RESUMEN
Immune-mediated necrotizing myopathy (IMNM) is a rare and newly recognized autoimmune disease within the spectrum of idiopathic inflammatory myopathies. It is characterized by myositis-specific autoantibodies, elevated serum creatine kinase levels, inflammatory infiltrate, and weakness. IMNM can be classified into three subtypes based on the presence or absence of specific autoantibodies: anti-signal recognition particle myositis, anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase myositis, and seronegative IMNM. In recent years, IMNM has gained increasing attention and emerged as a research hotspot. Recent studies have suggested that the pathogenesis of IMNM is linked to aberrant activation of immune system, including immune responses mediated by antibodies, complement, and immune cells, particularly macrophages, as well as abnormal release of inflammatory factors. Non-immune mechanisms such as autophagy and endoplasmic reticulum stress also participate in this process. Additionally, genetic variations associated with IMNM have been identified, providing new insights into the genetic mechanisms of the disease. Progress has also been made in IMNM treatment research, including the use of immunosuppressants and the development of biologics. Despite the challenges in understanding the etiology and treatment of IMNM, the latest research findings offer important guidance and insights for delving deeper into the disease's pathogenic mechanisms and identifying new therapeutic strategies.
Asunto(s)
Autoanticuerpos , Miositis , Humanos , Miositis/inmunología , Miositis/terapia , Miositis/patología , Miositis/diagnóstico , Miositis/etiología , Autoanticuerpos/inmunología , Necrosis/inmunología , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/terapia , Enfermedades Autoinmunes/etiología , Enfermedades Autoinmunes/diagnóstico , Animales , Inmunosupresores/uso terapéutico , Músculo Esquelético/inmunología , Músculo Esquelético/patología , Músculo Esquelético/metabolismoRESUMEN
Infections and neurodegenerative diseases induce neuroinflammation, but affected individuals often show nonneural symptoms including muscle pain and muscle fatigue. The molecular pathways by which neuroinflammation causes pathologies outside the central nervous system (CNS) are poorly understood. We developed multiple models to investigate the impact of CNS stressors on motor function and found that Escherichia coli infections and SARS-CoV-2 protein expression caused reactive oxygen species (ROS) to accumulate in the brain. ROS induced expression of the cytokine Unpaired 3 (Upd3) in Drosophila and its ortholog, IL-6, in mice. CNS-derived Upd3/IL-6 activated the JAK-STAT pathway in skeletal muscle, which caused muscle mitochondrial dysfunction and impaired motor function. We observed similar phenotypes after expressing toxic amyloid-ß (Aß42) in the CNS. Infection and chronic disease therefore activate a systemic brain-muscle signaling axis in which CNS-derived cytokines bypass the connectome and directly regulate muscle physiology, highlighting IL-6 as a therapeutic target to treat disease-associated muscle dysfunction.
