Cytoplasmic chromatin triggers inflammation in senescence and cancer

Chromatin is traditionally viewed as a nuclear entity that regulates gene expression and silencing. However, we recently discovered the presence of cytoplasmic chromatin fragments that pinch off from intact nuclei of primary cells during senescence, a form of terminal cell-cycle arrest associated with pro-inflammatory responses. The functional significance of chromatin in the cytoplasm is unclear. Here we show that cytoplasmic chromatin activates the innate immunity cytosolic DNA-sensing cGAS-STING (cyclic GMP-AMP synthase linked to stimulator of interferon genes) pathway, leading both to short-term inflammation to restrain activated oncogenes and to chronic inflammation that associates with tissue destruction and cancer. The cytoplasmic chromatin-cGAS-STING pathway promotes the senescence-associated secretory phenotype in primary human cells and in mice. Mice deficient in STING show impaired immuno-surveillance of oncogenic RAS and reduced tissue inflammation upon ionizing radiation. Furthermore, this pathway is activated in cancer cells, and correlates with pro-inflammatory gene expression in human cancers. Overall, our findings indicate that genomic DNA serves as a reservoir to initiate a pro-inflammatory pathway in the cytoplasm in senescence and cancer. Targeting the cytoplasmic chromatin-mediated pathway may hold promise in treating inflammation-related disorders

Is the Soleus a Sentinel Muscle for Impaired Aerobic Capacity in Heart Failure?

Purpose: Skeletal muscle wasting is well documented in chronic heart failure (CHF). This article provides a more detailed understanding of the morphology behind this muscle wasting and the relation between muscle morphology, strength, and exercise capacity in CHF. We investigated the effect of CHF on lower limb lean mass, detailed muscle–tendon architecture of the individual triceps surae muscles (soleus (SOL), medial gastrocnemius, and lateral gastrocnemius) and how these parameters relate to exercise capacity and strength. Methods: Eleven patients with CHF and 15 age-matched controls were recruited. Lower limb lean mass was assessed by dual energy x-ray absorptiometry and the architecture of skeletal muscle and tendon properties by ultrasound. Plantarflexor strength was assessed by dynamometry. Results: Patients with CHF exhibited approximately 25% lower combined triceps surae volume and physiological cross-sectional area (PCSA) compared with those of control subjects (P < 0.05), driven in large part by reductions in the SOL. Only the SOL volume and the SOL and medial gastrocnemius physiological cross-sectional area were statistically different between groups after normalizing to lean body mass and body surface area, respectively. Total lower limb lean mass did not differ between CHF and control subjects, further highlighting the SOL specificity of muscle wasting in CHF. Moreover, the volume of the SOL and plantarflexor strength correlated strongly with peak oxygen uptake (V˙O2peak) in patients with CHF. Conclusions: These findings suggest that the SOL may be a sentinel skeletal muscle in CHF and provide a rationale for including plantarflexor muscle training in CHF care

Innate immune DNA sensing pathways: STING, AIMII and the regulation of interferon production and inflammatory responses

The early detection of microbes is the responsibility of the innate immune system which has evolved to sense pathogen derived molecules such as lipopolysaccharides and non-self nucleic acid, to trigger host defense countermeasures. These sensors include the RIG-I-like helicase (RLH) family that specifically recognizes viral RNA, as well as the cytoplasmic, nucleotide binding oligermerization domain (NOD)-like receptor and Toll-like receptor (TLR) pathways that sense a variety of microbial derived molecules. Comprehending how the cell senses foreign DNA, generated by certain viruses, bacteria and possibly parasites has proven elusive but is of significant importance since such information could shed insight into the causes of microbial related disease, including viral associated cancers and autoimmune disorders. Plasmacytoid dendritic cells are known to utilize TLR9 to detect pathogen-associated DNA and to trigger the production of type I interferon (IFN), as well as other cytokines, although alternate key DNA detecting sensors remain to be identified. Recently however, a molecule referred to as AIM2 (absent in melanoma 2) was found to be essential for mediating inflammatory reactions triggered by cytoplasmic DNA. In addition, an endoplasmic reticulum associated protein referred to as STING (for stimulator of interferon genes) was demonstrated as being pivotal for facilitating IFN production in response to intracellular DNA and a variety of DNA pathogens. Here, we review recent discoveries relating to the detection of foreign DNA, including the importance of the STING and AIM2 and the activation of innate signaling pathways

