Abstract
This study provides a comprehensive evaluation of the cutaneous adipose tissue (CAT) transcriptome in patients with psoriasis and investigates the effects of IL-17 blockade on CAT inflammation through a randomized placebo-controlled trial using secukinumab (ObePso-S study, ClinicalTrials.gov NCT03055494). RNA sequencing analysis of CAT biopsies from 82 patients with psoriasis revealed 2132 differentially expressed transcripts compared with healthy controls. Notably, significant gene dysregulation was observed in both lesional skin (LS)-CAT and non-lesional (NL)-CAT, including activation of IL-17–driven pathways, antimicrobial peptide–related, and neutrophil degranulation signatures. Stratification by obesity demonstrated that obese psoriatic CAT exhibited a more than 2-fold higher number of differentially expressed genes than non-obese counterparts, suggesting a synergistic interaction between psoriasis and obesity in driving CAT inflammation. Treatment with secukinumab markedly improved inflammatory signatures in psoriatic CAT, with greater improvements observed in obese patients. These findings reveal a pronounced and partially IL-17–dependent inflammatory phenotype in psoriatic CAT, challenge the conventional concept of psoriasis as a solely superficial skin disease, and highlight CAT as an important contributor to systemic inflammation in psoriasis.
Authors
Naomi Shishido-Takahashi, Sandra Garcet, Inna Cueto, Hong Beom Hur, Elisa Muscianisi, Jennifer Steadman, Andrew Blauvelt, James G. Krueger
Abstract
Adeno-associated viruses (AAVs) have been used in gene therapy, especially for inherited retinal diseases. Despite their effectiveness in gene transduction, immune responses to the AAV capsid and transgene products have been reported, which can compromise both the efficacy and the safety of AAV-mediated therapies. The eye is regarded as an immune-privileged organ where immune activity is constitutively suppressed. Here, we highlight that immunomonitoring in an ocular gene transfer reveals variable immune responses, whatever the species (human clinical trial, nonhuman primates, mice), the site of injection, the cassette, and the dose. We further explored factors contributing to this variability, investigating the potential correlation among immune parameters in a controlled experimental setting. In a syngeneic murine model after a subretinal injection of AAV, our results highlight an interindividual variability of immune parameters, emphasizing the importance of considering inherent variability among individuals when designing personalized therapies.
Authors
Duohao Ren, Gaelle A. Chauveau, Julie Vendomele, Emilie Cabon, Audrey Pineiro, Catherine Vignal-Clermont, Hanadi Saliba, Giuseppe Ronzitti, Anne Galy, Deniz Dalkara, Juliette Pulman, Divya Ail, Sylvain Fisson
Abstract
Short QT syndrome is a heritable arrhythmia disorder linked to sudden cardiac death. We recently identified that individuals with alternating hemiplegia of childhood (AHC), a rare neurodevelopmental disorder, can exhibit shortened corrected QT intervals and elevated risk for ventricular fibrillation. This is especially true for patients with AHC heterozygous for the recurrent ATP1A3-D801N variant, though the underlying cardiac mechanism remains unclear. We hypothesized that the D801N missense impairs Na+/K+-ATPase function, causing Ca2+ overload, shortened action potential duration (APD), and arrhythmias. Using in silico modeling and patient-derived induced pluripotent stem cell cardiomyocytes (iPSC-CMsD801N), we observed shorter APD, elevated intracellular and sarcoplasmic reticulum Ca2+ levels, and delayed afterdepolarizations (DADs) compared with WT. Additionally, increased Ca²+ influx via the Na+/Ca2+ exchanger (NCX1) during depolarization was observed in iPSC-CMsD801N. Simulations and in vitro experiments suggest that reduced ATPase function accelerated inactivation of L-type Ca2+ channels. Pharmacologic inhibition of NCX1 with ORM-10103 normalized APD and reduced DADs. These findings support a Ca2+-mediated mechanism for arrhythmogenesis in ATP1A3-D801N carriers and identify NCX1 as a potential therapeutic target.