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Encéfalo , COVID-19 , Músculo Esquelético , Transducción de Señal , Animales , Encéfalo/inmunología , Encéfalo/metabolismo , Transducción de Señal/inmunología , Ratones , Músculo Esquelético/inmunología , Músculo Esquelético/metabolismo , COVID-19/inmunología , Enfermedad Crónica , Interleucina-6/metabolismo , Interleucina-6/inmunología , Infecciones por Escherichia coli/inmunología , Especies Reactivas de Oxígeno/metabolismo , Especies Reactivas de Oxígeno/inmunología , Proteínas de Drosophila/metabolismo , Proteínas de Drosophila/inmunología , Proteínas de Drosophila/genética , SARS-CoV-2/inmunología , Drosophila melanogaster/inmunología , Péptidos beta-Amiloides/metabolismo , Humanos , Ratones Endogámicos C57BLRESUMEN
Background: Sarcopenia is a condition characterized by the age-related loss of skeletal muscle mass and function. The pathogenesis of the disease is influenced by chronic low-grade inflammation. However, the specific changes in the immune landscape changes of sarcopenic muscle are not yet fully understood. Methods: To gain insights into the immune cell composition and interactions, we combined single-nucleus RNA sequencing data, bulk RNA sequencing dataset, and comprehensive bioinformatic analyses on the skeletal muscle samples from young, aged, and sarcopenic individuals. Histological staining was then performed on skeletal muscles to validate the distribution of immune cells in clinical samples. Results: We analyzed the transcriptomes of 101,862 single nuclei, revealing a total of 10 major cell types and 6 subclusters of immune cell types within the human skeletal muscle tissues. Notable variations were identified in the immune microenvironment between young and aged skeletal muscle. Among the immune cells from skeletal muscle microenvironment, macrophages constituted the largest fraction. A specific marker gene LYVE1 for skeletal muscle resident macrophages was further identified. Cellular subclasses included four distinct groups of resident macrophages, which play different roles in physiological or non-physiological conditions. Utilizing bulk RNA sequencing data, we observed a significant enrichment of macrophage-rich inflammation in sarcopenia. Conclusions: Our findings demonstrate age-related changes in the composition and cross-talk of immune cells in human skeletal muscle microenvironment, which contribute to chronic inflammation in aged or sarcopenia muscle. Furthermore, macrophages emerge as a potential therapeutic target, thus advancing our understanding of the pathogenesis of sarcopenia.
Asunto(s)
Perfilación de la Expresión Génica , Músculo Esquelético , Sarcopenia , Transcriptoma , Sarcopenia/inmunología , Sarcopenia/genética , Sarcopenia/patología , Humanos , Músculo Esquelético/inmunología , Músculo Esquelético/patología , Músculo Esquelético/metabolismo , Anciano , Masculino , Adulto , Macrófagos/inmunología , Macrófagos/metabolismo , Femenino , Persona de Mediana Edad , Microambiente Celular/inmunología , Microambiente Celular/genética , Envejecimiento/inmunología , Envejecimiento/genéticaRESUMEN
Patients with chronic liver disease (CLD) often present with significant frailty, sarcopenia, and impaired immune function. However, the mechanisms driving the development of these age-related phenotypes are not fully understood. To determine whether accelerated biological aging may play a role in CLD, epigenetic, transcriptomic, and phenotypic assessments were performed on the skeletal muscle tissue and immune cells of CLD patients and age-matched healthy controls. Accelerated biological aging of the skeletal muscle tissue of CLD patients was detected, as evidenced by an increase in epigenetic age compared with chronological age (mean +2.2 ± 4.8 years compared with healthy controls at -3.0 ± 3.2 years, p = 0.0001). Considering disease etiology, age acceleration was significantly greater in both the alcohol-related (ArLD) (p = 0.01) and nonalcoholic fatty liver disease (NAFLD) (p = 0.0026) subgroups than in the healthy control subgroup, with no age acceleration observed in the immune-mediated subgroup or healthy control subgroup (p = 0.3). The skeletal muscle transcriptome was also enriched for genes associated with cellular senescence. Similarly, blood cell epigenetic age was significantly greater than that in control individuals, as calculated using the PhenoAge (p < 0.0001), DunedinPACE (p < 0.0001), or Hannum (p = 0.01) epigenetic clocks, with no difference using the Horvath clock. Analysis of the IMM-Age score indicated a prematurely aged immune phenotype in CLD patients that was 2-fold greater than that observed in age-matched healthy controls (p < 0.0001). These findings suggested that accelerated cellular aging may contribute to a phenotype associated with advanced age in CLD patients. Therefore, therapeutic interventions to reduce biological aging in CLD patients may improve health outcomes.