Virus infection is controlled by hematopoietic and stromal cell sensing of murine cytomegalovirus through STING

Recognition of DNA viruses, such as cytomegaloviruses (CMVs), through pattern-recognition receptor (PRR) pathways involving MyD88 or STING constitute a first-line defense against infections mainly through production of type I interferon (IFN-I). However, the role of these pathways in different tissues is incompletely understood, an issue particularly relevant to the CMVs which have broad tissue tropisms. Herein, we contrasted anti-viral effects of MyD88 versus STING in distinct cell types that are infected with murine CMV (MCMV). Bone marrow chimeras revealed STING-mediated MCMV control in hematological cells, similar to MyD88. However, unlike MyD88, STING also contributed to viral control in non-hematological, stromal cells. Infected splenic stromal cells produced IFN-I in a cGAS-STING-dependent and MyD88-independent manner, while we confirmed plasmacytoid dendritic cell IFN-I had inverse requirements. MCMV-induced natural killer cytotoxicity was dependent on MyD88 and STING. Thus, MyD88 and STING contribute to MCMV control in distinct cell types that initiate downstream immune responses

Global, regional, and national incidence and mortality for HIV, tuberculosis, and malaria during 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013

BACKGROUND: The Millennium Declaration in 2000 brought special global attention to HIV, tuberculosis, and malaria through the formulation of Millennium Development Goal (MDG) 6. The Global Burden of Disease 2013 study provides a consistent and comprehensive approach to disease estimation for between 1990 and 2013, and an opportunity to assess whether accelerated progress has occured since the Millennium Declaration. METHODS: To estimate incidence and mortality for HIV, we used the UNAIDS Spectrum model appropriately modified based on a systematic review of available studies of mortality with and without antiretroviral therapy (ART). For concentrated epidemics, we calibrated Spectrum models to fit vital registration data corrected for misclassification of HIV deaths. In generalised epidemics, we minimised a loss function to select epidemic curves most consistent with prevalence data and demographic data for all-cause mortality. We analysed counterfactual scenarios for HIV to assess years of life saved through prevention of mother-to-child transmission (PMTCT) and ART. For tuberculosis, we analysed vital registration and verbal autopsy data to estimate mortality using cause of death ensemble modelling. We analysed data for corrected case-notifications, expert opinions on the case-detection rate, prevalence surveys, and estimated cause-specific mortality using Bayesian meta-regression to generate consistent trends in all parameters. We analysed malaria mortality and incidence using an updated cause of death database, a systematic analysis of verbal autopsy validation studies for malaria, and recent studies (2010-13) of incidence, drug resistance, and coverage of insecticide-treated bednets. FINDINGS: Globally in 2013, there were 1·8 million new HIV infections (95% uncertainty interval 1·7 million to 2·1 million), 29·2 million prevalent HIV cases (28·1 to 31·7), and 1·3 million HIV deaths (1·3 to 1·5). At the peak of the epidemic in 2005, HIV caused 1·7 million deaths (1·6 million to 1·9 million). Concentrated epidemics in Latin America and eastern Europe are substantially smaller than previously estimated. Through interventions including PMTCT and ART, 19·1 million life-years (16·6 million to 21·5 million) have been saved, 70·3% (65·4 to 76·1) in developing countries. From 2000 to 2011, the ratio of development assistance for health for HIV to years of life saved through intervention was US$4498 in developing countries. Including in HIV-positive individuals, all-form tuberculosis incidence was 7·5 million (7·4 million to 7·7 million), prevalence was 11·9 million (11·6 million to 12·2 million), and number of deaths was 1·4 million (1·3 million to 1·5 million) in 2013. In the same year and in only individuals who were HIV-negative, all-form tuberculosis incidence was 7·1 million (6·9 million to 7·3 million), prevalence was 11·2 million (10·8 million to 11·6 million), and number of deaths was 1·3 million (1·2 million to 1·4 million). Annualised rates of change (ARC) for incidence, prevalence, and death became negative after 2000. Tuberculosis in HIV-negative individuals disproportionately occurs in men and boys (versus women and girls); 64·0% of cases (63·6 to 64·3) and 64·7% of deaths (60·8 to 70·3). Globally, malaria cases and deaths grew rapidly from 1990 reaching a peak of 232 million cases (143 million to 387 million) in 2003 and 1·2 million deaths (1·1 million to 1·4 million) in 2004. Since 2004, child deaths from malaria in sub-Saharan Africa have decreased by 31·5% (15·7 to 44·1). Outside of Africa, malaria mortality has been steadily decreasing since 1990. INTERPRETATION: Our estimates of the number of people living with HIV are 18·7% smaller than UNAIDS's estimates in 2012. The number of people living with malaria is larger than estimated by WHO. The number of people living with HIV, tuberculosis, or malaria have all decreased since 2000. At the global level, upward trends for malaria and HIV deaths have been reversed and declines in tuberculosis deaths have accelerated. 101 countries (74 of which are developing) still have increasing HIV incidence. Substantial progress since the Millennium Declaration is an encouraging sign of the effect of global action. FUNDING: Bill & Melinda Gates Foundation

