Inflammation
Abstract
Clonal hematopoiesis due to TET2-driver mutations (CH) is associated with coronary heart disease and worse prognosis among patients with aortic valve stenosis (AVS). However, it is unknown what role CH plays in the pathogenesis of AVS. In a meta-analysis of All Of Us, BioVU, and the UK Biobank, patients with CHIP exhibited an increased risk of AVS, with a higher risk among patients with TET2 or ASXL1 mutations. Single-cell RNA-sequencing of immune cells from AVS patients harboring TET2 CH-driver mutations revealed monocytes with heightened pro-inflammatory signatures and increased expression of pro-calcific paracrine signaling factors, most notably Oncostatin M (OSM). Secreted factors from TET2-silenced macrophages increased in vitro calcium deposition by mesenchymal cells, which was ablated by OSM silencing. Atheroprone Ldlr–/– mice receiving CH-mimicking Tet2–/– bone marrow transplants displayed greater calcium deposition in aortic valves. Together, these results demonstrate that monocytes with CH promote aortic valve calcification, and that patients with CH are at increased risk of AVS.
Authors
Wesley T. Abplanalp, Michael A. Raddatz, Bianca Schuhmacher, Silvia Mas-Peiro, María A. Zuriaga, Nuria Matesanz, José J. Fuster, Yash Pershad, Caitlyn Vlasschaert, Alexander J. Silver, Eric H. Farber-Eger, Yaomin Xu, Quinn S. Wells, Delara Shahidi, Sameen Fatima, Xiao Yang, Adwitiya A.P. Boruah, Akshay Ware, Maximilian Merten, Moritz von Scheidt, David John, Mariana Shumliakivska, Marion Muhly-Reinholz, Mariuca Vasa-Nicotera, Stefan Guenter, Michael R. Savona, Brian R. Lindman, Stefanie Dimmeler, Alexander G. Bick, Andreas M. Zeiher
Abstract
Influenza and other respiratory viral pathogens remain leading causes of mortality and morbidity. Circadian rhythms play a critical role in regulating immune responses and can confer temporal protection from influenza infection. Here, we investigated whether this protection requires rhythmic function after the initial infection by manipulating environmental cycles. We found that disrupting environmental lighting cues within a critical window of vulnerability abrogated the time-of-day-specific protection. This poor outcome was mediated by a dysregulated immune response, as evidenced by the accumulation of inflammatory monocytes and CD8+ T cells in the lungs and a transcriptomic profile indicative of an exaggerated inflammation. Disruption of the light cycle did not affect outcomes in a clock mutant, indicating that it acts through the host’s circadian clock. Importantly, rhythmic meal timing mitigated the adverse effects of disrupted light cycles, supporting the idea that external cues acting through different body clocks can compensate for one another. Together, these findings underscore the critical interplay between environmental timing cues and endogenous circadian rhythms in determining influenza outcomes and offer translational insight into optimizing care for critically ill patients with respiratory viral infections.
Authors
Oindrila Paul, Thomas G. Brooks, Alisha Shetty, Y. Jane Choi, Martina Towers, Lora J. Assi, James P. Garifallou, Kaitlyn Forrest, Alecia Cameron, Amita Sehgal, Gregory Grant, Shaon Sengupta
Abstract
Demyelination associated microglia (DMAM) orchestrate the regenerative response to demyelination by clearing myelin debris and promoting oligodendrocyte maturation. Peroxisomal metabolism has emerged as a candidate regulator of DMAMs, though the cell-intrinsic contribution in microglia remains undefined. Here we elucidate the role of peroxisome integrity in DMAMs using cuprizone mediated demyelination coupled with conditional knockout of peroxisome biogenesis factor 5 (PEX5) in microglia. Absent demyelination, PEX5 conditional knockout (PEX5cKO) had minimal impact on homeostatic microglia. However, during cuprizone-induced demyelination, the emergence of DMAMs unmasked a critical requirement for peroxisome integrity. At peak demyelination, PEX5cKO DMAMs exhibited increased lipid droplet burden and reduced lipophagy suggestive of impaired lipid catabolism. Although lipid droplet burden declined during the remyelination phase, PEX5cKO DMAMs accumulated intralysosomal crystals and curvilinear profiles, which features were largely absent in controls. Aberrant lipid processing was accompanied by elevated lysosomal damage markers and downregulation of the lipid exporter gene Apoe, consistent with defective lipid clearance. Furthermore, the disruptions in PEX5cKO DMAMs were associated with defective myelin debris clearance and impaired remyelination. Together, these findings delineate a stage-specific role for peroxisomes in coordinating lipid processing pathways essential to DMAM function and necessary for enabling a pro-remyelinating environment.
