Enhanced pathogenicity of Th17 cells due to natalizumab treatment: Implications for MS disease rebound.

After natalizumab (NAT) cessation, some multiple sclerosis (MS) patients experience a severe disease rebound. The rebound pathophysiology is still unclear; however, it has been linked to interleukin-17-producing T-helper (Th17) cells. We demonstrate that during NAT treatment, MCAM+CCR6+Th17 cells gradually acquire a pathogenic profile, including proinflammatory cytokine production, pathogenic transcriptional signatures, brain endothelial barrier impairment, and oligodendrocyte damage via induction of apoptotic pathways. This is accompanied by an increase in Th17 cell frequencies in the cerebrospinal fluid of NAT-treated patients. Notably, Th17 cells derived from NAT-treated patients, who later developed a disease rebound upon treatment cessation, displayed a distinct transcriptional pathogenicity profile associated with altered migratory properties. Accordingly, increased brain infiltration of patient Th17 cells was illustrated in a humanized mouse model and brain histology from a rebound patient. Therefore, peripheral blood-accumulated MCAM+CCR6+Th17 cells might be involved in rebound pathophysiology, and monitoring of changes in Th17 cell pathogenicity in patients before/during NAT treatment cessation might enable rebound risk assessment in the future.

A meta-analysis of genome-wide studies of resilience in the German population.

Resilience is the capacity to adapt to stressful life events. As such, this trait is associated with physical and mental functions and conditions. Here, we aimed to identify the genetic factors contributing to shape resilience. We performed variant- and gene-based meta-analyses of genome-wide association studies from six German cohorts (N = 15822) using the 11-item version of the Resilience Scale (RS-11) as outcome measure. Variant- and gene-level results were combined to explore the biological context using network analysis. In addition, we conducted tests of correlation between RS-11 and the polygenic scores (PGSs) for 12 personality and mental health traits in one of these cohorts (PROCAM-2, N = 3879). The variant-based analysis found no signals associated with resilience at the genome-wide level (p < 5 × 10-8), but suggested five genomic loci (p < 1 × 10-5). The gene-based analysis identified three genes (ROBO1, CIB3 and LYPD4) associated with resilience at genome-wide level (p < 2.48 × 10-6) and 32 potential candidates (p < 1 × 10-4). Network analysis revealed enrichment of biological pathways related to neuronal proliferation and differentiation, synaptic organization, immune responses and vascular homeostasis. We also found significant correlations (FDR < 0.05) between RS-11 and the PGSs for neuroticism and general happiness. Overall, our observations suggest low heritability of resilience. Large, international efforts will be required to uncover the genetic factors that contribute to shape trait resilience. Nevertheless, as the largest investigation of the genetics of resilience in general population to date, our study already offers valuable insights into the biology potentially underlying resilience and resilience's relationship with other personality traits and mental health.

Reduced plakoglobin increases the risk of sodium current defects and atrial conduction abnormalities in response to androgenic anabolic steroid abuse.

Androgenic anabolic steroids (AAS) are commonly abused by young men. Male sex and increased AAS levels are associated with earlier and more severe manifestation of common cardiac conditions, such as atrial fibrillation, and rare ones, such as arrhythmogenic right ventricular cardiomyopathy (ARVC). Clinical observations suggest a potential atrial involvement in ARVC. Arrhythmogenic right ventricular cardiomyopathy is caused by desmosomal gene defects, including reduced plakoglobin expression. Here, we analysed clinical records from 146 ARVC patients to identify that ARVC is more common in males than females. Patients with ARVC also had an increased incidence of atrial arrhythmias and P wave changes. To study desmosomal vulnerability and the effects of AAS on the atria, young adult male mice, heterozygously deficient for plakoglobin (Plako+/-), and wild type (WT) littermates were chronically exposed to 5α-dihydrotestosterone (DHT) or placebo. The DHT increased atrial expression of pro-hypertrophic, fibrotic and inflammatory transcripts. In mice with reduced plakoglobin, DHT exaggerated P wave abnormalities, atrial conduction slowing, sodium current depletion, action potential amplitude reduction and the fall in action potential depolarization rate. Super-resolution microscopy revealed a decrease in NaV1.5 membrane clustering in Plako+/- atrial cardiomyocytes after DHT exposure. In summary, AAS combined with plakoglobin deficiency cause pathological atrial electrical remodelling in young male hearts. Male sex is likely to increase the risk of atrial arrhythmia, particularly in those with desmosomal gene variants. This risk is likely to be exaggerated further by AAS use. KEY POINTS: Androgenic male sex hormones, such as testosterone, might increase the risk of atrial fibrillation in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC), which is often caused by desmosomal gene defects (e.g. reduced plakoglobin expression). In this study, we observed a significantly higher proportion of males who had ARVC compared with females, and atrial arrhythmias and P wave changes represented a common observation in advanced ARVC stages. In mice with reduced plakoglobin expression, chronic administration of 5α-dihydrotestosterone led to P wave abnormalities, atrial conduction slowing, sodium current depletion and a decrease in membrane-localized NaV1.5 clusters. 5α-Dihydrotestosterone, therefore, represents a stimulus aggravating the pro-arrhythmic phenotype in carriers of desmosomal mutations and can affect atrial electrical function.