Simulating the effect of muscle weakness and contracture on neuromuscular control of normal gait in children

Altered neural control of movement and musculoskeletal deficiencies are common in children with spastic cerebral palsy (SCP), with muscle weakness and contracture commonly experienced. Both neural and musculoskeletal deficiencies are likely to contribute to abnormal gait, such as equinus gait (toe-walking), in children with SCP. However, it is not known whether the musculoskeletal deficiencies prevent normal gait or if neural control could be altered to achieve normal gait. This study examined the effect of simulated muscle weakness and contracture of the major plantarflexor/dorsiflexor muscles on the neuromuscular requirements for achieving normal walking gait in children. Initial muscle-driven simulations of walking with normal musculoskeletal properties by typically developing children were undertaken. Additional simulations with altered musculoskeletal properties were then undertaken; with muscle weakness and contracture simulated by reducing the maximum isometric force and tendon slack length, respectively, of selected muscles. Muscle activations and forces required across all simulations were then compared via waveform analysis. Maintenance of normal gait appeared robust to muscle weakness in isolation, with increased activation of weakened muscles the major compensatory strategy. With muscle contracture, reduced activation of the plantarflexors was required across the mid-portion of stance suggesting a greater contribution from passive forces. Increased activation and force during swing was also required from the tibialis anterior to counteract the increased passive forces from the simulated dorsiflexor muscle contracture. Improvements in plantarflexor and dorsiflexor motor function and muscle strength, concomitant with reductions in plantarflexor muscle stiffness may target the deficits associated with SCP that limit normal gait

Evaluating high-resolution computed tomography derived 3-D joint space metrics of the metacarpophalangeal joints between rheumatoid arthritis and age- and sex-matched control participants

IntroductionRheumatoid arthritis (RA) is commonly characterized by joint space narrowing. High-resolution peripheral quantitative computed tomography (HR-pQCT) provides unparalleled in vivo visualization and quantification of joint space in extremity joints commonly affected by RA, such as the 2nd and 3rd metacarpophalangeal joints. However, age, sex, and obesity can also influence joint space narrowing. Thus, this study aimed to determine whether HR-pQCT joint space metrics could distinguish between RA patients and controls, and determine the effects of age, sex and body mass index (BMI) on these joint space metrics.MethodsHR-pQCT joint space metrics (volume, width, standard deviation of width, maximum/minimum width, and asymmetry) were acquired from RA patients and age-and sex-matched healthy control participants 2nd and 3rd MCP joints. Joint health and functionality were assessed with ultrasound (i.e., effusion and inflammation), hand function tests, and questionnaires.ResultsHR-pQCT-derived 3D joint space metrics were not significantly different between RA and control groups (p &gt; 0.05), despite significant differences in inflammation and joint function (p &lt; 0.05). Joint space volume, mean joint space width (JSW), maximum JSW, minimum JSW were larger in males than females (p &lt; 0.05), while maximum JSW decreased with age. No significant association between joint space metrics and BMI were found.ConclusionHR-pQCT did not detect group level differences between RA and age-and sex-matched controls. Further research is necessary to determine whether this is due to a true lack of group level differences due to well-controlled RA, or the inability of HR-pQCT to detect a difference

STING signalling is terminated through ESCRT-dependent microautophagy of vesicles originating from recycling endosomes