Asunto(s)
Envejecimiento , Epigénesis Genética , Músculo Esquelético , Humanos , Músculo Esquelético/metabolismo , Músculo Esquelético/inmunología , Músculo Esquelético/patología , Masculino , Femenino , Persona de Mediana Edad , Envejecimiento/inmunología , Sistema Inmunológico/metabolismo , Sistema Inmunológico/inmunología , Transcriptoma , Adulto , Anciano , Enfermedad Crónica , Hepatopatías/inmunología , Hepatopatías/patología , Estudios de Casos y Controles , Perfilación de la Expresión GénicaRESUMEN
Brachio-cervical inflammatory myopathy (BCIM) is a rare inflammatory myopathy characterized by dysphagia, bilateral upper limb atrophy, limb-girdle muscle weakness, and myositis-specific antibody (MSA) negativity. BCIM has a low incidence and is commonly associated with autoimmune diseases. We present a case report of a 55-year-old man with progressive upper limb weakness and atrophy, diagnosed with flail arm syndrome (FAS). The initial electromyography revealed extensive spontaneous muscle activity and increased duration of motor unit potentials (MUPs). During follow-up, evidence of myogenic damage was observed, as indicated by a decreased duration of MUPs in the right biceps muscle. Laboratory and genetic testing ruled out hereditary or acquired diseases. Negative serological antibodies for myasthenia gravis. Hereditary or acquired diseases were ruled out through laboratory and genetic testing. Whole-body muscle magnetic resonance imaging (MRI) showed extensive edema and fat replacement in the bilateral upper limbs, scapular, and central axis muscles, while the lower extremities were relatively mildly affected. Muscle biopsy revealed numerous foci of inflammatory cells distributed throughout the muscle bundle, with predominant CD20, CD138, and CD68 expression, accompanied by a light infiltration of CD3 and CD4 expression. The muscle weakness improved with the combination of oral prednisone (initially 60 mg/day, tapered) and methotrexate (5 mg/week) treatment.
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Errores Diagnósticos , Miositis , Humanos , Persona de Mediana Edad , Masculino , Miositis/diagnóstico , Miositis/inmunología , Brazo , Músculo Esquelético/patología , Músculo Esquelético/inmunología , Debilidad Muscular/diagnóstico , Debilidad Muscular/etiología , Atrofia Muscular/diagnóstico , Electromiografía , Imagen por Resonancia MagnéticaRESUMEN
The recent outbreak of monkeypox virus (MPXV) was unprecedented in its size and distribution. Those living with uncontrolled HIV and low CD4 T cell counts might develop a fulminant clinical mpox course with increased mortality, secondary infections, and necrotizing lesions. Fatal cases display a high and widespread MPXV tissue burden. The underlying pathomechanisms are not fully understood. We report here the pathological findings of an MPXV-driven abscess in gastrocnemius muscle requiring surgery in an immunocompromised patient with severe mpox. Presence of virus particles and infectivity were confirmed by electron microscopy, expansion microscopy, and virus culture, respectively. MPXV tissue distribution by immunohistochemistry (IHC) showed a necrotic core with infection of different cell types. In contrast, at the lesion rim fibroblasts were mainly infected. Immune cells were almost absent in the necrotic core, but were abundant at the infection rim and predominantly macrophages. Further, we detected high amounts of alternatively activated GPNMB+-macrophages at the lesion border. Of note, macrophages only rarely colocalized with virus-infected cells. Insufficient clearance of infected cells and infection of lesion-associated fibroblasts sustained by the abundance of profibrotic macrophages might lead to the coalescing of lesions and the severe and persistent clinical mpox course observed in immunocompromised patients.
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Huésped Inmunocomprometido , Monkeypox virus , Mpox , Músculo Esquelético , Humanos , Músculo Esquelético/virología , Músculo Esquelético/patología , Músculo Esquelético/inmunología , Mpox/virología , Mpox/inmunología , Monkeypox virus/inmunología , Masculino , Macrófagos/inmunología , Macrófagos/virología , Fibroblastos/virología , Fibroblastos/inmunología , Inmunohistoquímica , Absceso/inmunología , Absceso/virología , Absceso/patología , Persona de Mediana EdadRESUMEN
Skeletal muscle plays an integral role in locomotion, but also as part of the integrative physiological system. Recent progress has identified crosstalk between skeletal muscle and various physiological systems, including the immune system. Both the musculoskeletal and immune systems are impacted by aging. Increased age is associated with decreased muscle mass and function, while the immune system undergoes "inflammaging" and immunosenescence. Exercise is identified as a preventative medicine that can mitigate loss of function for both systems. This review summarizes: (1) the inflammatory pathways active in skeletal muscle; and (2) the inflammatory and skeletal muscle response to unaccustomed exercise in younger and older adults. Compared to younger adults, it appears older individuals have a muted pro-inflammatory response and elevated anti-inflammatory response to exercise. This important difference could contribute to decreased regeneration and recovery following unaccustomed exercise in older adults, as well as in chronic disease. The current research provides specific information on the role inflammation plays in altering skeletal muscle form and function, and adaptation to exercise; however, the pursuit of more knowledge in this area will delineate specific interventions that may enhance skeletal muscle recovery and promote resiliency in this tissue particularly with aging.
