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Dysfunctional mitochondria in ageing T cells: a perspective on mitochondrial quality control mechanisms.

Dysfunctional mitochondria are a hallmark of T cell ageing and contribute to organismal ageing. This arises from the accumulation of reactive oxygen species (ROS), impaired mitochondrial dynamics, and inefficient removal of dysfunctional mitochondria. Both cell-intrinsic and cell-extrinsic mechanisms for removing mitochondria and their byproducts have been identified in T cells. In this review, we explore how T cells manage mitochondrial damage through changes in mitochondrial metabolism, mitophagy, asymmetric mitochondrial inheritance, and mitochondrial transfer, highlighting the impact of these mechanisms on T cell ageing and overall organismal ageing. We also discuss current therapeutic strategies aimed at removing dysfunctional mitochondria and their byproducts and propose potential new therapeutic targets that may reverse immune ageing or organismal ageing.

Rapamycin exerts its geroprotective effects in the ageing human immune system by enhancing resilience against DNA damage

Phenotypic Chemical Screening in CD4+ T Cells to Identify Epigenetic Inhibitors.

Chemical biology provides an attractive approach to identify genes involved in a particular biological process. This screening approach has its advantages because the assays are usually non-destructive, and analysis can be performed even if the mechanism of action is unknown. During an immune reaction, cells upregulate the expression and secretion of small proteins called cytokines that have specific effects on the interactions and communication between cells. Here, we describe the principles and steps involved in the execution of chemical screening for identifying epigenetic inhibitors that affect cytokine production in differentiated Th1, Th2, and Th17 cells. Our approach provides a rationale for identifying epigenetic chemical compounds that are capable of controlling CD4+ T-cell cytokine function that may be beneficial for treating inflammatory diseases.

Synovial tissue atlas in juvenile idiopathic arthritis reveals pathogenic niches associated with disease severity.

Precision application of targeted therapies is urgently needed to improve long-term clinical outcomes for children affected by inflammatory arthritis, known as juvenile idiopathic arthritis (JIA). Progress has been hampered by our limited understanding of the cellular basis of inflammation in the target tissue of the disease, the synovial membrane. Here, we analyzed biopsies from the inflamed joints of treatment-naïve children with JIA, early in the course of their disease, using single-cell RNA sequencing, multiplexed immunofluorescence, and spatial transcriptomics to establish a cellular atlas of the JIA synovium. We identified distinct spatial tissue niches, composed of specific stromal and immune cell populations. In addition, we localized genes linked to arthritis severity and disease risk to effector cell populations, including tissue resident SPP1+ macrophages and fibrin-associated myeloid cells. Combined analyses of synovial fluid and peripheral blood from matched individuals revealed differences in cellular composition, signaling pathways, and transcriptional programs across these distinct anatomical compartments. Furthermore, our analysis revealed several pathogenic cell populations that are shared with adult-onset inflammatory arthritis, as well as age-associated differences in tissue vascularity, prominence of innate immunity, and enrichment of TGF-β-responsive stromal subsets that up-regulate expression of disease risk-associated genes. Overall, our findings demonstrate the need for age-specific analyses of synovial tissue pathology to guide targeted treatment strategies in JIA.

Effects of Acute Time-Restricted Eating on Inflammation in Individuals With Psoriasis: Protocol for a Case-Control, Prospective Study.

