Abstract
Acute severe joint pain is a major symptom in gouty arthritis (GA), and its adequate treatment represents an unmet medical need. Mrgprb2, a specific mast cell receptor, has been implicated in the generation of chronic pain by mobilizing mast cell degranulation, yet its significance in GA pain and joint inflammation is still not well defined. Here, we found that Mrgprb2 was expressed in mouse synovial mast cells. In a murine model of GA, acute blockade or genetic deletion of Mrgprb2 significantly attenuated arthritis pain and hyperexcitability of joint nociceptors with significant reductions in innate immune cell recruitment in the synovium. Under naive conditions, activation of synovial Mrgprb2 was sufficient to excite peripheral terminals of joint nociceptors to induce acute joint hypernociception via the mobilization of mast cell degranulation. Additionally, the level of the neuropeptide substance P (SP) was elevated in the synovium of GA model mice. Using humanized MRGPRX2-knockin mice, we revealed that SP contributed to joint pain and inflammation by activating mast cells through Mrgprb2/MRGPRX2. These findings suggest that synovial mast cell–expressed Mrgprb2/MRGPRX2 merits consideration as a key neuroimmune player and a potential therapeutic target for treating GA pain and joint inflammation.
Authors
Lin Yang, Chengxi Liu, Jin Xiao, Yu Song, Huan Chen, Dan Li, Cong Zou, Tao Hong, Yinglan Liu, Dake Qi, Nathachit Limjunyawong, Wenjie Liu, Lintao Qu
Abstract
Mitochondria-derived acyl-coenzyme A (acyl-CoA) species chemically modify proteins, causing damage when acylation reactions are not adequately detoxified by enzymatic removal or protein turnover. Defects in genes encoding the mitochondrial respiratory complex and TCA cycle enzymes have been shown to increase acyl-CoA levels due to reduced enzymatic flux and result in proteome-wide hyperacylation. How pathologically elevated acyl-CoA levels contribute to bioenergetics failure in mitochondrial diseases is not well understood. Here, we demonstrate that bulk succinylation from succinyl-CoA excess consumes the enzymatic cofactor NAD+ and propagates mitochondrial respiratory defects in a zebrafish model of succinyl-CoA ligase deficiency, a childhood-onset encephalomyopathy. To explore this mechanism as a therapeutic target, we developed a workflow to monitor behavioral defects in sucla2–/– zebrafish and show that hypersuccinylation is associated with reduced locomotor behavior and impaired ability to execute food hunting patterns. Postembryonic NAD+ precursor supplementation restores NAD+ levels and improves locomotion and survival of sucla2–/– zebrafish. Mechanistically, nicotinamide and nicotinamide riboside require the NAD+-dependent desuccinylase Sirt5 to enhance oxidative metabolism and nitrogen elimination through the urea cycle. Collectively, NAD+ supplementation activates Sirt5 to protect against damage to mitochondria and locomotor circuits caused by protein succinylation.
Authors
Joy Richard, Giulia Lizzo, Noélie Rochat, Adrien Jouary, Pedro T.M. Silva, Alice Parisi, Stefan Christen, Sofia Moco, Michael B. Orger, Philipp Gut
Abstract
Survival in chronic myeloid leukemia (CML) was dramatically improved by development of tyrosine kinase inhibitors (TKIs) directed to the BCR:ABL1 oncogene. Unfortunately, ~30% of patients with CML develop TKI resistance during prolonged treatment, with enhanced blast crisis risk. Oxidation Resistance 1 (Oxr1) regulates antioxidant pathways that detoxify reactive oxygen species (ROS) generated by the phagocyte-NADPH oxidase. In the current studies, we found that Oxr1 expression increased in hematopoietic stem and progenitor cells (HSPCs) from CML mice versus controls, decreased during TKI-induced remission, and rose during chronic phase relapse. Oxr1 has long and short isoforms, and we found increased short, but decreased long, Oxr1 in mice or humans during CML relapse. We determined that long Oxr1 prevents ROS accumulation in CML marrow, but short Oxr1 is a dominant negative. Previously, we found exaggerated and sustained emergency granulopoiesis in CML mice, with repeated episodes facilitating relapse during TKI remission. In the current studies, we found knocking down Oxr1 in murine marrow further accelerated CML progression during this physiologic stress. We found increased DNA-damage in HSPCs from these mice, including a BCR:ABL1 kinase-domain mutation found in TKI-resistant human CML. These studies suggest that long Oxr1 detoxifies ROS to decrease mutagenesis in CML, but aberrant short Oxr1 expression enhances progression.