Asunto(s)
Envejecimiento , Ejercicio Físico , Inflamación , Músculo Esquelético , Humanos , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiología , Músculo Esquelético/inmunología , Envejecimiento/fisiología , Inflamación/metabolismo , Ejercicio Físico/fisiología , AnimalesRESUMEN
Neutrophils are emerging as an important player in skeletal muscle injury and repair. Neutrophils accumulate in injured tissue, thus releasing inflammatory factors, proteases and neutrophil extracellular traps (NETs) to clear muscle debris and pathogens when skeletal muscle is damaged. During the process of muscle repair, neutrophils can promote self-renewal and angiogenesis in satellite cells. When neutrophils are abnormally overactivated, neutrophils cause collagen deposition, functional impairment of satellite cells, and damage to the skeletal muscle vascular endothelium. Heterotopic ossification (HO) refers to abnormal bone formation in soft tissue. Skeletal muscle injury is one of the main causes of traumatic HO (tHO). Neutrophils play a pivotal role in activating BMPs and TGF-ß signals, thus promoting the differentiation of mesenchymal stem cells and progenitor cells into osteoblasts or osteoclasts to facilitate HO. Furthermore, NETs are specifically localized at the site of HO, thereby accelerating the formation of HO. Additionally, the overactivation of neutrophils contributes to the disruption of immune homeostasis to trigger HO. An understanding of the diverse roles of neutrophils will not only provide more information on the pathogenesis of skeletal muscle injury for repair and HO but also provides a foundation for the development of more efficacious treatment modalities for HO.
Asunto(s)
Inflamación , Músculo Esquelético , Neutrófilos , Osificación Heterotópica , Osteogénesis , Osificación Heterotópica/patología , Osificación Heterotópica/etiología , Osificación Heterotópica/inmunología , Osificación Heterotópica/metabolismo , Humanos , Neutrófilos/inmunología , Neutrófilos/metabolismo , Músculo Esquelético/patología , Músculo Esquelético/metabolismo , Músculo Esquelético/inmunología , Animales , Inflamación/patología , Inflamación/inmunología , Trampas Extracelulares/metabolismo , Trampas Extracelulares/inmunologíaRESUMEN
Immune-mediated necrotizing myopathy (IMNM) is a form of autoimmune myositis characterized by the presence of necrotic and regenerating process as a major finding in the muscle. Anti-SRP and anti-HMGCR have been identified as IMNM-specific autoantibodies. Patients with this disease often present with severe muscle weakness and markedly elevated serum creatine kinase (CK) levels. Differentiation from muscular dystrophy is challenging in certain cases. When patients meet the condition "subacute onset", "hyperCKemia over 1000 IU/L", and "clinical diagnosis of muscular dystrophy lacking molecular diagnosis", the possibility of IMNM should be considered. Autoantibody measurement, including of anti-SRP and HMGCR antibodies, is recommended. Treatment with corticosteroid in combination with immunosuppressants, intravenous immunoglobulin, and rituximab can be performed.
