Blockade of the CXCR3/CXCL10 axis ameliorates inflammation caused by immunoproteasome dysfunction

Immunoproteasomes regulate the degradation of ubiquitin-coupled proteins and generate peptides that are preferentially presented by MHC class I. Mutations in immunoproteasome subunits lead to immunoproteasome dysfunction, which causes proteasome-associated autoinflammatory syndromes (PRAAS) characterized by nodular erythema and partial lipodystrophy. It remains unclear, however, how immunoproteasome dysfunction leads to inflammatory symptoms. Here, we established mice harboring a mutation in Psmb8 (Psmb8-KI mice) and addressed this question. Psmb8-KI mice showed higher susceptibility to imiquimod-induced skin inflammation (IMS). Blockade of IL-6 or TNF-α partially suppressed IMS in both control and Psmb8-KI mice, but there was still more residual inflammation in the Psmb8-KI mice than in the control mice. DNA microarray analysis showed that treatment of J774 cells with proteasome inhibitors increased the expression of the Cxcl9 and Cxcl10 genes. Deficiency in Cxcr3, the gene encoding the receptor of CXCL9 and CXCL10, in control mice did not change IMS susceptibility, while deficiency in Cxcr3 in Psmb8-KI mice ameliorated IMS. Taken together, these findings demonstrate that this mutation in Psmb8 leads to hyperactivation of the CXCR3 pathway, which is responsible for the increased susceptibility of Psmb8-KI mice to IMS. These data suggest the CXCR3/CXCL10 axis as a new molecular target for treating PRAAS

Neurosecretory protein GL stimulates food intake, de novo lipogenesis, and onset of obesity.

Mechanisms underlying the central regulation of food intake and fat accumulation are not fully understood. We found that neurosecretory protein GL (NPGL), a newly-identified neuropeptide, increased food intake and white adipose tissue (WAT) in rats. NPGL-precursor gene overexpression in the hypothalamus caused increases in food intake, WAT, body mass, and circulating insulin when fed a high calorie diet. Intracerebroventricular administration of NPGL induced de novo lipogenesis in WAT, increased insulin, and it selectively induced carbohydrate intake. Neutralizing antibody administration decreased the size of lipid droplets in WAT. Npgl mRNA expression was upregulated by fasting and low insulin levels. Additionally, NPGL-producing cells were responsive to insulin. These results point to NPGL as a novel neuronal regulator that drives food intake and fat deposition through de novo lipogenesis and acts to maintain steady-state fat level in concert with insulin. Dysregulation of NPGL may be a root cause of obesity

Markers of Memory CD8

BNT162b2, a nucleoside-modified mRNA vaccine for SARS-CoV-2 spike glycoprotein (S), provides approximately 95% efficacy for preventing COVID-19. However, it remains unclear how effectively memory CD8+ T cells are generated and which genetic and environmental factors affect the generation and function of memory CD8+ T cells elicited by this vaccine. Here, we investigated the frequency and functions of memory CD8+ T cells 3 weeks after the second vaccination in the Japanese population. Using a peptide-MHC pentamer, we detected an increased number of memory CD8+ T cells together with increased serum anti-S protein antibody in females compared with that in males, but the frequency of pentamer-positive cells was not positively correlated with antibody titers. Memory precursor effector cells (KLRG1-CD127+) among both CD8+ cells and pentamer+ cells and effector cells (CD38-HLA-DR+) among pentamer+ cells were more abundant in females than in males. Upon S protein-mediated stimulation of T cells, the intensity of CD107a and granzyme B expression was increased in females compared with that in males, indicating stronger memory CD8+ T cell responses in females than in males. Our studies showed that the BNT162b2 vaccine elicits increased memory CD8+ T cell proliferation and secondary CTL responses in females compared with those in males in the Japanese population. These findings provide an important basis for the distinct sex difference in cellular immune responses to mRNA vaccination and suggest that memory precursor effector cells can be one of markers to evaluate and boost cellular immunity induced by BNT162b2

The prevalence of insomnia and restless legs syndrome among Japanese outpatients with rheumatic disease: A cross-sectional study