Authors
Weiqi Huang, Bin Liu, Liping Hu, Chi-Hao Luan, Priyam Patel, Elizabeth Bartom, Elizabeth A. Eklund
Abstract
Metabolic inflammation is closely linked to dynamic changes in circulating monocyte populations, yet how nutritional signals regulate this process remains unclear. ANGPTL8, a hepatokine rapidly induced by refeeding, emerged as a key regulator of postprandial monocyte dynamics. We examined ANGPTL8 expression in human and murine fasting-refeeding models and manipulated ANGPTL8 expression specifically in hepatocytes to assess its role in metabolic inflammation and insulin resistance in obese mice. ANGPTL8 overexpression elevated levels of circulating monocytes and proinflammatory cytokines, while its deletion reduced these parameters and conferred metabolic benefits. Mechanistically, recombinant ANGPTL8 stimulated CCL5 production in bone marrow–derived macrophages via P38 signaling activation, promoting monocyte recruitment and proinflammatory macrophage polarization. These effects were mitigated by CCR5 antagonism. Rescue experiments demonstrated that CCL5 supplementation in Angptl8-deficient mice restored monocyte levels and inflammatory responses. Functionally, ANGPTL8 worsened insulin resistance and glucose intolerance in obese mice, effects that were reversed by its deletion and recapitulated by CCL5 administration. These findings suggest that ANGPTL8 functions as a nutritional checkpoint that links feeding status to monocyte-mediated inflammation through the CCL5-CCR5 axis. By driving monocytosis and proinflammatory macrophage activation, ANGPTL8 exacerbates metabolic dysfunction. Targeting the ANGPTL8-CCL5-CCR5 pathway may therefore offer a promising therapeutic strategy for managing obesity-related metabolic diseases.
Authors
Ran-Ran Kan, Si-Yi Wang, Xiao-Yu Meng, Li Huang, Yu-Xi Xiang, Bei-Bei Mao, Hua-Jie Zou, Ya-Ming Guo, Li-Meng Pan, Pei-Qiong Luo, Yan Yang, Zhe-Long Liu, De-Lin Ma, Wen-Jun Li, Yong Chen, Dan-Pei Li, Xue-Feng Yu
Abstract
Acute rheumatic fever (ARF) and associated rheumatic heart disease are serious sequelae after infection with group A Streptococcus (Strep A). Autoantibodies are thought to contribute to pathogenesis, with deeper exploration of the autoantibody repertoire needed to improve mechanistic understanding and identify new biomarkers. Phage immunoprecipitation sequencing (PhIP-Seq) with the HuScan library (>250,000 overlapping 90-mer peptides spanning the human proteome) was utilized to analyze autoreactivity in sera from children with ARF, uncomplicated Strep A pharyngitis, and matched healthy controls. A global proteome-wide increase in autoantigen reactivity was observed in ARF, as was marked heterogeneity between patients. Public epitopes, common between individuals with ARF were rare, and comprised less than 1% of all enriched peptides. Differential analysis identified both unknown and previously identified ARF autoantigens, including PPP1R12B, a myosin phosphatase complex regulatory subunit expressed in cardiac muscle, and members of the collagen protein family, respectively. Pathway analysis found antigens from the disease-relevant processes encompassing sarcomere and heart morphogenesis were targeted. In sum, PhIP-Seq has substantially expanded the spectrum of autoantigens in ARF, and reveals the rarity of public epitopes in the disease. It provides further support for the role of epitope spreading in pathogenesis and has identified PPP1R12B as an enriched autoantigen.