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Autoanticuerpos , Necrosis , Humanos , Autoanticuerpos/inmunología , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/diagnóstico , Miositis/inmunología , Miositis/diagnóstico , Hidroximetilglutaril-CoA Reductasas/inmunología , Inmunoglobulinas Intravenosas/administración & dosificación , Músculo Esquelético/patología , Músculo Esquelético/inmunología , Partícula de Reconocimiento de Señal/inmunologíaRESUMEN
The link between type I IFN and adaptive immunity, especially T-cell immunity, in JDM still remained largely unclear. This study aimed to understand the effect of elevated type I IFN signaling on CD8+ T cell-associated muscle damage in juvenile dermatomyositis (JDM). This study used flow cytometry (FC) and RTâPCR were used to examine the circulating cell ratio and type I IFN response. And scRNA-seq was used to examine peripheral immunity in 6 active JDM patients, 3 stable JDM patients, 3 juvenile IMNM patients and 3 age-matched healthy children. In vivo validation experiments were conducted using a mouse model induced by STING agonists and an experimental autoimmune myositis model (EAM). In vitro experiments were conducted using isolated CD8+ T-cells from JDM patients and mice. We found that active JDM patients showed an extensive type I IFN response and a decreased CD8+ T-cell ratio in the periphery (P < 0.05), which was correlated with muscle involvement (P < 0.05). Both new active JDM patients and all active JDM patients showed decreased CD8+ TCM cell ratios compared with age and gender matched stable JDM patients (P < 0.05). Compared with new pediatirc systemic lupus erythematosus (SLE) patients, new active JDM patients displayed decreased CD8+ T-cell and CD8+ TCM cell ratios (P < 0.05). Active JDM patient skeletal muscle biopsies displayed an elevated type I IFN response, upregulated MHC-I expression and CD8+ T-cell infiltration, which was validated in EAM mice. sc-RNAseq demonstrated that type I IFN signalling is the kinetic factor of abnormal differentiation and enhances the cytotoxicity of peripheral CD8+ T cells in active JDM patients, which was confirmed by in vivo and in vitro validation experiments. In summary, the elevated type I IFN signalling affected the differentiation and function of CD8+ T cells in active JDM patients. Skeletal muscle-infiltrating CD8+ T cells might migrate from the periphery under the drive of type I IFN and increased MHC I signals. Therapies targeting autoantigen-specific CD8+ T cells may represent a potential new treatment direction.
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Autoantígenos , Linfocitos T CD8-positivos , Dermatomiositis , Interferón Tipo I , Músculo Esquelético , Transducción de Señal , Humanos , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Interferón Tipo I/metabolismo , Animales , Músculo Esquelético/inmunología , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Ratones , Transducción de Señal/inmunología , Autoantígenos/inmunología , Femenino , Dermatomiositis/inmunología , Dermatomiositis/patología , Dermatomiositis/metabolismo , Masculino , Niño , Modelos Animales de Enfermedad , Adolescente , PreescolarRESUMEN
Immune checkpoint therapies (ICT) can induce life-threatening immune-related adverse events, including myocarditis and myositis, which are rare but often concurrent. The molecular pathways and immune subsets underlying these toxicities remain poorly understood. To address this need, we performed single-cell RNA sequencing of heart and skeletal muscle biopsies obtained from living patients with cancers treated with ICTs and admitted to the hospital with myocarditis and/or myositis (overlapping myocarditis plus myositis, n = 10; myocarditis-only, n = 1) or ICT-exposed patients ruled out for toxicity utilized as controls (n = 9). All biopsies were obtained within 96 hours of clinical presentation. Analyses of 58,523 cells revealed CD8+ T cells with a cytotoxic phenotype expressing activation/exhaustion markers in both myocarditis and myositis. Furthermore, the analyses identified a population of myeloid cells expressing tissue-resident signatures and FcγRIIIa (CD16a), which is known to bind IgG and regulate complement activation. Immunohistochemistry of affected cardiac and skeletal muscle tissues revealed protein expression of pan-IgG and complement product C4d, which were associated with the presence of high-titer serum autoantibodies against muscle antigens in a subset of patients. We further identified a population of inflammatory IL1B+TNF+ myeloid cells specifically enriched in myocarditis and associated with greater toxicity severity and poorer clinical outcomes. These results provide insight into the myeloid subsets present in human immune-related myocarditis and myositis tissues and nominate new targets for investigation into rational treatments to overcome these high-mortality toxicities. See related Spotlight by Fankhauser et al., p. 954.