The prevalence of symptomatic insomnia and the prevalence of restless legs syndrome (RLS) are known to be higher among patients with rheumatic diseases compared to the general population. The prevalences of insomnia and RLS reported in a questionnaire by Japanese patients with rheumatic diseases at an outpatient clinic were analyzed herein. The association between the patients\u27 disease activity and their sleep quality was analyzed. Of 121 rheumatic disease patients, 70 were enrolled. The median (interquartile range) age at enrollment was 62.0 (47.8-68.0) years. There were 58 women (82.9%) and 12 men (17.1%), and 43 patients (61.4%) with rheumatoid arthritis (RA), nine (12.9%) with systemic lupus erythematosus (SLE), and 18 (25.7%) with other rheumatic diseases. Twenty patients (28.6%) had one or more moderate-to-severe insomnia symptoms, and 10 (14.3%) were diagnosed with RLS. Among the patients with RA, the swollen joint count based on a 28-joint assessment (SJC28) was significantly higher in the insomnia group (n = 13) compared to the non-insomnia group (n = 30) (p = 0.006). A classification and regression tree (CART) analysis showed that the cut-off points of ?3 mg/day prednisolone (PSL) treatment and <16.54% as the transferrin saturation (TSAT) value would best predict RLS in rheumatic disease. Patients with rheumatic disease had a high prevalence of symptomatic insomnia and RLS. A higher dose of PSL and lower TSAT were associated with the occurrence of RLS. Copyright

Stimulation of the farnesoid X receptor promotes M2 macrophage polarization

FXR is a key molecule that modulates anti-inflammatory activity in the intestinal-liver axis. Although FXR has pleiotropic functions including regulation of liver inflammation and activation of macrophages, it remains unclear whether it is involved in macrophage polarization. In this paper we demonstrated that stimulation of macrophages derived from the bone marrow using an FXR agonist activated polarization toward M2 but not M1 macrophages. The treatment of mice with chitin skewed macrophage polarization towards M2 macrophages, while co-treatment with an FXR agonist further promoted the polarization toward M2 macrophages in vivo. This skewed polarization towards M2 macrophages by an FXR agonist was accompanied by increased expression of signaling molecules related to the retinoic acid receptor. Inhibition of the retinoic acid receptor suppressed FXR agonist-mediated M2 macrophage polarization, indicating that this polarization was, at least, partly dependent on the retinoic acid receptor pathway. These data demonstrate that FXR has a role in polarization toward M2 macrophages and suggest a possible therapeutic potential of FXR agonists in M2 macrophage-related conditions

Impact of Native Coronary Artery Calcification on Lesion Outcome Following Drug-Coated Balloon Angioplasty for Treatment of In-Stent Restenosis

This study aimed to clarify whether native coronary artery（CA） calcification before index percutaneous coronary intervention（PCI） has an impact on the effectiveness of drug-coated balloon（DCB） angioplasty for the treatment of in-stent restenosis（ISR）. 100consecutive patients with 166ISR lesions underwent quantitative coronary angiography（QCA） before and after index PCI and before and after DCB angioplasty for ISR. CA calcification before index PCI was assessed by angiography and results were analyzed to reveal the predictive values for target lesion revascularization（TLR） and major adverse cardiac events（MACE）. During 1.03±1.03years of follow-up, TLR occurred in 44lesions（26.5%） and MACE in 33 patients（33%）. On multivariate analysis, CA calcification before index PCI（p=0.016）, and % diameter of stenosis（%DS）≥73%（p=0.023） and minimal lumen diameter（MLD）<0.65mm（p=0.001） before DCB angioplasty were independent predictors for TLR after DCB angioplasty. MACE was also associated with CA calcification before index PCI（p=0.01）, and %DS≥73%（p=0.001） and MLD<0.65mm（p=0.01） before DCB angioplasty, but only %DS≥73% before DCB angioplasty was an independent predictor for MACE after DCB angioplasty（p=0.039）. The combination of CA calcification before index PCI and these QCA factors before DCB angioplasty was an independent and more powerful predictor for MACE than the QCA factors alone（p<0.001）. Thereafter, the combination of CA calcification and %DS≥73% before DCB angioplasty stratified the risk of MACE after DCB angioplasty（p<0.05）. CA calcification before index PCI, as well as anatomical information at ISR, have an impact on outcome after DCB angioplasty for ISR

Cross-talk between autoimmunity and tumor immunity

Both autoimmunity and tumor immunity are immune responses against self-tissues or cells. However, the precise similarity or difference between them remains unclear. In this study, to understand a novel mechanism of tumor immunity, we performed transplantation experiments with a murine autoimmune model, C57BL/6J (B6)/lpr mice. A melanoma cell line, B16F10 cells, or granulocyte macrophage colony-stimulating factor- overexpressing B16F10 (B16F10/mGM) cells were transplanted into B6 or B6/lpr mice. Tumor growth by transplanted B16F10/mGM cells was significantly accelerated in B6/lpr mice compared with that in B6 mice. The accumulation of M1 macrophages in the tumor tissues of B6/lpr recipient mice was significantly lower compared with that in the control mice. In vitro co-culture experiment showed that impaired differentiation into M1 macrophages was observed in B6/lpr mice. The number of tumor vessels and vascular endothelial growth factor (VEGF) expression were also significantly enhanced in the tumor tissues of B6/lpr mice compared with those in the B6 mice. Moreover, VEGF expression was correlated with the increased expression of hypoxia-inducible factor-1α in the tumor tissues of B6/lpr mice. These results suggest that dysfunctional tumor immunity and enhanced angiogenesis in autoimmunity influence tumor growth