Authors
Reuben McGregor, Lauren H. Carlton, Timothy J. O’Donnell, Elliot Merritt, Campbell R. Sheen, Florina Chan Mow, William John Martin, Michael G. Baker, Nigel Wilson, Uri Laserson, Nicole J. Moreland
Abstract
Cytomegalovirus (CMV) is a prevalent β-herpesvirus that persists asymptomatically in immunocompetent hosts. In people with HIV-1 (PWH), CMV is associated with HIV-1 persistence and particular inflammatory-related comorbidities. The true causative role of CMV in HIV-associated pathologies, however, remains unclear given that nearly all PWH are coinfected with CMV. In this study, we examined acute phase immune and virological dynamics in cohorts of SIV-infected rhesus macaques (RMs) that were naturally seropositive or -negative for rhesus CMV (RhCMV). We observed prior to SIV, RhCMV expanded a polyclonal population of target CCR5+CD4+ T cells in gut and lymph nodes that expressed the chemotactic receptor CXCR3 and were largely not specific for RhCMV. Upon SIV infection, RhCMV+ RMs exhibited higher peak viremia and elevated levels of SIV DNA in the upper and lower intestine. Greater seeding of SIV DNA was associated with a maintenance of CCR5-expressing CD4+ T cells that were enriched within the RhCMV+ gut along a CXCR3/CXCL9 chemotactic axis. Overall, the data suggest that RhCMV can promote SIV susceptibility within a diverse, polyclonal pool of CD4+ T cells that are not entirely RhCMV specific.
Authors
Chrysostomos Perdios, Naveen Suresh Babu, Celeste D. Coleman, Anna T. Brown, Shevon N. Alexander, Matilda J. Moström, Carolina Allers, Lara Doyle-Meyers, Christine M. Fennessey, Lori A. Rowe, Brandon F. Keele, Amitinder Kaur, Michael L. Freeman, Joseph C. Mudd
Abstract
Autoimmune diabetes encompasses rapidly progressive type 1 diabetes mellitus (T1D) and indolent latent autoimmune diabetes in adults (LADA), which represent distinct inflammatory set points along a shared autoimmune spectrum. Yet, the immunological mechanisms that determine these divergent inflammatory states remain unresolved. We performed single-cell RNA sequencing with paired T and B cell receptor profiling on over 400,000 PBMCs from patients with LADA, newly diagnosed T1D, and individuals acting as healthy controls. PBMC composition was comparable across cohorts, indicating that qualitative rather than quantitative immune differences underlie disease heterogeneity. In T1D, pan-lineage activation of NF-κB, EGFR, MAPK, and hypoxia pathways, coupled with a TNF-centered communication hub, enhanced MHC signaling, disrupted adhesion, and promoted systemic inflammation. LADA, by contrast, exhibited global suppression of NF-κB/EGFR activity, retention of moderate JAK/STAT tone, reinforced NK cell inhibitory checkpoints via HLA-C–KIR2DL3/3DL1 interaction, and stabilized CD8+ T cell synapses through HLA-C–CD8 binding, collectively restraining effector activation. Single-cell V(D)J analysis revealed multiclonal, patient-unique adaptive repertoires, emphasizing the primacy of signaling context over receptor convergence. These findings define autoimmune diabetes as an inflammatory-inhibitory set-point continuum, positioning the NF-κB/EGFR–JAK/STAT gradient and HLA-C–KIR axis as potential therapeutic targets to preserve residual β cell function.
