and Methods] The subjects were 19 healthy female adults in their 20s who consented to participate in the present study. Electromyography (EMG) was used to examine respiratory muscle activity, and a spirometer was used to examine vital capacity before and during contraction of the PFM. [Results] There were statistically significant differences in the sternocleidomastoid (SCM), rectus abdominis (RA), external oblique (EO), transverse abdominis/internal oblique (TrA/IO), and maximal voluntary ventilation (MVV) when the PFM was contracted. [Conclusion] Contraction of the PFM can be effective in promoting activation of the respiratory muscles and vital capacity. Therefore, the PFM should be considered to improve the effects of respiratory activity.Key words: Pelvic floor muscles, Respiratory muscles, Maximal voluntary ventilation     

Impact of decline-board squat exercises and knee joint angles on the muscle activity of the lower limbs

[Purpose] This study aims to investigate how squat exercises on a decline board and how the knee joint angles affect the muscle activity of the lower limbs. [Subjects] The subjects were 26 normal adults. [Methods] A Tumble Forms wedge device was used as the decline board, and the knee joint angles were measured with a goniometer. To examine the muscle activity of the biceps femoris, rectus femoris, gastrocnemius lateralis, and tibialis anterior of the lower limbs, a comparison analysis with electromyography was conducted. [Results] The muscle activity of the biceps femoris, rectus femoris, gastrocnemius lateralis, and tibialis anterior increased with increased knee joint angles, both for squat exercises on the decline board and on a flat floor. When the knee joint angle was 45°, 60°, and 90°, the muscle activity of the rectus femoris was significantly higher and that of the tibialis anterior was significantly lower during squat exercises on the decline board than on the flat floor. When the knee joint angle was 90°, the muscle activity of the gastrocnemius lateralis was significantly lower. [Conclusion] Squat exercises on a decline board are an effective intervention to increase the muscle activity of the rectus femoris with increased knee joint angles.Key words: Decline board, Squat exercise, Range of motion     

Analysis of isokinetic muscle strength for sports physiotherapy research in Korean ssireum athletes

[Purpose] The purpose of the present study was to elucidate the muscle conditions such as the isokinetic muscle of Korean ssireum athletes. [Subjects and Methods] This study enrolled 25 elite ssireum athletes. We measured body composition and peak torque at an angular speed at 60°/s using an isokinetic muscle strength dynamometer. [Results] The lean body mass of the left upper limb was significantly higher than that of the right upper limb. However, the lean body mass of the left lower limb was significantly lower than that of the right lower limb. The peak torque for left elbow flexion was significantly higher than that for right elbow flexion. Conversely, the peak torque for left elbow extension was significantly lower than that for right elbow extension. Furthermore, the peak torque for the left knee was significantly lower than that for the right knee for both flexion and extension. [Conclusion] The data from this study elucidate in part the muscle conditions of Korean ssireum athletes, which can be used to establish a reference for the scientific study of sports physiotherapy.Key words: Isokinetic muscle strength, Ssireum athletes, Sports physiotherapy     

The effects of prism glasses and intensive upper limb exercise on hemineglect,upper limb function,and activities of daily living in stroke patients: a case series

[Purpose] This study aimed to examine the effects of visual field with prism glasses, and intensive upper limb functional training on reduction of hemineglect and improvement in upper limb function and activities of daily living in three stroke patients with hemineglect. [Subjects] This study included three stroke patients hospitalized in a sanatorium. [Methods] Intervention treatment involving prism glass use for 12 hours and 30 minutes and paretic side upper limb training was conducted 5 days a week for 15 weeks. Three upper limb training tasks (hitting a balloon, passing through a ring, and reading a newspaper) were performed for 10 minutes each session, for a total of 30 minutes. Line by Section, Motor-Free Visual Perception Test-3 (MVPT-3), Manual Function Test (MFT), Box & Block Test (BBT), and Assessment of Motor and Process Skills (AMPS) were conducted before and after intervention. [Results] Subjects’ hemineglect decreased and upper limb function on the paretic side improved after intervention, which enhanced activities of daily living. [Conclusion] Prism glass use and paretic upper limb functional training effectively ameliorated stroke patients’ hemineglect and improved upper limb function. Future research should focus on prism glasses that provide a wide visual field for use in patients with different conditions.Key words: Fresnel prism, Unilateral neglect, Visual field     

A comparison of driving errors in patients with left or right hemispheric lesions after stroke

[Purpose] The aim of this study was to compare the incidence of driving errors among patients with left or right hemispheric lesions due to stroke. [Subjects and Methods] Thirty stroke patients participated in the study. Driving errors were assessed using a virtual reality driving simulator. [Results] Significant differences were shown in center line crossing frequency, accident rate, brake reaction time, total driving error scores, and overall driving safety between participants with left or right hemispheric lesions. [Conclusion] Driving rehabilitation specialists should consider hemispheric function when teaching driving skills to stroke survivors, because patients with lesions in the left or right hemispheres after stroke show differences in driving skills.Key words: Stroke, Driving error, Hemispheric lesion