Use of vonoprazan for management of systemic sclerosis‑related gastroesophageal reflux disease

Gastroesophageal reflux disease (GERD) in systemic sclerosis (SSc) can significantly reduce a patient\u27s quality of life. GERD in SSc is occasionally resistant to conventional anti-acid treatment. Vonoprazan is an H+/K+-ATPase blocker that is approved in Japan for treatment of GERD. The aim of the present study was to evaluate the efficacy of vonoprazan in SSc-related GERD. The frequency scale for symptoms of GERD (FSSG) scores were collected before and after vono-prazan treatment in 15 SSc patients with GERD. Additionally, endoscopic esophagogastroduodenoscopy was performed in select patients. Conventional proton pump inhibitors or hista-mine-2 receptor antagonists had been previously administered in 93% (14/15) of the patients. Although the baseline esophago-gastroduodenoscopy examination did not show severe erosion in the majority of patients,the mean total FSSG score before vonoprazan treatment was notably high (25.2±10.7) compared to a normal score of <8. After vonoprazan treatment, the FSSG score decreased to 9.6±7.0. The mean improvement rate of the total FSSG, acid reflux and dysmotility scores were 60.8±21.2% (P=0.0004), 67.3±24.8% (P<0.0001) and 55.4±26.0% (P=0.0022), respectively.These results suggest that vonoprazan may be a potentially effective treatment for GERD in patients with SSc

Higher medical costs for CKD patients with a rapid decline in eGFR: A cohort study from the Japanese general population

To investigate how changes in eGFR can affect medical costs, a regional cohort of national health insurance beneficiaries in Japan was developed from a nationwide database system (Kokuho database, KDB), and non-individualized data were obtained. From 105,661 people, subjects on chronic dialysis and subjects without consecutive medical checkups were excluded. Finally, medical costs in the follow-up year categorized by annual changes in eGFR between baseline and the next year were longitudinally examined in 70,627 people ranging in age from 40 to 74 years. Global mean costs for subjects with a rapid decrease in eGFR (<=-30%/year) were the highest among all Delta eGFR categories. In men, the cost was 1.42 times that for a stable eGFR. A total of 6,268 (19.4%) men and 5,381 (14.0%) women with eGFR <60 ml/min/1.73 m(2) were identified in the baseline year. The mean cost was higher with a low eGFR than without a low eGFR, and there were also higher proportions newly initiating dialysis in 2014 (low eGFR with rapid decrease in eGFR vs. with stable eGFR: 9.61% vs. 0.02% in women, P<0.001). Moreover, the costs for low eGFR subjects with a rapid decrease in eGFR were more than twice those of non-low eGFR subjects with a rapid decrease in eGFR and also compared to low eGFR subjects with a stable eGFR. Moreover, initiating chronic dialysis was considered one of the major causes of high medical costs in women with rapid eGFR decline. To the best of our knowledge, this is the first study of renal disease using a cohort developed from the KDB system recently established in Japan

EWSR1-ATF1融合遺伝子を持つ歯原性明細胞癌細胞株の樹立と性状解析

Objective: Clear cell odontogenic carcinoma (CCOC) is a rare malignant odontogenic tumor (MOT) characterized by sheets and lobules of vacuolated and clear cells. To understand the biology of CCOC, we established a new cell line, CCOC-T, with EWSR1-ATF1 fusion gene from a mandible tumor with distant metastasis and characterized this cell line. Materials and methods: To detect the EWSR1-ATF1 fusion gene, we used three CCOC cases, including the present case, by RT-PCR and FISH analysis. We characterized established CCOC-T cells by checking cell growth, invasion and the expression of odontogenic factors and bone-related factors. Moreover, the gene expression profile of CCOC-T cells was examined by microarray analysis. Results: Histologically, the primary tumor was comprised of cords and nests containing clear and squamoid cells separated by fibrous septa. In addition, ameloblastomatous islands with palisaded peripheral cells were observed, indicating probable odontogenic origin. This tumor expressed the fusion gene EWSR1-ATF1, which underlies the etiology of hyalinizing clear cell carcinoma (HCCC) and potentially that of CCOC. We found a breakpoint in the EWSR1-ATF1 fusion to be the same as that reported in HCCC. Established CCOC-T cells grew extremely slowly, but the cells showed highly invasive activity. Moreover, CCOC-T cells expressed bone-related molecules, odontogenic factors, and epithelial mesenchymal transition (EMT)-related molecules. Conclusion: To the best of our knowledge, this is the first report on the establishment of a CCOC cell line. CCOC-T cells serve as a useful in vitro model for understanding the pathogenesis and nature of MOT