Authors
Joseph A. Barnes-Vélez, Xiaohong Zhang, Yaren L. Peña Señeriz, Kiersten A. Scott, Yinglu Guan, Jian Hu
Abstract
Colitis-associated cancer (CAC) arises from a complex interplay between host and environmental factors. In this report, we investigated the role of the gut microbiome using Winnie mice, a UC-like model with a missense mutation in the Muc2 gene. Upon rederivation from a conventional (CONV) to a specific-pathogen-free (SPF) facility, Winnie mice developed severe colitis and, notably, spontaneous CAC that progressively worsened over time. In contrast, CONV Winnie showed only mild colitis but no tumorigenesis. By comparison, when rederived into germ-free (GF) conditions, SPF Winnie mice were protected from colitis and colon tumors, indicating an essential role for the gut microbiome in the development of CAC in these mice. Using shotgun metagenomics, metabolomics, and lipidomics, we identified a distinct pro-inflammatory microbial and metabolic signature that potentially drives the transition from colitis to CAC. Fecal microbiota transplantation (FMT), using either SPF Winnie or WT (Bl/6) donors into GF Winnie recipients, demonstrated that while colitis developed regardless of the donor, only FMT from SPF Winnie donors resulted in CAC. Our studies present a relevant model of CAC, providing strong evidence that the microbiome plays a key role in its pathogenesis, thereby challenging the concept of colon cancer as a strictly non-transmissible disease.
Authors
Giulio Verna, Stefania De Santis, Bianca N. Islam, Eduardo M. Sommella, Danilo Licastro, Liangliang Zhang, Fabiano De Almelda Celio, Emily N. Miller, Fabrizio Merciai, Vicky Caponigro, Wei Xin, Pietro Campiglia, Theresa T. Pizarro, Marcello Chieppa, Fabio Cominelli
Abstract
Chronic inflammation leads to tissue fibrosis which can disrupt the function of the parenchyma of the organ and ultimately lead to organ failure. The most prevalent form of this occurs in chronic hepatitis which leads to liver fibrosis and, ultimately, cirrhosis and hepatic failure. Although there is no specific treatment for fibrosis, the phosphodiesterase 4 (PDE4) competitive inhibitors have been shown to ameliorate fibrosis in rodent models. However, competitive inhibitors of PDE4 have shown significantly reduced effectiveness due to severe gastrointestinal side effects. The PDE4 family is composed of four genes (PDE4A–D) with each having up to 9 differentially spliced isoforms. Here, we report that PDE4D expression is specifically elevated during the hepatic fibrosis stage of liver disease progression. Furthermore, the expression of the long isoforms of PDE4D is selectively elevated in activated hepatic stellate cells, leading to the enhanced accumulation of extracellular matrix components. In a mouse model of liver fibrosis, genetic ablation of PDE4D or pharmacological inhibition using D159687, a selective allosteric inhibitor targeting the long isoforms of PDE4D, suppresses the expression of inflammatory and profibrogenic genes. These findings establish the long isoforms of PDE4D as key drivers of liver fibrosis and highlight their potential as therapeutic targets to ameliorate liver fibrosis.
Authors
Jeonghan Kim, Heeeun Yoon, Seoung Chan Joe, Antoine Smith, Jinsung Park, Geunhye Hong, Ji Myeong Ha, Eun Bae Kim, Ekihiro Seki, Myung K. Kim, Hae-Ock Lee, Ho-Shik Kim, Jay H. Chung
Abstract
Authors
Jarne Beliën, Amber De Visscher, Bethany Pillay, Marjon Wouters, Verena Kienapfel, Eline Bernaerts, Tania Mitera, Nele Berghmans, Bénédicte Dubois, Leen Moens, Patrick Matthys, Isabelle Meyts
Abstract
Infiltration of T-cell acute lymphoblastic leukemia (T-ALL) into the meninges worsens prognosis, underscoring the need to understand mechanisms driving meningeal involvement. Here, we show that T-ALL cells expressing CXCR3 exploit normal T-cell function to infiltrate the inflamed meninges. CXCR3 deletion hampered disease progression and extramedullary dissemination by reducing leukemic cell proliferation and migration. Conversely, forced expression of CXCR3 facilitated T-ALL trafficking to the meninges. We identified the ubiquitin-specific protease 7 as a key regulator of CXCR3 protein stability in T-ALL. Furthermore, we discovered elevated levels of CXCL10, a CXCR3 ligand, in the cerebrospinal fluid from T-ALL patients and leukemia-bearing mice. Our studies demonstrate that meningeal stromal cells, specifically pericytes and fibroblasts, induce CXCL10 expression in response to leukemia, and that loss of CXCL10 attenuated T-ALL influx into the meninges. Moreover, we report that leukemia-derived proinflammatory cytokines, TNFα, IL27 and IFNγ, induced CXCL10 in the meningeal stroma. Pharmacological inhibition or deletion of CXCR3 or CXCL10 reduced T-ALL cell migration and adhesion to meningeal stromal cells. Finally, we reveal that CXCR3 and CXCL10 upregulated VLA-4/VCAM-1 signaling, promoting cell-cell adhesion and thus T-ALL retention in the meninges. Our findings highlight the pivotal role of CXCR3-CXCL10 signaling in T-ALL progression and meningeal colonization.