Human atherosclerotic plaque transcriptomics reveals endothelial beta-2 spectrin as a potential regulator a leaky plaque microvasculature phenotype.

The presence of atherosclerotic plaque vessels is a critical factor in plaque destabilization. This may be attributable to the leaky phenotype of these microvessels, although direct proof for this notion is lacking. In this study, we investigated molecular and cellular patterns of stable and hemorrhaged human plaque to identify novel drivers of intraplaque vessel dysfunction. From transcriptome data of a human atherosclerotic lesion cohort, we reconstructed a co-expression network, identifying a gene module strongly and selectively correlated with both plaque microvascular density and inflammation. Spectrin Beta Non-Erythrocytic 1 (sptbn1) was identified as one of the central hubs of this module (along with zeb1 and dock1) and was selected for further study based on its predominant endothelial expression. Silencing of sptbn1 enhanced leukocyte transmigration and vascular permeability in vitro, characterized by an increased number of focal adhesions and reduced junctional VE-cadherin. In vivo, sptbn1 knockdown in zebrafish impaired the development of the caudal vein plexus. Mechanistically, increased substrate stiffness was associated with sptbn1 downregulation in endothelial cells in vitro and in human vessels. Plaque SPTBN1 mRNA and protein expression were found to correlate with an enhanced presence of intraplaque hemorrhage and future cardiovascular disease (CVD) events during follow-up. In conclusion, we identify SPTBN1 as a central hub gene in a gene program correlating with plaque vascularisation. SPTBN1 was regulated by substrate stiffness in vitro while silencing blocked vascular development in vivo, and compromised barrier function in vitro. Together, SPTBN1 is identified as a new potential regulator of the leaky phenotype of atherosclerotic plaque microvessels.

MicroRNA-216a is essential for cardiac angiogenesis.

While it is experimentally supported that impaired myocardial vascularization contributes to a mismatch between myocardial oxygen demand and supply, a mechanistic basis for disruption of coordinated tissue growth and angiogenesis in heart failure remains poorly understood. Silencing strategies that impair microRNA biogenesis have firmly implicated microRNAs in the regulation of angiogenesis, and individual microRNAs prove to be crucial in developmental or tumor angiogenesis. A high-throughput functional screening for the analysis of a whole-genome microRNA silencing library with regard to their phenotypic effect on endothelial cell proliferation as a key parameter, revealed several anti- and pro-proliferative microRNAs. Among those was miR-216a, a pro-angiogenic microRNA which is enriched in cardiac microvascular endothelial cells and reduced in expression under cardiac stress conditions. miR-216a null mice display dramatic cardiac phenotypes related to impaired myocardial vascularization and unbalanced autophagy and inflammation, supporting a model where microRNA regulation of microvascularization impacts the cardiac response to stress.

Genomic instability in the naturally and prematurely aged myocardium.