Authors
Minu-Tshyeto K. Bidzimou, Padmapriya Muralidharan, Zhushan Zhang, Danyal Raza, Daniel Needs, Bo Sun, Robin M. Perelli, Mary E. Moya-Mendez, P.K. Rakesh Manivannan, Arsen S. Hunanyan, Abbigail Helfer, Christine Q. Simmons, Alfred L. George Jr., Donald M. Bers, Nenad Bursac, Mohamad A. Mikati, Andrew P. Landstrom
Abstract
Supernumerary centrosomes are a hallmark of cancer. To maintain viability, cancer cells cluster these centrosomes during mitosis, enabling bipolar division similar to that of normal cells. Disruption of this centrosome clustering leads to multipolar anaphase and apoptosis (anaphase catastrophe), which selectively eliminates cancer cells harboring supernumerary centrosomes. In this context, because the motor protein KIFC1 contributes to centrosome clustering, we investigated whether targeting of this mechanism through KIFC1 inhibition could be exploited in small-cell lung cancer (SCLC), an aggressive malignancy with limited treatment options and poor prognosis. Through in silico and in vitro analyses, as well as IHC of clinical samples, we found that KIFC1 is overexpressed and that centrosome amplification occurs more frequently in SCLC compared with normal tissues and other cancer types. Pharmacological and genetic inhibition of KIFC1 disrupted the clustering of supernumerary centrosomes, triggered multipolar mitosis, and exerted antineoplastic effects in SCLC cells, with minimal effects on noncancerous cells. These findings were validated and extended in vivo using SCLC xenograft models. Finally, cotargeting KIFC1 and the centrosome duplication regulator PLK4 further enhanced growth suppression in SCLC cells. Together, these results suggest that disrupting centrosome clustering and triggering anaphase catastrophe via KIFC1 inhibition may represent a promising therapeutic strategy for SCLC.
Authors
Natsuki Nakagawa, Minemichi Toda, Akiko Kunita, Masafumi Horie, Masakatsu Tokunaga, Hiroaki Ikushima, Mirei Ka, Takahiro Iida, Manabu Shigeoka, Yukinobu Ito, Takahiro Ando, Kousuke Watanabe, Yasunori Ota, Xi Liu, Ethan Dmitrovsky, Hidenori Kage, Masanori Kawakami
Abstract
Antiretroviral therapy (ART) has prolonged the life expectancy of persons living with HIV, the majority of whom are now older than 50 years. Aging people with HIV are at increased risk for cardiovascular events driven by HIV-related inflammation and hypercoagulation. Apixaban is a factor Xa inhibitor that reduces cardiovascular risks and treats stroke, deep vein thrombosis, and pulmonary embolism. We assessed apixaban’s impact on key parameters of HIV/SIV pathogenesis in SIV-infected, aged rhesus macaques (RMs) receiving ART. Inflammation, coagulation, T cell subsets, B cells, and macrophages and their immune activation status were monitored throughout the study. We found no significant differences between the apixaban-treated and control groups for virus replication or CD4+ T cell recovery in blood and tissues after ART. Apixaban did not significantly affect D-dimer, immune activation, or inflammation of SIV-infected, ART-treated RMs. Apixaban-treated RMs experienced multiple bleeding episodes, tissue hemorrhages, and myocardial infarctions, as demonstrated by pathological examination of necropsy-collected tissues. Given apixaban’s lack of effect on immune activation, CD4+ T cell restoration, and inflammation, along with increased risk of hemorrhage, factor Xa inhibition may not be an efficient or safe option to target and prevent cardiovascular events in aging people with HIV.