STING炎症シグナルの終結分子機構 --新規細胞内分解システムの発見--. 京都大学プレスリリース. 2023-03-14.Stimulator of interferon genes (STING) is essential for the type I interferon response against a variety of DNA pathogens. Upon emergence of cytosolic DNA, STING translocates from the endoplasmic reticulum to the Golgi where STING activates the downstream kinase TBK1, then to lysosome through recycling endosomes (REs) for its degradation. Although the molecular machinery of STING activation is extensively studied and defined, the one underlying STING degradation and inactivation has not yet been fully elucidated. Here we show that STING is degraded by the endosomal sorting complexes required for transport (ESCRT)-driven microautophagy. Airyscan super-resolution microscopy and correlative light/electron microscopy suggest that STING-positive vesicles of an RE origin are directly encapsulated into Lamp1-positive compartments. Screening of mammalian Vps genes, the yeast homologues of which regulate Golgi-to-vacuole transport, shows that ESCRT proteins are essential for the STING encapsulation into Lamp1-positive compartments. Knockdown of Tsg101 and Vps4, components of ESCRT, results in the accumulation of STING vesicles in the cytosol, leading to the sustained type I interferon response. Knockdown of Tsg101 in human primary T cells leads to an increase the expression of interferon-stimulated genes. STING undergoes K63-linked ubiquitination at lysine 288 during its transit through the Golgi/REs, and this ubiquitination is required for STING degradation. Our results reveal a molecular mechanism that prevents hyperactivation of innate immune signalling, which operates at REs

Modulation of the cGAS-STING DNA sensing pathway by gammaherpesviruses

Kaposi’s sarcoma-associated herpesvirus (KSHV) is a DNA virus that is linked to several human malignancies. The cGMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) pathway is able to detect KSHV during primary infection and regulates the reactivation of KSHV from latency. We screened KSHV proteins for their ability to inhibit this pathway and block IFN-β activation. One KSHV protein, vIRF1, inhibited this pathway by preventing STING from interacting with TBK1 and inhibiting STING’s phosphorylation and concomitant activation. Moreover, depletion of vIRF1 in the context of KSHV infection prevented efficient viral reactivation and replication, and increased the host IFN response to KSHV. Collectively, our results demonstrate that the modulation of this pathway is important for viral transmission and the lifelong persistence of gammaherpesviruses in the human population

Innate Immune System Regulated by Stimulator of Interferon Genes, a Cytosolic DNA Sensor, Regulates Endothelial Function

BACKGROUND: Sterile inflammation caused by metabolic disorders impairs endothelial function; however, the underlying mechanism by which hyperglycemia induces inflammation remains obscure. Recent studies have suggested that stimulator of interferon genes (STING), a key cytosolic DNA sensor in the innate immune system, contributes to the pathogenesis of inflammatory diseases. This study examines the role of the STING in endothelial dysfunction in streptozotocin-induced diabetic mice. METHODS AND RESULTS: Injection of streptozotocin promoted the expression of STING and DNA damage markers in the aorta of wild-type mice. Streptozotocin elevated blood glucose and lipid levels in both wild-type and STING-deficient mice, which showed no statistical differences. Genetic deletion of STING ameliorated endothelial dysfunction as determined by the vascular relaxation in response to acetylcholine (P<0.001) and increased endothelial nitric oxide synthase phosphorylation in the aorta (P<0.05) in STZ-injected mice. Endothelium-independent vascular response to sodium nitroprusside did not differ. Treatment with a direct STING agonist, cyclic GMP-AMP, or mitochondrial DNA increased inflammatory molecule expression (eg, VCAM1 and IFNB) and decreased endothelial nitric oxide synthase phosphorylation in human umbilical vein endothelial cells, partially through the STING pathway. Cyclic GMP-AMP significantly impaired endothelial function of aortic segments obtained from wild-type mice, which was ameliorated in the presence of C-176, a STING inhibitor, or a neutralizing interferon-β antibody. Furthermore, the administration of C-176 ameliorated endothelial dysfunction in STZ-induced diabetic mice (P<0.01). CONCLUSIONS: The DNA damage response regulated by STING impairs endothelial function. STING signaling may be a potential therapeutic target of endothelial dysfunction caused by hyperglycemia.journal articl