Genomic instability, the unresolved accumulation of DNA variants, is hypothesized as one of the contributors to the natural aging process. We assessed the frequency of unresolved DNA damage reaching the transcriptome of the murine myocardium during the course of natural aging and in hearts from four distinct mouse models of premature aging with established aging-related cardiac dysfunctions. RNA sequencing and variant calling based on total RNA sequencing was compared between hearts from naturally aging mice, mice with cardiomyocyte-specific deficiency of Ercc1, a component of the DNA repair machinery, mice with reduced mitochondrial antioxidant capacity, Tert-deficient mice with reduced telomere length, and a mouse model of human Hutchinson-Gilford progeria syndrome (HGPS). Our results demonstrate that no enrichment in variants is evident in the naturally aging murine hearts until 2 y of age from the HGPS mouse model or mice with reduced telomere lengths. In contrast, a dramatic accumulation of variants was evident in Ercc1 cardiomyocyte-specific knockout mice with deficient DNA repair machinery, in mice with reduced mitochondrial antioxidant capacity, and in the intestine, liver, and lung of naturally aging mice. Our data demonstrate that genomic instability does not evidently contribute to naturally aging of the mouse heart in contrast to other organs and support the contention that the endogenous DNA repair machinery is remarkably active to maintain genomic integrity in cardiac cells throughout life.

Intercellular transfer of miR-200c-3p impairs the angiogenic capacity of cardiac endothelial cells.

As mediators of intercellular communication, extracellular vesicles containing molecular cargo, such as microRNAs, are secreted by cells and taken up by recipient cells to influence their cellular phenotype and function. Here we report that cardiac stress-induced differential microRNA content, with miR-200c-3p being one of the most enriched, in cardiomyocyte-derived extracellular vesicles mediates functional cross-talk with endothelial cells. Silencing of miR-200c-3p in mice subjected to chronic increased cardiac pressure overload resulted in attenuated hypertrophy, smaller fibrotic areas, higher capillary density, and preserved cardiac ejection fraction. We were able to maximally rescue microvascular and cardiac function with very low doses of antagomir, which specifically silences miR-200c-3p expression in non-myocyte cells. Our results reveal vesicle transfer of miR-200c-3p from cardiomyocytes to cardiac endothelial cells, underlining the importance of cardiac intercellular communication in the pathophysiology of heart failure.

Cardiac chamber-specific genetic alterations suggest candidate genes and pathways implicating the left ventricle in the pathogenesis of atrial fibrillation.

It is believed that the atria play a predominant role in the initiation and maintenance of atrial fibrillation (AF), while the role of left ventricular dysfunction in the pathophysiology remains enigmatic. We sought to dissect chamber specificity of AF-associated transcriptional changes using RNA-sequencing. We performed intra- and inter-chamber differential expression analyses comparing AF against sinus rhythm to identify genes specifically dysregulated in human left atria, right atria, and left ventricle (LV), and integrated known AF genetic associations with expression quantitative trait loci datasets to inform the potential for disease causal contributions within each chamber. Inter-chamber patterns changed drastically. Vast AF-associated transcriptional changes specific to LV, enriched for biological pathway terms implicating mitochondrial function, developmental processes and immunity, were supported at the genetic level, but no major enrichments for candidate genes specific to the atria were found. Our observations suggest an active role of the LV in the pathogenesis of AF.

Empirical Investigation of Genomic Clusters Associated With Height and the Risk of Postmenopausal Breast and Colorectal Cancer in the Netherlands Cohort Study.

We empirically investigated genomic clusters associated with both height and postmenopausal breast cancer (BC) or colorectal cancer (CRC) (or both) in the Netherlands Cohort Study to unravel shared underlying mechanisms between height and these cancers. The Netherlands Cohort Study (1986-2006) includes 120,852 participants (case-cohort study: nsubcohort = 5,000; 20.3 years of follow-up). Variants in clusters on chromosomes 2, 4, 5, 6 (2 clusters), 10, and 20 were genotyped using toenail DNA. Cluster-specific genetic risk scores were modeled in relation to height and postmenopausal BC and CRC risk using age-adjusted linear regression and multivariable-adjusted Cox regression, respectively. Only the chromosome 10 cluster risk score was associated with all 3 phenotypes in the same sex (women); that is, it was associated with increased height (ßcontinuous = 0.34, P = 0.014), increased risk of hormone-receptor-positive BC (for estrogen-receptor-positive BC, hazard ratio (HRcontinuous score) = 1.10 (95% confidence interval (CI): 1.02, 1.20); for progesterone-receptor-positive BC, HRcontinuous score = 1.15 (95% CI: 1.04, 1.26)), and increased risk of distal colon (HRcontinuous score = 1.13, 95% CI: 1.01, 1.27) and rectal (HRcontinuous score = 1.14, 95% CI: 0.99, 1.30) cancer. The chromosome 10 cluster variants were all annotated to the zinc finger MIZ-type containing 1 gene (ZMIZ1), which is involved in androgen receptor activity. This suggests that hormone-related growth mechanisms could influence both height and postmenopausal BC and CRC.

