Th22 Cells Promote Osteoclast Differentiation via Production of IL-22 in Rheumatoid Arthritis

T helper (Th) cells can differentiate into functionally distinct subsets and play a pivotal role in inflammatory and autoimmune diseases such as rheumatoid arthritis (RA). Th22 cells have been identified as a new subset secreting interleukin (IL)-22. Although elevated levels of IL-22 in the synovial fluids of RA patients were reported, its pathological roles remain unclear. Here, we demonstrated that IL-22 was characteristically produced from CD3+CD4+CC-chemokine receptor (CCR)4+CCR6+CCR10+ cells and their ability of the production of IL-22 markedly exceeded that of other Th subsets and the subset, thereby, designated Th22 cells. Th22 cells were efficiently induced by the stimulation with tumor necrosis factor-α, IL-6, and IL-1β. Th22 cells were markedly infiltrated in synovial tissue in patients with active RA, but not in patients with osteoarthritis (OA). CCL17, CCL20, and CCL28, which are chemokine ligands of CCR4, CCR6, and CCR10, respectively, were abundantly expressed in RA synovial tissue compared to OA. By in vitro Trans-well migration assay, Th22 cells efficiently migrated toward CCL28. Co-culture of Th22 cells, which were sorted from peripheral blood, with monocytes in the presence of macrophage colony-stimulating factor and receptor activator of nuclear factor (NF)-κB ligand induced osteoclasts formation more efficiently than that of either Th1 cells or Th17 cells. Furthermore, IL-22 markedly augmented osteoclast differentiation by promoting nuclear factor of activated T cells c1 expression in CD14+ monocytes. Contrarily, the addition of IFN-γ to the culture significantly decreased osteoclasts number, whereas IL-17 had marginal effects. IL-22 neutralizing antibody inhibited osteoclast formation in the co-culture of Th22 cells with CD14+ monocytes. Collectively, the results indicated that Th22 cells, which co-express chemokine receptors CCR4, CCR6, and CCR10, possess strong potency of tissue migration and accumulate into inflamed synovial tissues where the ligands such as CCL28 are highly expressed. Thus, Th22 cells have the capacity to promote osteoclast differentiation through production of IL-22 and thus play a pivotal role in bone destruction in patients with RA

Identification of a tomato UDP-arabinosyltransferase for airborne volatile reception

植物間コミュニケーションの仕組みを解明 --受容した香りを防御物質に変える遺伝子発見--. 京都大学プレスリリース. 2023-02-28.Volatiles from herbivore-infested plants function as a chemical warning of future herbivory for neighboring plants. (Z)-3-Hexenol emitted from tomato plants infested by common cutworms is taken up by uninfested plants and converted to (Z)-3-hexenyl β-vicianoside (HexVic). Here we show that a wild tomato species (Solanum pennellii) shows limited HexVic accumulation compared to a domesticated tomato species (Solanum lycopersicum) after (Z)-3-hexenol exposure. Common cutworms grow better on an introgression line containing an S. pennellii chromosome 11 segment that impairs HexVic accumulation, suggesting that (Z)-3-hexenol diglycosylation is involved in the defense of tomato against herbivory. We finally reveal that HexVic accumulation is genetically associated with a uridine diphosphate-glycosyltransferase (UGT) gene cluster that harbors UGT91R1 on chromosome 11. Biochemical and transgenic analyses of UGT91R1 show that it preferentially catalyzes (Z)-3-hexenyl β-D-glucopyranoside arabinosylation to produce HexVic in planta