BACKGROUND: Psoriasis is a chronic inflammatory disease associated with multiple comorbidities, including metabolic syndrome and cardiovascular disease. Although specific dietary interventions, such as intermittent fasting and caloric restriction, have been shown to ameliorate inflammation and promote weight loss, the effect of these interventions independent of weight loss remains unclear. Time-restricted eating (TRE), a type of intermittent fasting, limits the daily eating window to a fixed number of hours. Recent studies suggest TRE may improve immune function in individuals with metabolic syndrome and cardiovascular risk factors. A crucial advantage of TRE over other investigated dietary restriction strategies is its reported high adherence rate, making it a more feasible intervention for long-term use. Therefore, exploring the effects of TRE on metabolic and immunological parameters in psoriasis is warranted. OBJECTIVE: This study was designed to evaluate the effects of short-term, isocaloric TRE, independent of weight loss, on immune cell function and serum metabolite profiles of volunteers with mild-to-moderate psoriasis compared to healthy individuals. METHODS: This case-control, prospective study was performed on 10 healthy male participants and 10 age-, BMI-, and sex-matched individuals with mild-to-moderate psoriasis. All individuals with psoriasis had stable disease and were being treated with topical therapies without any exposure to immunomodulatory biologics. This study was conducted at the National Institutes of Health Clinical Center. Immune profiles, glucose handling, energy expenditure, and participants' weights were assessed at baseline and after 3 days of TRE following a daily 6-hour eating window and 18-hour fast. RESULTS: The trial commenced in June 2021 and was completed in February 2023. A total of 20 participants were enrolled-10 with mild-to-moderate psoriasis and 10 age-, BMI-, and sex-matched healthy individuals. As of the time of manuscript submission, data processing is ongoing. Multiomic datasets, including gene expression, surface and intracellular protein levels, and metabolite profiles, are being generated from peripheral blood mononuclear cells, CD4+-enriched T-cells, and serum samples. The integrated bioinformatics analyses will be reported once the data analysis is completed. CONCLUSIONS: This clinical protocol was designed to characterize the effects of short term (3-day) TRE on psoriasis, independent of weight loss, by comparing immune cell regulatory responses between healthy individuals and those with psoriasis. More specifically, we aim to map the molecular pathways activated by TRE and assess how they affect immune cell composition, activation, and metabolism. Additionally, components of the metabolic response to isocaloric TRE are being explored. Insights into how dietary interventions impact metabolism and the immune system will enhance our understanding of the pathogenesis of psoriasis and may reveal new therapeutic avenues for managing this inflammatory condition. TRIAL REGISTRATION: ClinicalTrials.gov NCT04728165; https://clinicaltrials.gov/study/NCT04728165.

Successful treatment of refractory chilblain lupus erythematosus with bosentan

TASL is required for age-related B cell formation and autoimmunity

The COVIDTrach prospective cohort study on outcomes in 1982 tracheostomised COVID-19 patients during the first and second UK pandemic waves

COVIDTrach is a UK-wide, prospective cohort study evaluating tracheostomised COVID-19 patient outcomes and operator disease transmission. Early in the pandemic controversy surrounded optimal timing of tracheostomy insertion, however meta-analyses have since addressed this uncertainty. We report on our cohort’s data and outcomes to help inform the management of this disease and compare our findings to the literature. Our inclusion criteria were COVID-19 patients aged ≥ 18 undergoing tracheostomy following invasive ventilation. We recorded relevant characteristics, clinical parameters, intra-operative details and outcome data. Predictors for mortality and time to ventilatory wean were determined. Among 1982 patients, there was a 21% post-tracheostomy mortality and median intubation to tracheostomy time of 15 days (IQR 11–21). The median time to successful ventilatory wean post-tracheostomy was 12 days (IQR 7–20). Advancing age, greater FiO2 and PEEP requirements and inotrope or anticoagulant use were associated with increased mortality (p < 0.05) and time to wean success (p < 0.01). Higher CRP predicted increased mortality (p < 0.05), while NIV use and extended pre-tracheostomy ventilation predicted prolonged wean time (p < 0.01). The death risk for tracheostomy performed ≤ 7 or ≥ 14 days of ventilation was equivocal (OR 1.01, 95% CI [0.37–2.72]) but lower between 8 and 14 days (OR = 0.64, 95% CI [0.47–0.86]) (p = 0.01). Eight operators tested positive within two weeks of performing a tracheostomy. Our mortality rates were similar to cohort studies but lower than early versus late tracheostomy designs. In contrast to the literature, we found reduced mortality when tracheostomy was performed 8–14 days post-intubation, with more favourable wean time and wean and decannulation rates.

Immunotherapy for locally advanced head and neck cancer

Perivascular RELMα-positive synovial macrophages recruit monocytes at the onset of inflammatory arthritis.