Validation of a predictive model for identifying an increased risk for recurrence in adolescents and young adults with a first provoked thromboembolism.

BACKGROUND: To develop and validate a predictive model to determinate patients at increased risk to suffer from recurrence following a first provoked deep vein thrombosis (VTE). METHODS: Predictive variables, i.e. male sex [1 point], inherited thrombophilia (IT) status (none [0 points], single [1 point], combined variants [2 points]), blood group non-0, and age at first VTE onset were included into a risk assessment model, which was derived in 511 patients and then validated in 509 independent subjects. RESULTS: VTE recurrence risk score (maximum 4 points, range 0-3) was below two for patients scored as low-risk (LRS) and ≥2 for patients at high-risk (HRS). Within a median time of 3 years after withdrawal of anticoagulation (AC) recurrence rate in LRG (derivation) was 11.8% versus 26.0% in HRS (p < 0.001). In the validation cohort within 2.2 years the recurrence rate was 9.8% in LRS versus 30.1% in HRS (p < 0.001). In multivariable analysis adjusted for age at first VTE and blood group the recurrent risk in HRS was significantly increased compared with the LRS (derivation: hazard/95% confidence interval: 3.7/1.75-7.91; validation: 4.7/2.24-9.81; combined 5.2/1.92-13.9). Model specificity (sensitivity) was 79.0% (52.0%) in the derivation cohort compared with 78.0% (43.0%) in the validation group. In conclusion, in the prediction model presented here the risk of VTE recurrence was associated with male gender and combined ITs. Based on the negative predictive value calculated the model may identify patients with a first provoked VTE not being at risk for recurrence.

Assessment of angiogenesis-related parameters in juvenile idiopathic arthritis-associated uveitis.

PURPOSE: Juvenile idiopathic arthritis-associated uveitis (JIAU) may run a chronic and treatment-resistant course, and occasionally, alterations of the iris vasculature may be observed clinically. METHODS: Iris tissue (IT), aqueous humor (AH) and serum samples from patients with clinically inactive JIAU (n = 30), acute anterior uveitis (AAU; n = 18), and primary open angle glaucoma (POAG; n = 20) were obtained during trabeculectomy or cataract surgery. Samples were analyzed by RNA-Seq, qRT-PCR, LC-IMS, Western-Blot, and LEGENDplex™ analysis. Pattern of iris vasculature in JIAU patients was assessed qualitatively via fluorescein and indocyanine green angiography (FLA/ICGA). RESULTS: RNA-Seq of IT showed significantly differential expression (DE) of 136 genes between JIAU and POAG, of which 15 were associated with angiogenesis. qRT-PCR, performed to validate RNA-Seq results, showed upregulation of the angiogenesis-related genes Kdr, Angpt-1, Tie-1, Tie-2 and Mmrn2 in IT (JIAU vs POAG, p > 0.05). LC-IMS of IT revealed a total number of 56 DE proteins (JIAU vs POAG), of which Angiopoetin, Lumican and Decorin were associated with angiogenesis and showed increased (p > 0.05) expression on Western-Blot analysis. LEGENDplex™ analysis showed upregulation of ANGPT-2 in AH from JIAU compared to AAU and POAG, whereas VEGF was upregulated in AAU. Iris vascular leakage, hypoperfusion and neovascularization were observed by FLA/ICGA in JIA patients with treatment-refractory complicated course of uveitis. CONCLUSION: Angiogenesis-related factors could play a role in long-standing complicated JIAU, leading to clinically visible alterations in selected cases.

Evolutionarily conserved transcriptional landscape of the heart defining the chamber specific physiology.