Authors
Ivan I. Golodnikov, Elizaveta S. Podshivalova, Vadim I. Chechekhin, Anatoliy V. Zubritskiy, Alina A. Matrosova, Nikita A. Sergeev, Margarita D. Samsonova, Yaroslav V. Dvoryanchikov, Tatiana V. Nikonova, Ekaterina V. Bondarenko, Marina Yu. Loguinova, Yulia A. Medvedeva, Dmitry N. Laptev, Rita I. Khusainova, Ildar R. Minniakhmetov, Marina V. Shestakova, Natalia G. Mokrysheva, Ivan I. Dedov
Abstract
Juvenile idiopathic arthritis (JIA) is the most prevalent chronic inflammatory arthritis of childhood, yet the spatial organization in the synovium remains poorly understood. Here, we perform subcellular-resolution spatial transcriptomic profiling of synovial tissue from patients with active JIA. We identify diverse immune and stromal cell populations and reconstruct spatially defined cellular niches. Applying a newly developed spatial colocalization analysis pipeline, we uncover microanatomical structures, including endothelial-fibroblast interactions mediated by NOTCH signaling, and a CXCL9/CXCR3 signaling axis between inflammatory macrophages and CD8+ T cells, alongside the characterization of other resident macrophage subsets. We also detect and characterize tertiary lymphoid structures marked by CXCL13/CXCR5 and CCL19-mediated signaling from Tph cells and immunoregulatory DCs, analogous to those observed in other autoimmune diseases. Finally, comparative analysis with rheumatoid arthritis reveals JIA-enriched cell states, including NOTCH3+ and CXCL12+ sublining fibroblasts, suggesting potentially differential inflammatory programs in pediatric versus adult arthritis. These findings provide a spatially resolved molecular framework of JIA synovitis and introduce a generalizable computational pipeline for spatial colocalization analysis in tissue inflammation.
Authors
Jun Inamo, Roselyn Fierkens, Michael R. Clay, Anna Helena Jonsson, Clara Lin, Kari Hayes, Nathan Rogers, Heather Leach, Kentaro Yomogida
Abstract
Glioblastoma (GBM) is an aggressive brain tumor that often progresses despite resection and treatment. Timely and continuous assessment of GBM progression is critical to expedite secondary surgery or enrollment in clinical trials. However, current progression detection requires costly and specialized MRI examinations, which, in the absence of new symptoms or signs, are usually scheduled every 2–3 months. Here, we hypothesized that changes in daily activity are associated with GBM growth and disease progression. We found that wheel-running activity in GBM-bearing mice declined as tumors grew and preceded weight loss and circadian breakdown by over a week. Temozolomide treatment in the morning, but not evening, significantly reduced tumor size and restored daily locomotion in mice. In a pilot study of 6 patients with GBM wearing an actigraphy watch, wrist movement provided a feasible and continuous longitudinal indicator of daily activity with 1-minute resolution. After tumor resection and radiation, daily activity declined in 2 patients 19 and 55 days before detection of progression by MRI but did not change for the 4 patients with stable disease. These results suggest that daily activity tracking using wearable devices may serve as a real-time indicator and potential monitoring tool for GBM progression and treatment efficacy.
Authors
Maria F. Gonzalez-Aponte, Sofia V. Salvatore, Anna R. Damato, Ruth G.N. Katumba, Grayson R. Talcott, Omar H. Butt, Jian L. Campian, Jingqin Luo, Joshua B. Rubin, Olivia J. Walch, Erik D. Herzog
Abstract
FGF13, a noncanonical fibroblast growth factor (FGF) and member of the fibroblast growth factor homologous factor (FHF) subset, lacks a signal sequence and was previously reported to remain intracellular, where it regulates voltage-gated sodium channels (VGSCs) at least in part through direct interaction with the cytoplasmic C-terminus of VGSCs. Recent reports suggest FGF13 is secreted and regulates neuronal VGSCs through interactions with extracellular domains of integral plasma membrane proteins, yet supportive data are limited. Using rigorous positive and negative controls, we show that transfected FGF13 is not secreted from cultured cells in a heterologous expression system, nor is endogenous FGF13 secreted from cultured neurons. Furthermore, using multiple unbiased screens including proximity labeling proteomics, our results suggest FGF13 remains within membranes and is unavailable to interact directly with extracellular protein domains.
Authors
Mattia Malvezzi, Haiying Zhang, Patrick Towers, David C. Lyden, Steven O. Marx, Geoffrey S. Pitt
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