Unhealthy food intake restriction awareness and mortality

Background: Improving diets requires an awareness of the need to limit foods for which excessive consumption is a health problem. Since there are limited reports on the link between this awareness and mortality risk, we examined the association between awareness of limiting food intake (energy, fat, and sweets) and all-cause mortality in a Japanese cohort study. Methods: Participants comprised 58,772 residents (27,294 men; 31,478 women) aged 35–69 years who completed baseline surveys of the Japan Multi-Institutional Collaborative Cohort Study from 2004 to 2014. Hazard ratios (HRs) for all-cause mortality and 95% confidence intervals (CIs) were estimated by sex using a Cox proportional hazard model, with adjustment for related factors. Mediation analysis with fat intake as a mediator was also conducted. Results: The mean follow-up period was 11 years and 2,516 people died. Estimated energy and fat intakes according to the Food Frequency Questionnaire were lower in those with awareness of limiting food intake than in those without this awareness. Women with awareness of limiting fat intake showed a significant decrease in mortality risk (HR=0.73; 95% CI, 0.55 to 0.94). Mediation analysis revealed that this association was due to the direct effect of the awareness of limiting fat intake and that the total effect was not mediated by actual fat intake. Awareness of limiting energy or sweets intake was not related to mortality risk reduction. Conclusion: Awareness of limiting food intake had a limited effect on reducing all-cause mortality risk

Comprehensive DNA Methylation Analysis of Retrotransposons in Male Germ Cells

De novo DNA methylation of retrotransposons is critical for silencing. Here, we use DNA methylation analysis to examine retrotransposons in mouse male germ cells. DNA methylation of long interspersed nuclear elements (LINEs) is dependent on piRNA, and younger LINEs exhibit greater piRNA dependence. In contrast, most long terminal repeat (LTR) retrotransposons produce lower levels of piRNAs and do not show significant piRNA dependence. The relationship between DNA methylation and corresponding piRNA expression of several LTR retrotransposons was reduced in Mili-null cells, but not Miwi2-null cells. These observations raise the possibility of piRNA-dependent DNA methylation without Miwi2. Therefore, it appears that the molecular mechanisms of the gene silencing of retrotransposons are more complicated than previously thought

Relationship between PIWIL4-Mediated H3K4me2 Demethylation and piRNA-Dependent DNA Methylation

Summary: Retrotransposon genes are silenced by DNA methylation because of potential harm due to insertional mutagenesis. DNA methylation of retrotransposon genes is erased and re-established during male germ cell development. Both piRNA-dependent and piRNA-independent mechanisms are active during the re-establishment process, with the piRNA-independent mechanism occurring first. In this study, we analyzed the role of PIWIL4/MIWI2 in the modification of histone H3 and subsequent piRNA-dependent DNA methylation. Dimethylation at H3K4 is highly enriched at piRNA-dependent methylated regions and anti-correlated with de novo DNA methylation during the phase of piRNA-independent DNA methylation. In addition, PIWIL4, which binds the H3K4 demethylases KDM1A and KDM5B, is required for removing H3K4me2 marks. These data show that PIWIL4 plays important roles in histone modification and piRNA-dependent DNA methylation. : Nagamori et al. report that H3K4me2 is enriched at piRNA-dependent regions, such as LINE1s/L1s, in embryonic germ cells. H3K4me2 is subsequently erased in a PIWIL4-dependent manner. They postulate that preferential interaction of PIWIL4 with KDM1A and KDM5B plays a critical role in PIWIL4-dependent methylation erasure. Keywords: germ cell, spermatogenesis, DNA methylation, piRNA, gonocyt

MIWI2 as an Effector of DNA Methylation and Gene Silencing in Embryonic Male Germ Cells

During the development of mammalian embryonic germ cells, global demethylation and de novo DNA methylation take place. In mouse embryonic germ cells, two PIWI family proteins, MILI and MIWI2, are essential for the de novo DNA methylation of retrotransposons, presumably through PIWI-interacting RNAs (piRNAs). Although piRNA-associated MIWI2 has been reported to play critical roles in the process, its molecular mechanisms have remained unclear. To identify the mechanism, transgenic mice were produced; they contained a fusion protein of MIWI2 and a zinc finger (ZF) that recognized the promoter region of a type A LINE-1 gene. The ZF-MIWI2 fusion protein brought about DNA methylation, suppression of the type A LINE-1 gene, and a partial rescue of the impaired spermatogenesis of MILI-null mice. In addition, ZF-MIWI2 was associated with the proteins involved in DNA methylation. These data indicate that MIWI2 functions as an effector of de novo DNA methylation of the retrotransposon