Cardiovascular disease (CVD) remains the leading cause of death worldwide. A deeper characterization of regional transcription patterns within different heart chambers may aid to improve our understanding of the molecular mechanisms involved in myocardial function and further, our ability to develop novel therapeutic strategies. Here, we used RNA sequencing to determine differentially expressed protein coding (PC) and long non-coding (lncRNA) transcripts within the heart chambers across seven vertebrate species and identified evolutionarily conserved chamber specific genes, lncRNAs and pathways. We investigated lncRNA homologs based on sequence, secondary structure, synteny and expressional conservation and found most lncRNAs to be conserved by synteny. Regional co-expression patterns of transcripts are modulated by multiple factors, including genomic overlap, strandedness and transcript biotype. Finally, we provide a community resource designated EvoACTG, which informs researchers on the conserved yet intertwined nature of the coding and non-coding cardiac transcriptome across popular model organisms in CVD research.

Climate change facilitates a parasite's host exploitation via temperature-mediated immunometabolic processes.

Global climate change can influence organismic interactions like those between hosts and parasites. Rising temperatures may exacerbate the exploitation of hosts by parasites, especially in ectothermic systems. The metabolic activity of ectotherms is strongly linked to temperature and generally increases when temperatures rise. We hypothesized that temperature change in combination with parasite infection interferes with the host's immunometabolism. We used a parasite, the avian cestode Schistocephalus solidus, which taps most of its resources from the metabolism of an ectothermic intermediate host, the three-spined stickleback. We experimentally exposed sticklebacks to this parasite, and studied liver transcriptomes 50 days after infection at 13°C and 24°C, to assess their immunometabolic responses. Furthermore, we monitored fitness parameters of the parasite and examined immunity and body condition of the sticklebacks at 13°C, 18°C and 24°C after 36, 50 and 64 days of infection. At low temperatures (13°C), S. solidus growth was constrained, presumably also by the more active stickleback's immune system, thus delaying its infectivity for the final host to 64 days. Warmer temperature (18°C and 24°C) enhanced S. solidus growth, and it became infective to the final host already after 36 days. Overall, S. solidus produced many more viable offspring after development at elevated temperatures. In contrast, stickleback hosts had lower body conditions, and their immune system was less active at warm temperature. The stickleback's liver transcriptome revealed that mainly metabolic processes were differentially regulated between temperatures, whereas immune genes were not strongly affected. Temperature effects on gene expression were strongly enhanced in infected sticklebacks, and even in exposed-but-not-infected hosts. These data suggest that the parasite exposure in concert with rising temperature, as to be expected with global climate change, shifted the host's immunometabolism, thus providing nutrients for the enormous growth of the parasite and, at the same time suppressing immune defence.

Induction of ICER is superseded by smICER, challenging the impact of ICER under chronic beta-adrenergic stimulation.

ICER (inducible cAMP early repressor) isoforms are transcriptional repressors encoded by the Crem (cAMP responsive element modulator) gene. They were linked to the regulation of a multitude of cellular processes and pathophysiological mechanisms. Here, we show for the first time that two independent induction patterns for CREM repressor isoforms exist in the heart, namely for ICER and smICER (small ICER), which are induced in response to ß-adrenergic stimulation in a transient- and saturation-like manner, respectively. This time-shifted induction pattern, driven by two internal promoters in the Crem gene, leads to the predominant transcription of smIcer after prolonged ß-adrenergic stimulation. Using an ICER knockout mouse model with preserved smICER induction, we show that the transient-like induction of Icer itself has minor effects on gene regulation, cardiac hypertrophy or contractile function in the heart. We conclude that the functions previously linked to ICER may be rather attributed to smICER, also beyond the cardiac background.

Dynamic risk assessment to improve quality of care in patients with atrial fibrillation: the 7th AFNET/EHRA Consensus Conference.