Authors
Cuiling Xu, Haritha Annapureddy, Lilly Carson, Vansh Khurana, Ranjit Sivanandham, Sindhuja Sivanandham, Tianyu He, Kevin D. Raehtz, Janet Kim, Christie Biber, Norma Arbujas-Silva, Mohammed Daira, Sudhapriya Kandasamy, Matthew J. Feinstein, Irini Sereti, Cristian Apetrei, Ivona Pandrea
Abstract
At-home blood collection devices (ABCDs) can facilitate study participation for remote and rural cohorts. Previous studies used ABCDs to interrogate samples by proteomics and sequencing approaches. We wanted to address the question of whether this approach could be used to assess live immune cells with high-parameter flow cytometry to enable remote immune monitoring. We first compared blood from standard venipuncture with ABCD blood draws, followed by assessment of the impact of sample shipping on immune cell viability and phenotyping. We found that capillary blood collected with a Tasso+ device and concurrently drawn venipuncture blood samples had highly congruent immune cell composition and phenotype. Shipment of Tasso+ samples via the United States Postal Service altered the myeloid compartment, but T cell numbers, subsets, and phenotypes remained remarkably stable compared with non-shipped samples. Finally, we describe a flow cytometry analysis framework that allowed for direct sample comparison even when samples were stained and analyzed over a time period of 1.5 years. Overall, our data highlight the feasibility of using ABCDs combined with subsequent flow cytometry analysis for remote immune monitoring. Additionally, our study also identifies areas that could be improved to further promote the use of ABCDs for immune monitoring.
Authors
Andrew J. Konecny, Fang Yun Lim, Eva Domenjo-Vila, Erika Lovas, Rachel L. Blazevic, Louise E. Kimball, Michael Boeckh, Alpana Waghmare, Martin Prlic
Vancomycin eliminates gut deoxycholic acid, restoring ER proteostasis in ILC2s and relieving colitis
Abstract
Ulcerative colitis (UC) remission is marked by gut microbiota restructuring, but how microbial metabolites influence immune-mediated tissue repair is unclear. Here, we demonstrate that oral vancomycin alleviates colitis symptoms in murine models, mirroring its clinical efficacy in inducing remission in patients with UC. Mechanistically, vancomycin’s therapeutic effect is achieved by reducing deoxycholic acid (DCA). We reveal that DCA impairs mucosal repair driven by group 2 innate lymphoid cells (ILC2s) by inducing ER stress through direct binding to thioredoxin-related transmembrane protein 2 (TMX2). This interaction disrupts TMX2’s role in protein folding, triggering unresolved unfolded protein response via hyperactivation of PERK/eIF2α signaling, which suppresses the production of pro-healing molecules by ILC2s. Pharmacological inhibition of PERK phosphorylation restores ILC2 function and accelerates colitis resolution. Our work uncovers a pathogenic microbiota/DCA/ILC2 axis that obstructs mucosal healing and positions vancomycin as a targeted strategy to eliminate DCA, thereby promoting UC remission.
Authors
Qiuheng Tian, Han Liu, Xiang Gu, Jing Shen, Xi Yuan, Mengqi Zheng, Yunjiao Zhai, Yatai Chen, Penghu Han, Yangchun Ma, Wei Xin, Hongyue Ma, Yu Li, Sihan Wang, Lei Guo, Detian Yuan, Yanbo Yu, Shiyang Li
Abstract
Giant cell aortitis (GCA) is an inflammatory disease of the aortic wall with a characteristic giant cell pattern on pathology and can lead to life-threatening aortic aneurysm and dissection. Pathogenic GCA mechanisms underlying aortic inflammation and persistence remain elusive. Here, we demonstrate the complexity of medial layer destruction and immune cell infiltration in clinical granulomatous GCA and lymphoplasmacytic IgG4-related aortitis samples using imaging-based gene expression profiling. Single-cell spatial profiling revealed aortic wall remodeling in the GCA aortas, highlighting substantial phenotypic modulation in stromal cells, including vascular smooth muscle cells (SMCs) and fibroblasts. Specifically, we observed the expansion of stromal cells expressing Tenascin-C (TNC) mRNA and spatially refined TNC accumulation in lesion areas. We confirmed these findings histologically using diseased aortas resected from individuals with giant cell arteritis and clinically isolated aortitis. Mechanistically, our data suggest that TNC promotes a proinflammatory phenotype in primary human SMCs, elevating IL-6 levels partially through the TLR4/NF-κB pathway. IL-6 signaling propagates the proinflammatory loop by activating STAT3. Pharmacological blockade of the IL-6 receptor using tocilizumab alleviated the TNC-driven proinflammatory phenotype. We propose that TNC acts as a local catalyst of inflammatory disease persistence mainly via IL-6 signaling activation and offers a potential avenue for sustained disease remission.