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Miocarditis , Miositis , Humanos , Miocarditis/inmunología , Miositis/inmunología , Masculino , Femenino , Persona de Mediana Edad , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Anciano , Neoplasias/inmunología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Adulto , Receptores de IgG/metabolismo , Músculo Esquelético/inmunología , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Análisis de la Célula IndividualRESUMEN
Muscle regeneration is a complex process orchestrated by multiple steps. Recent findings indicate that inflammatory responses could play central roles in bridging initial muscle injury responses and timely muscle injury reparation. The various types of immune cells and cytokines have crucial roles in muscle regeneration process. In this review, we provide an overview of the functions of acute inflammation in muscle regeneration.
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Sistema Inmunológico , Músculo Esquelético , Regeneración , Regeneración/inmunología , Regeneración/fisiología , Animales , Humanos , Músculo Esquelético/fisiología , Músculo Esquelético/inmunología , Inflamación/inmunología , Citocinas/metabolismoRESUMEN
Exercise has long been acknowledged for its powerful disease-preventing, health-promoting effects. However, the cellular and molecular mechanisms responsible for the beneficial effects of exercise are not fully understood. Inflammation is a component of the stress response to exercise. Recent work has revealed that such inflammation is not merely a symptom of exertion; rather, it is a key regulator of exercise adaptations, particularly in skeletal muscle. The purpose of this piece is to provide a conceptual framework that we hope will integrate exercise immunology with exercise physiology, muscle biology, and cellular immunology. We start with an overview of early studies in the field of exercise immunology, followed by an exploration of the importance of stromal cells and immunocytes in the maintenance of muscle homeostasis based on studies of experimental muscle injury. Subsequently, we discuss recent advances in our understanding of the functions and physiological relevance of the immune system in exercised muscle. Finally, we highlight a potential immunological basis for the benefits of exercise in musculoskeletal diseases and aging.
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Adaptación Fisiológica , Ejercicio Físico , Músculo Esquelético , Humanos , Músculo Esquelético/inmunología , Músculo Esquelético/fisiología , Ejercicio Físico/fisiología , Adaptación Fisiológica/inmunología , Animales , Inflamación/inmunologíaRESUMEN
Balenine is one of the endogenous imidazole dipeptides derived from marine products. It is composed of beta-alanine and 3-methyl-L-histidine, which exist mainly in the muscles of marine organisms. The physiological functions of dietary balenine are not well-known. In this study, we investigated whether the supplementation of dietary balenine was associated with muscle function in a cardiotoxin-indued muscle degeneration/regeneration model. Through morphological observation, we found that the supplementation of balenine-enriched extract promoted the regeneration stage. In addition, the expression of regeneration-related myogenic marker genes, such as paired box protein 7, MyoD1, myogenin, and Myh3, in a group of mice fed a balenine-enriched extract diet was higher than that in a group fed a normal diet. Moreover, the supplementation of balenine-enriched extract promoted the expression of anti-inflammatory cytokines as well as pro-inflammatory cytokines at the degeneration stage. Interestingly, phagocytic activity in the balenine group was significantly higher than that in the control group in vitro. These results suggest that balenine may promote the progress of muscle regeneration by increasing the phagocytic activity of macrophages.
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Dipéptidos , Macrófagos , Músculo Esquelético , Fagocitosis , Animales , Citocinas/metabolismo , Dipéptidos/metabolismo , Dipéptidos/farmacología , Imidazoles/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/fisiología , Ratones , Músculo Esquelético/inmunología , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiología , Fagocitosis/efectos de los fármacosRESUMEN
Hydroxyl-methyl-glutaryl-Co-A reductase (HMGCR) immune mediated necrotising myopathy (IMNM) is a rare autoimmune myositis that is thought to be triggered by statins and responds to immunomodulation. We report a case of a woman in her 30s with HMGCR IMNM without a history of statin exposure who had a clear flare of her myositis after beginning mushroom supplements. Mushrooms are natural HMGCR inhibitors, and this is the first case to demonstrate a flare triggered by mushrooms in a patient with known HMGCR IMNM. This case highlights the importance of reviewing diet and supplements in patients with IMNM. It also emphasises the importance of strict statin avoidance for patients with IMNM even when the myositis is under good control.