AIMS: The risk of developing atrial fibrillation (AF) and its complications continues to increase, despite good progress in preventing AF-related strokes. METHODS AND RESULTS: This article summarizes the outcomes of the 7th Consensus Conference of the Atrial Fibrillation NETwork (AFNET) and the European Heart Rhythm Association (EHRA) held in Lisbon in March 2019. Sixty-five international AF specialists met to present new data and find consensus on pressing issues in AF prevention, management and future research to improve care for patients with AF and prevent AF-related complications. This article is the main outcome of an interactive, iterative discussion between breakout specialist groups and the meeting plenary. AF patients have dynamic risk profiles requiring repeated assessment and risk-based therapy stratification to optimize quality of care. Interrogation of deeply phenotyped datasets with outcomes will lead to a better understanding of the cardiac and systemic effects of AF, interacting with comorbidities and predisposing factors, enabling stratified therapy. New proposals include an algorithm for the acute management of patients with AF and heart failure, a call for a refined, data-driven assessment of stroke risk, suggestions for anticoagulation use in special populations, and a call for rhythm control therapy selection based on risk of AF recurrence. CONCLUSION: The remaining morbidity and mortality in patients with AF needs better characterization. Likely drivers of the remaining AF-related problems are AF burden, potentially treatable by rhythm control therapy, and concomitant conditions, potentially treatable by treating these conditions. Identifying the drivers of AF-related complications holds promise for stratified therapy.

A genetic variant alters the secondary structure of the lncRNA H19 and is associated with dilated cardiomyopathy.

lncRNAs are at the core of many regulatory processes and have also been recognized to be involved in various complex diseases. They affect gene regulation through direct interactions with RNA, DNA or proteins. Accordingly, lncRNA structure is likely to be essential for their regulatory function. Point mutations, which manifest as SNPs (single nucleotide polymorphisms) in genome screens, can substantially alter their function and, subsequently, the expression of their downstream regulated genes. To test the effect of SNPs on structure, we investigated lncRNAs associated with dilated cardiomyopathy. Among 322 human candidate lncRNAs, we demonstrate first the significant association of an SNP located in lncRNA H19 using data from 1084 diseased and 751 control patients. H19 is generally highly expressed in the heart, with a complex expression pattern during heart development. Next, we used MFE (minimum free energy) folding to demonstrate a significant refolding in the secondary structure of this 861 nt long lncRNA. Since MFE folding may overlook the importance of sub-optimal structures, we showed that this refolding also manifests in the overall Boltzmann structure ensemble. There, the composition of structures is tremendously affected in their thermodynamic probabilities through the genetic variant. Finally, we confirmed these results experimentally, using SHAPE-Seq, corroborating that SNPs affecting such structures may explain hidden genetic variance not accounted for through genome wide association studies. Our results suggest that structural changes in lncRNAs, and lncRNA H19 in particular, affect regulatory processes and represent optimal targets for further in-depth studies probing their molecular interactions.

Role of prothrombin 19911 A>G polymorphism, blood group and male gender in patients with venous thromboembolism: Results of a German cohort study.

The role of the A>G polymorphism at position 19911 in the prothrombin gene (factor [F] 2 at rs3136516) as a risk factor for venous thromboembolism [VTE] is still unclear. To evaluate the presence of the F2 polymorphism in VTE patients compared to healthy blood donors and to adjust the results for common inherited thrombophilias [IT], age at onset and blood group [BG], and to calculate the risk of VTE recurrence. We investigated 1012 Caucasian patients with a diagnosis of VTE for the presence of the F2 rs3136516 polymorphism and compared these with 902 healthy blood donors. Odds ratios [OR] together with their 95% confidence intervals were calculated adjusted for F5 at rs6025, F2 at rs1799963, blood group, age and gender. In addition, we evaluated the risk of recurrent VTE during patient follow-up calculating hazard ratios [HR] together with their 95% CI. Compared with the AA wildtype, the F2 GG and AG genotypes (rs3136516) were associated with VTE (OR 1.48 and 1.45). The OR in F5 carriers compared to controls was 5.68 and 2.38 in patients with F2 (rs1799963). BG "non-O" was significantly more often diagnosed in patients compared to BG "O" (OR 2.74). VTE recurrence more often occurred in males (HR 2.3) and in carriers with combined thrombophilia (HR 2.11). Noteworthy, the rs3136516 polymorphism alone was not associated significantly with recurrence. In Caucasian patients with VTE the F2 GG/GA genotypes (rs3136516) were moderate risk factors for VTE. Recurrence was associated with male gender and combined thrombophilia.

Nur77 serves as a molecular brake of the metabolic switch during T cell activation to restrict autoimmunity.