Significance of nailfold videocapillaroscopy in patients with idiopathic inflammatory myopathies

Objective: The aim of this study was to investigate the clinical and immunological significance of nailfold videocapillaroscopy (NVC) abnormalities in patients with idiopathic inflammatory myopathies (IIMs). Methods: Seventy consecutive Japanese patients with untreated IIMs, enrolled between April 2014 and August 2017, were prospectively studied. Clinical features, NVC findings, autoantibody profile by immunoprecipitation and ELISA, and histopathological findings of skin biopsies of DM rash were assessed at baseline and after 1-year of immunosuppressive therapy. Results: NVC abnormalities were found in 55.7% (39/70) of IIM patients, with significantly higher prevalence in DM (65.4%) compared with PM (27.8%) (P = 0.01). In subsets of patients classified by autoantibody specificities, the prevalence of NVC abnormalities was significantly higher in patients with anti-MDA5 (87.5%) and anti-transcriptional intermediary factor 1 gamma (88.9%) vs anti-aminoacyl-tRNA synthetase (26.9%, P < 0.001). Perivascular lymphocytic infiltration in the upper dermis of skin rash biopsy of DM was more severe in patients with NVC abnormalities (P < 0.05). Unexpectedly, NVC abnormalities disappeared in 75% of IIM patients after 1-year of immunosuppressive therapy in contrast to stable NVC changes seen in scleroderma patients. Conclusion: Nailfold microvascular abnormalities were common in DM patients, associated with anti-MDA5 and transcriptional intermediary factor 1 gamma antibodies, and perivascular inflammation in skin histology. NVC abnormalities in IIMs may become clinically useful markers for defining subsets of DM and understanding the pathogenesis of the clinical features seen in these patients

Predictive impact of absolute lymphocyte counts for progression-free survival in human epidermal growth factor receptor 2-positive advanced breast cancer treated with pertuzumab and trastuzumab plus eribulin or nab-paclitaxel

Abstracts Background Although peripheral blood-based parameters (PBBPs) are reported as prognostic indicators in patients with breast cancers, their utility has not been studied in human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer (ABC). Tumor-infiltrating lymphocytes (TILs) might be a predictive factor in patients with HER2-positive ABC treated with pertuzumab and trastuzumab (PT) plus docetaxel. We aimed to evaluate whether PBBPs could have predictive value in HER2-positive ABC treated with pertuzumab and trastuzumab (PT) combined with eribulin (ERI) or nab-paclitaxel (Nab-PTX). Methods Data from 51 patients included in two single-arm, phase II trials were included in this retrospective-prospective study; the ERI + PT (N = 30) and Nab-PTX + PT (N = 21) combinations were registered under clinical trials number UMIN000012375 and UMIN000006838, respectively. We assessed PBBPs using prospectively collected data and investigated the association with progression-free survival (PFS); we evaluated absolute lymphocyte count (ALC), neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR). The cutoff values for ALC, NLR, and PLR were set at 1000 or 1500 cells/μL, 2, and 250, respectively. Results PFS was significantly improved in patients with ALC ≥1500/μL compared to those with ALC 1000–, <1500/μL or ALC < 1000/μL (P = 0.0106). High baseline ALC was significantly associated with improved PFS (≥1500/μL; hazard ratio [HR]: 0.3715; 95% confidence interval [CI]: 0.1735–0.7955; P = 0.0108). In contrast, improved PFS was not significantly associated with NLR or PLR. Improved PFS in patients with ALC ≥1500/μL was observed irrespective of visceral metastasis or chemotherapy regimen. Conclusions Our results showed that baseline ALC was a predictive factor for PFS in HER2-positive ABC treated with PT irrespective of combined chemotherapy regimen. Anti-tumor effects might be mediated not only by the tumor microenvironment, but also by systemic peripheral circulating lymphocytes. Baseline systemic parameters such as peripheral lymphocyte count might be beneficial in addition to disease extent for predicting the efficacy of PT treatment. Trial registration UMIN000012375, registration date: 21NOV2013, and UMIN000006838, registration date: 6DEC2011