Authors
Hui Shi, Ying Tang, Jing Li, Ora Gewurz-Singer, Bo Yang, Dogukan Mizrak
Abstract
Temporomandibular joint osteoarthritis (TMJOA), a prevalent subtype of temporomandibular disorders, is characterized by progressive cartilage degradation and subchondral bone destruction. Despite advancements in understanding TMJOA pathogenesis, the molecular mechanisms underlying its progression remain unclear. In this study, elevated Slit guidance ligand 2 (SLIT2) expression was observed in TMJ tissues of unilateral anterior crossbite–induced TMJOA mice and synovial fluid from patients with TMJOA, correlating with disease severity. Furthermore, SLIT2 overexpression in transgenic mice intensified TMJOA progression, whereas heterozygous deletion of roundabout guidance receptor 1/2 (ROBO1/2) alleviated cartilage and bone damage. Mechanistically, SLIT2 promoted ROBO1-LRP6 complex formation, facilitating LRP6 phosphorylation and β-catenin nuclear translocation. This cascade upregulated matrix-degrading enzymes while downregulating cartilage structural proteins, exacerbating cartilage destruction and subchondral bone loss. These findings suggest that the SLIT2/ROBO1/LRP6 axis may represent a potential therapeutic target for TMJOA and provide mechanistic insights into disease progression.
Authors
Guan Luo, Baoyi Chen, Wenjun Chen, Huiyi Lin, Weiqi Guo, Qingbin Zhang, Jiang Li, Lijing Wang, Janak Lal Pathak, Yuhui Yang, Weijun Zhang, Xiaoyu Zhang, Beining Zheng, Ziyi Wang, Shiting Wei, Jiaxin He, Wei-Jie Zhou, Chang Liu
Abstract
Current treatment protocols for most types of cancers require chemotherapeutic agents that are associated with significant side effects, including chemotherapy-induced peripheral neuropathy (CIPN). Currently, there are no effective CIPN prevention strategies, and current treatment approaches remain limited. The enzyme purine nucleoside phosphorylase (PNPase) actively modulates both oxidative injury and cellular damage. Here, we tested the hypothesis that the signs and symptoms of CIPN are due to a chemotherapy-induced dysregulation of the purine metabolome. We assessed the effect of PNPase inhibition on paclitaxel-induced (PAC-induced) CIPN. Female adult Sprague-Dawley rats were treated with PAC and randomized to oral treatment with either the PNPase inhibitor 8-aminoguanine (8-AG) or its vehicle. Some rats were injected with shRNA against PNPase prior to PAC injections. PAC-treated rats exhibited multiple abnormalities: mechanical allodynia and changes in damaging purines, intraepidermal nerve fiber (IENF) density, and signaling cascades involved in mitochondrial disruption and axonal damage. Inhibition of PNPase improved behavioral function (mechanical allodynia), rescued the loss/damage of IENF, and normalized markers for mitochondrial dysfunction and nerve damage. These findings support the hypothesis that inhibition of PNPase prevented (and potentially reversed) CIPN through several mechanisms that included a reduction in neuronal damage and development of mechanical allodynia.
Authors
Lori A. Birder, Amanda Wolf-Johnston, Jonathan Franks, Mara L.G. Sullivan, Simon C. Watkins, Anthony J. Kanai, Vladimir B. Ritov, Edwin K. Jackson
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