Macrophages, monocytes and neutrophils are major types of myeloid cells involved in inflammatory diseases, such as rheumatoid arthritis (RA). Recent scRNA-seq studies identified a remarkable diversity of synovial macrophages but, with the exception of lining macrophages, their geographical location and specific roles remain largely unexplored. Here, we localized the RELMα-positive macrophages, predicted to produce high levels of monocyte-recruiting chemokines, to the synovial interstitium and more specifically, to the vicinity of interstitial blood vessels. Using complementary reporter mouse models, CCL2mCherry to label CCL2-producing cells, and CCR2CRE/mKate2 marking CCR2 expressing monocytes, we demonstrated that RELMα-positive perivascular macrophages secrete CCL2 assisting in the recruitment of monocytes predominantly to the synovial interstitium at the onset of antigen-induced arthritis. The inflamed synovial environment guides the differentiation of the recruited monocytes into tissue-resident macrophages, including but not limited to macrophages expressing VSIG4, a characteristic marker of lining macrophages. Thus, RELMα-positive macrophages orchestrate monocyte recruitment to the synovium during articular inflammation, contributing to a local replenishment of synovial lining macrophages.

From complexity to consensus: A roadmap for neutrophil classification.

Neutrophils, previously considered a homogeneous immune cell population, exhibit substantial heterogeneity. Their diverse phenotypic and functional states are shaped by tissue microenvironments and disease-specific signals. However, the lack of robust fate-mapping methods and standardized classification criteria has led to overlapping and ambiguous descriptions of neutrophil heterogeneity. The growing number of neutrophil subpopulations reported in recent years highlights the need for a standardized framework to report how they might relate to each other. Here, we propose a framework that integrates maturation, tissue localization, and functional adaptations. This standardized system aims to harmonize research efforts, foster clearer cross-disciplinary communication, and accelerate both fundamental discoveries in neutrophil biology and the development of targeted therapies.

Author Correction: Matrix-producing neutrophils populate and shield the skin.

Matrix-producing neutrophils populate and shield the skin.

Defence from environmental threats is provided by physical barriers that confer mechanical protection and prevent the entry of microorganisms1. If microorganisms overcome those barriers, however, innate immune cells use toxic chemicals to kill the invading cells2,3. Here we examine immune diversity across tissues and identify a population of neutrophils in the skin that expresses a broad repertoire of proteins and enzymes needed to build the extracellular matrix. In the naive skin, these matrix-producing neutrophils contribute to the composition and structure of the extracellular matrix, reinforce its mechanical properties and promote barrier function. After injury, these neutrophils build 'rings' of matrix around wounds, which shield against foreign molecules and bacteria. This structural program relies on TGFβ signalling; disabling the TGFβ receptor in neutrophils impaired ring formation around wounds and facilitated bacterial invasion. We infer that the innate immune system has evolved diverse strategies for defence, including one that physically shields the host from the outside world.

Neutrophil nucleus: shaping the past and the future.

Neutrophils are innate immune cells that are key to protecting the host against infection and maintaining body homeostasis. However, if dysregulated, they can contribute to disease, such as in cancer or chronic autoinflammatory disorders. Recent studies have highlighted the heterogeneity in the neutrophil compartment and identified the presence of immature neutrophils and their precursors in these pathologies. Therefore, understanding neutrophil maturity and the mechanisms through which they contribute to disease is critical. Neutrophils were first characterized morphologically by Ehrlich in 1879 using microscopy, and since then, different technologies have been used to assess neutrophil maturity. The advances in the imaging field, including state-of-the-art microscopy and machine learning algorithms for image analysis, reinforce the use of neutrophil nuclear morphology as a fundamental marker of maturity, applicable for objective classification in clinical diagnostics. New emerging approaches, such as the capture of changes in chromatin topology, will provide mechanistic links between the nuclear shape, chromatin organization, and transcriptional regulation during neutrophil maturation.

Plasma iron controls neutrophil production and function.