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Agaricales , Enfermedades Autoinmunes , Suplementos Dietéticos , Enfermedades Musculares , Adulto , Autoanticuerpos/inmunología , Enfermedades Autoinmunes/inducido químicamente , Enfermedades Autoinmunes/diagnóstico , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/patología , Suplementos Dietéticos/efectos adversos , Femenino , Humanos , Hidroximetilglutaril-CoA Reductasas/efectos adversos , Hidroximetilglutaril-CoA Reductasas/inmunología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Músculo Esquelético/inmunología , Músculo Esquelético/patología , Enfermedades Musculares/inducido químicamente , Enfermedades Musculares/diagnóstico , Enfermedades Musculares/inmunología , Enfermedades Musculares/patología , Miositis/inducido químicamente , Miositis/diagnóstico , Miositis/inmunología , Miositis/patología , Necrosis/inducido químicamente , Necrosis/inmunología , Fitoterapia/efectos adversos , Brote de los SíntomasRESUMEN
Bariatric surgery (BS) is an effective treatment for obesity. Adipose tissue, liver tissue and skeletal muscle are important metabolic tissues. This study investigated hub genes and their association with immune infiltration in these metabolic tissues of obese patients after BS by bioinformatic analysis with Gene Expression Omnibus datasets. Differentially expressed genes (DEGs) were identified, and a protein-protein interaction network was constructed to identify hub genes. As a result, 121 common DEGs were identified and mainly enriched in cytokine-cytokine receptor interactions, chemokine signaling pathway, neutrophil activation and immune responses. Immune cell infiltration analysis showed that the abundance of M1 macrophages was significantly lower in adipose and liver tissue after BS (p<0.05). Ten hub genes (TYROBP, TLR8, FGR, NCF2, HCK, CCL2, LAPTM5, MNDA and S100A9) that were all downregulated after BS were also associated with immune cells. Consistently, results in the validated dataset showed that the expression levels of these hub genes were increased in obese patients and mice, and decreased after BS. In conclusion, this study analysed the potential immune and inflammatory mechanisms of BS in three key metabolic tissues of obese patients, and revealed hub genes associated with immune cell infiltration, thus providing potential targets for obesity treatment.
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Cirugía Bariátrica , Fenómenos del Sistema Inmunológico , Obesidad , Tejido Adiposo/inmunología , Animales , Quimiocinas , Citocinas , Perfilación de la Expresión Génica , Humanos , Fenómenos del Sistema Inmunológico/genética , Hígado/inmunología , Ratones , Músculo Esquelético/inmunología , Neutrófilos , Obesidad/complicaciones , Obesidad/genética , Obesidad/metabolismo , Receptores de CitocinasRESUMEN
Volumetric muscle loss (VML) overwhelms the innate regenerative capacity of mammalian skeletal muscle (SkM), leading to numerous disabilities and reduced quality of life. Immune cells are critical responders to muscle injury and guide tissue resident stem cell and progenitor-mediated myogenic repair. However, how immune cell infiltration and intercellular communication networks with muscle stem cells are altered following VML and drive pathological outcomes remains underexplored. Herein, we contrast the cellular and molecular mechanisms of VML injuries that result in the fibrotic degeneration or regeneration of SkM. Following degenerative VML injuries, we observed the heightened infiltration of natural killer (NK) cells as well as the persistence of neutrophils beyond 2 wk postinjury. Functional validation of NK cells revealed an antagonistic role in neutrophil accumulation in part via inducing apoptosis and CCR1-mediated chemotaxis. The persistent infiltration of neutrophils in degenerative VML injuries was found to contribute to impairments in muscle stem cell regenerative function, which was also attenuated by transforming growth factor beta 1 (TGFß1). Blocking TGFß signaling reduced neutrophil accumulation and fibrosis and improved muscle-specific force. Collectively, these results enhance our understanding of immune cellstem cell cross talk that drives regenerative dysfunction and provide further insight into possible avenues for fibrotic therapy exploration.