T cells critically depend on reprogramming of metabolic signatures to meet the bioenergetic demands during activation and clonal expansion. Here we identify the transcription factor Nur77 as a cell-intrinsic modulator of T cell activation. Nur77-deficient T cells are highly proliferative, and lack of Nur77 is associated with enhanced T cell activation and increased susceptibility for T cell-mediated inflammatory diseases, such as CNS autoimmunity, allergic contact dermatitis and collagen-induced arthritis. Importantly, Nur77 serves as key regulator of energy metabolism in T cells, restricting mitochondrial respiration and glycolysis and controlling switching between different energy pathways. Transcriptional network analysis revealed that Nur77 modulates the expression of metabolic genes, most likely in close interaction with other transcription factors, especially estrogen-related receptor α. In summary, we identify Nur77 as a transcriptional regulator of T cell metabolism, which elevates the threshold for T cell activation and confers protection in different T cell-mediated inflammatory diseases.

CD163 expression defines specific, IRF8-dependent, immune-modulatory macrophages in the bone marrow.

BACKGROUND: Scavenger receptor CD163 is exclusively expressed on monocytes/macrophages and is widely used as a marker for alternatively activated macrophages. However, the role of CD163 is not yet clear. OBJECTIVES: We sought to examine the function of CD163 in steady-state as well as in sterile and infectious inflammation. METHODS: Expression of CD163 was analyzed under normal and inflammatory conditions in mice. Functional relevance of CD163 was investigated in models of inflammation in wild-type and CD163-/- mice. RESULTS: We describe a subpopulation of bone marrow-resident macrophages (BMRMs) characterized by a high expression of CD163 and functionally distinct from classical bone marrow-derived macrophages. Development of CD163+ BMRMs is strictly dependent on IFN regulatory factor-8. CD163+ BMRMs show a specific transcriptome and cytokine secretion pattern demonstrating a specific immunomodulatory profile of these cells. Accordingly, CD163-/- mice show a stronger inflammation in allergic contact dermatitis, indicating a regulatory role of CD163. However, CD163-/- mice are highly susceptible to S aureus infections, demonstrating the relevance of CD163 for antimicrobial defense as well. CONCLUSIONS: Our data indicate that anti-inflammatory and immunosuppressive mechanisms are not necessarily associated with a decreased antimicrobial activity. In contrast, our data define a novel macrophage population that controls overwhelming inflammation on one hand but is also necessary for an effective control of infections on the other hand.

A novel isoform of myosin 18A (Myo18Aγ) is an essential sarcomeric protein in mouse heart.

Whereas myosin 18B (Myo18B) is known to be a critical sarcomeric protein, the function of myosin 18A (Myo18A) is unclear, although it has been implicated in cell motility and Golgi shape. Here, we show that homozygous deletion (homozygous tm1a, tm1b, or tm1d alleles) of Myo18a in mouse is embryonic lethal. Reminiscent of Myo18b, Myo18a was highly expressed in the embryo heart, and cardiac-restricted Myo18a deletion in mice was embryonic lethal. Surprisingly, using Western blot analysis, we were unable to detect the known isoforms of Myo18A, Myo18Aα and Myo18Aß, in mouse heart using a custom C-terminal antibody. However, alternative anti-Myo18A antibodies detected a larger than expected protein, and RNA-Seq analysis indicated that a novel Myo18A transcript is expressed in mouse ventricular myocytes (and human heart). Cloning and sequencing revealed that this cardiac isoform, denoted Myo18Aγ, lacks the PDZ-containing N terminus of Myo18Aα but includes an alternative N-terminal extension and a long serine-rich C terminus. EGFP-tagged Myo18Aγ expressed in ventricular myocytes localized to the level of A-bands in sarcomeres, and Myo18a knockout embryos at day 10.5 exhibited disorganized sarcomeres with wavy thick filaments. We additionally generated myeloid-restricted Myo18a knockout mice to investigate the role of Myo18A in nonmuscle cells, exemplified by macrophages, which express more Myo18Aß than Myo18Aα, but no defects in cell shape, motility, or Golgi shape were detected. In summary, we have identified a previously unrecognized sarcomere component, a large novel isoform (denoted Myo18Aγ) of Myo18A. Thus, both members of class XVIII myosins are critical components of cardiac sarcomeres.