Low plasma iron (hypoferremia) induced by hepcidin is a conserved inflammatory response that protects against infections but inhibits erythropoiesis. How hypoferremia influences leukocytogenesis is unclear. Using proteomic data, we predicted that neutrophil production would be profoundly more iron-demanding than generation of other white blood cell types. Accordingly in mice, hepcidin-mediated hypoferremia substantially reduced numbers of granulocytes but not monocytes, lymphocytes, or dendritic cells. Neutrophil rebound after anti-Gr-1-induced neutropenia was blunted during hypoferremia but was rescued by supplemental iron. Similarly, hypoferremia markedly inhibited pharmacologically stimulated granulopoiesis mediated by granulocyte colony-stimulating factor and inflammation-induced accumulation of neutrophils in the spleen and peritoneal cavity. Furthermore, hypoferremia specifically altered neutrophil effector functions, suppressing antibacterial mechanisms but enhancing mitochondrial reactive oxygen species-dependent NETosis associated with chronic inflammation. Notably, antagonizing endogenous hepcidin during acute inflammation enhanced production of neutrophils. We propose plasma iron modulates the profile of innate immunity by controlling monocyte-to-neutrophil ratio and neutrophil activity in a therapeutically targetable system.

Macrophage heterogeneity in cardiometabolic disease

Diesel exhaust particles activate macrophages and IRF5 expression in atherosclerosis

Peripheral neuronal sensitization and neurovascular remodelling in osteoarthritis pain.

Pain is the primary complaint in individuals with osteoarthritis (OA) and changes as the disease progresses. Anatomical changes in several joint structures potentially contribute to pain, including the increased innervation of the periosteum, synovium and subchondral bone, and the pathological innervation of articular cartilage, which is aneural under physiological conditions. Research has focused on molecules that sensitize afferent neurons, such as neuropeptides, neurotrophins, pro-inflammatory cytokines and ion channels. The neurotrophin nerve growth factor (NGF) is the best validated target in OA pain, with proven analgesic effects in preclinical and clinical studies, although the development of NGF-targeted therapeutics has been hampered by serious side effects. One relatively neglected area of research is the contribution to OA pain of the molecular pathways that mediate remodelling of nerves in disease. Remodelling requires coordination between the nerve and the associated vasculature, along with signals that are received from the surrounding parenchyma. Key cell guidance molecules, including angiogenic factors, ephrins, semaphorins and SLIT proteins are involved in nerve growth during development, and their expression is increased in osteoarthritic joints.

Skeletal Muscle Tissue Engineering: From Tissue Regeneration to Biorobotics.

With its remarkable adaptability, energy efficiency, and mechanical compliance, skeletal muscle is a powerful source of inspiration for innovations in engineering and robotics. Originally driven by the clinical need to address large irreparable muscle defects, skeletal muscle tissue engineering (SMTE) has evolved into a versatile strategy reaching beyond medical applications into the field of biorobotics. This review highlights recent advancements in SMTE, including innovations in scaffold design, cell sourcing, usage of external physicochemical cues, and bioreactor technologies. Furthermore, this article explores the emerging synergies between SMTE and robotics, focusing on the use of robotic systems to enhance bioreactor performance and the development of biohybrid devices integrating engineered muscle tissue. These interdisciplinary approaches aim to improve functional recovery outcomes while inspiring novel biohybrid technologies at the intersection of engineering and regenerative medicine.

Systemic Lupus Erythematosus With Cardiac Tamponade and Myocardial Edema in the Early Postpartum Period.

BACKGROUND: Pericardial effusions are frequently caused by inflammatory diseases. In cases of serosal inflammation, which often present with concomitant systemic symptoms, cardiac tamponade can occur, requiring emergency drainage. Nevertheless, it is rare for the index presentation of a previously undiagnosed inflammatory disease to be with cardiac tamponade. CASE SUMMARY: We describe a case of a young woman who presented in the postpartum period with cardiac tamponade. Further investigations confirmed that the underlying diagnosis was systemic lupus erythematosus (SLE). DISCUSSION: SLE can be associated with pericardial effusion but rarely causes cardiac tamponade. Herein, we describe a case of an index presentation of SLE in the postpartum period with a large pericardial effusion and tamponade. Cardiac imaging showed myocardial edema, reflective of associated myocarditis. TAKE-HOME MESSAGES: SLE can present in the immediate postpartum period, and acute management of tamponade in this context includes drainage of the effusion and immunosuppressive therapy.