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Células Asesinas Naturales , Músculo Esquelético , Enfermedades Musculares , Neutrófilos , Regeneración , Células Satélite del Músculo Esquelético , Animales , Fibrosis , Células Asesinas Naturales/inmunología , Ratones , Músculo Esquelético/inmunología , Músculo Esquelético/patología , Enfermedades Musculares/inmunología , Enfermedades Musculares/patología , Infiltración Neutrófila , Neutrófilos/inmunología , Regeneración/inmunología , Células Satélite del Músculo Esquelético/inmunología , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
Dysregulation of the balance between pro-inflammatory and anti-inflammatory macrophages has a key function in the pathogenesis of Duchenne muscular dystrophy (DMD), a fatal genetic disease. We postulate that an evolutionarily ancient protective mechanism against infection, known as trained immunity, drives pathological inflammation in DMD. Here we show that bone marrow-derived macrophages from a murine model of DMD (mdx) exhibit cardinal features of trained immunity, consisting of transcriptional hyperresponsiveness associated with metabolic and epigenetic remodeling. The hyperresponsive phenotype is transmissible by bone marrow transplantation to previously healthy mice and persists for up to 11 weeks post-transplant. Mechanistically, training is induced by muscle extract in vitro. The functional and epigenetic changes in bone marrow-derived macrophages from dystrophic mice are TLR4-dependent. Adoptive transfer experiments further support the TLR4-dependence of trained macrophages homing to damaged muscles from the bone marrow. Collectively, this suggests that a TLR4-regulated, memory-like capacity of innate immunity induced at the level of the bone marrow promotes dysregulated inflammation in DMD.
Asunto(s)
Trasplante de Médula Ósea , Inmunidad Innata/inmunología , Macrófagos/inmunología , Músculo Esquelético/patología , Distrofia Muscular de Duchenne/patología , Receptor Toll-Like 4/inmunología , Animales , Células de la Médula Ósea/inmunología , Línea Celular , Modelos Animales de Enfermedad , Inflamación/inmunología , Células L , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos mdx , Ratones Noqueados , Músculo Esquelético/inmunología , Distrofia Muscular de Duchenne/inmunología , Extractos de Tejidos/farmacología , Transcripción Genética/genéticaRESUMEN
Endurance exercise induces various adaptations that yield health benefits; however, the underlying molecular mechanism has not been fully elucidated. Given that it has recently been accepted that inflammatory responses are required for a specific muscle adaptation after exercise, this study investigated whether toll-like receptor (TLR) 4, a pattern recognition receptor that induces proinflammatory cytokines, is responsible for exercise-induced adaptations in mouse skeletal muscle. The TLR4 mutant (TLR4m) and intact TLR4 control mice were each divided into 2 groups (sedentary and voluntary wheel running) and were housed for six weeks. Next, we removed the plantaris muscle and evaluated the expression of cytokines and muscle regulators. Exercise increased cytokine expression in the controls, whereas a smaller increase was observed in the TLR4m mice. Mitochondrial markers and mitochondrial biogenesis inducers, including peroxisome proliferator-activated receptor beta and heat shock protein 72, were increased in the exercised controls, whereas this upregulation was attenuated in the TLR4m mice. In contrast, exercise increased the expression of molecules such as peroxisome proliferator-activated receptor-gamma coactivator 1-alpha and glucose transporter 4 in both the controls and TLR4m mice. Our findings indicate that exercise adaptations such as mitochondrial biogenesis are mediated via TLR4, and that TLR4-mediated inflammatory responses could be involved in the mechanism of adaptation.