Authors
Nitesh D. Sharma, Esra'a Keewan, Wojciech Ornatowski, Silpita Paul, Monique Nysus, Christopher C. Barnett, Julie Wolfson, Quiteria Jacquez, Bianca L. Myers, Huining Kang, Katherine E. Zychowski, Stuart S. Winter, Mignon L. Loh, Stephen P. Hunger, Eliseo F. Castillo, Tom Taghon, Christina Halsey, Tou Yia Vue, Nicholas Jones, Panagiotis Ntziachristos, Ksenia Matlawska-Wasowska
Abstract
The interaction between cells and extracellular matrix (ECM) has been recognized in mechanism of fibrotic diseases. Collagen type VII (collagen VII) is an ECM component which plays an important role in cell-ECM interaction, particularly in cell anchoring and maintaining ECM integrity. Pleural mesothelial cells (PMCs) drive inflammatory reactions and ECM production in pleura. However, the role of collagen VII and PMCs in pleural fibrosis was poorly understood. In this study, collagen VII protein was found increase in pleura of patients with tuberculous pleural fibrosis. Investigation of cellular and animal models revealed that collagen VII began to increase at early stage in pleural fibrotic process. Increase of collagen VII occurred ahead of collagen I and α-SMA in PMCs and pleura of animal models. Inhibition of collagen VII by mesothelial cell-specific deletion of collagen VII gene (WT1-Cre+-COL7A1flox/flox) attenuated mouse experimental pleural fibrosis. At last, it was found that excessive collagen VII changed collagen conformation which resulted in elevation of ECM stiffness. Elevation of ECM stiffness activated integrin/PI3K-AKT/JUN signaling and promoted more ECM deposition, as well as mediated pleural fibrosis. In conclusion, excessive collagen VII mediated pleural fibrosis via increasing extracellular matrix stiffness.
Authors
Qian Li, Xin-Liang He, Shuai-Jun Chen, Qian Niu, Tan-Ze Cao, Xiao-Ling Cui, Zi-Heng Jia, He-De Zhang, Xiao Feng, Ye-Han Jiang, Li-Mei Liang, Pei-Pei Cheng, Shi-He Hu, Liang Xiong, Meng Wang, Hong Ye, Wan-Li Ma
Abstract
Deficits in the mitochondrial energy-generating machinery cause mitochondrial disease (MD), a group of untreatable and usually fatal disorders. Among many severe symptoms, refractory epileptic events are a common neurological presentation of MD. However, the neuronal substrates and circuits for MD-induced epilepsy remain unclear. Here, using mouse models of Leigh Syndrome, a severe form of MD associated to epilepsy, that lack mitochondrial complex I subunit NDUFS4 in a constitutive or conditional manner, we demonstrate that mitochondrial dysfunction leads to a reduction in the number of GABAergic neurons in the rostral external globus pallidus (GPe), and identify a specific affectation of pallidal Lhx6-expressing inhibitory neurons, contributing to altered GPe excitability. Our findings further reveal that viral vector-mediated Ndufs4 re-expression in the GPe effectively prevents seizures and improves the survival in the models. Additionally, we highlight the subthalamic nucleus (STN) as a critical structure in the neural circuit involved in mitochondrial epilepsy, as its inhibition effectively reduces epileptic events. Thus, we have identified a role for pallido-subthalamic projections in the development of epilepsy in the context of mitochondrial dysfunction. Our results suggest STN inhibition as a potential therapeutic intervention for refractory epilepsy in patients with MD providing promising leads in the quest to identify effective treatments.
Authors
Laura Sánchez-Benito, Melania González-Torres, Irene Fernández-González, Laura Cutando, María Royo, Joan Compte, Miquel Vila, Sandra Jurado, Elisenda Sanz, Albert Quintana
Abstract
Immune cells are constantly exposed to microbiota-derived compounds that can engage innate recognition receptors. How this constitutive stimulation is down-modulated to avoid systemic inflammation and auto-immunity is poorly understood. Here we show that Aryl hydrocarbon Receptor (AhR) deficiency in monocytes unleashes spontaneous cytokine responses in vivo, driven by STING-mediated tonic sensing of microbiota. This effect was specific to monocytes, as mice deficient for AhR specifically in macrophages did not show any dysregulation of tonic cytokine responses. AhR inhibition also increased tonic cytokine production in human monocytes. Finally, in patients with systemic juvenile idiopathic arthritis, low AhR activity in monocytes correlated with elevated cytokine responses. Our findings evidence an essential role for AhR in monocytes in restraining tonic microbiota sensing and in maintaining immune homeostasis.
Authors
Adeline Cros, Alessandra Rigamonti, Alba de Juan, Alice Coillard, Mathilde Rieux-Laucat, Darawan Tabtim-On, Emeline Papillon, Christel Goudot, Alma-Martina Cepika, Romain Banchereau, Virginia Pascual, Marianne Burbage, Burkhard Becher, Elodie Segura
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ISSN: 0021-9738 (print), 1558-8238 (online)