Inflammation
Abstract
Inflammatory diseases contribute to secondary osteoporosis. Hypertension is a highly prevalent inflammatory condition that is clinically associated with reduced bone mineral density and increased risk for fragility fracture. In this study, we showed that a significant loss in bone mass and strength occurs in two pre-clinical models of hypertension. This accompanied increases in immune cell populations, including monocytes, macrophages, and IL-17A-producing T cell subtypes in the bone marrow of hypertensive mice. Neutralizing IL-17A in angiotensin (ang) II-infused mice blunted hypertension-induced loss of bone mass and strength due to decreased osteoclastogenesis. Likewise, the inhibition of the CSF-1 receptor blunted loss of bone mass and prevented loss of bone strength in hypertensive mice. In an analysis of UK Biobank data, circulating bone remodeling markers exhibited striking associations with blood pressure and bone mineral density in > 27,000 humans. These findings illustrate a potential mechanism by which hypertension activates immune cells in the bone marrow, encouraging osteoclastogenesis and eventual loss in bone mass and strength.
Authors
Elizabeth M. Hennen, Sasidhar Uppuganti, Néstor de la Visitación, Wei Chen, Jaya Krishnan, Lawrence A. Vecchi III, David M. Patrick, Mateusz Siedlinski, Matteo Lemoli, Rachel Delgado, Mark P. de Caestecker, Wenhan Chang, Tomasz J. Guzik, Rachelle W. Johnson, David G. Harrison, Jeffry S. Nyman
Abstract
Crypt hyperplasia is a key feature of celiac disease and several other small intestinal inflammatory conditions. Analysis of the gut epithelial crypt zone by mass spectrometry-based tissue proteomics revealed a strong interferon-γ (IFN-γ) signal in active celiac disease. This signal, hallmarked by increased expression of MHC molecules, was paralleled by diminished expression of proteins associated with fatty acid metabolism. Crypt hyperplasia and the same proteomic changes were observed in wild type mice administered IFN-γ. In mice with conditional knockout of the IFN-γ receptor in gut epithelial cells these signature morphological and proteomic changes were not induced on IFN-γ administration. IFN-γ is thus a driver of crypt hyperplasia in celiac disease by acting directly on crypt epithelial cells. The results are relevant to other enteropathies with involvement of IFN-γ.
Authors
Jorunn Stamnaes, Daniel Stray, M. Fleur du Pré, Louise F. Risnes, Alisa E. Dewan, Jakeer Shaik, Maria Stensland, Knut E.A. Lundin, Ludvig M. Sollid
Abstract
Diabetic peripheral neuropathy (DPN) is a prevalent complication of diabetes mellitus caused by metabolic toxicity to peripheral axons. We aimed to gain deep mechanistic insight into the disease using transcriptomics on tibial and sural nerves recovered from lower leg amputations in a mostly diabetic population and control sural nerves from cross facial nerve graft surgery. First, comparing DPN versus control sural nerves revealed inflammatory activation and sensory changes in DPN. Second, when comparing mixed sensory and motor tibial and purely sensory sural nerves, we identified key pathway differences in affected DPN nerves, with distinct immunological features observed in sural nerves. Third, spatial transcriptomics of sural nerves revealed shifts in immune cell types associated with axonal loss progression. We also found clear evidence of neuronal transcript changes, like PRPH, in nerves with axonal loss, suggesting perturbed RNA transport into distal sensory axons. This motivated further investigation into neuronal mRNA localization in peripheral nerve axons, generating evidence of robust localization of mRNAs such as SCN9A and TRPV1 in human sensory axons. Our work provides insight into altered cellular and transcriptomic profiles in human nerves in DPN and highlights sensory axon mRNA transport as a potential contributor to nerve degeneration.
Authors
Diana Tavares-Ferreira, Breanna Q. Shen, Juliet M. Mwirigi, Stephanie Shiers, Ishwarya Sankaranarayanan, Akshitha Sreerangapuri, Miriam B. Kotamarti, Nikhil N. Inturi, Khadijah Mazhar, Eroboghene E. Ubogu, Geneva L. Thomas, Trapper Lalli, Shai M. Rozen, Dane K. Wukich, Theodore J. Price
Abstract
Through a combination of single-cell/single-nucleus RNA-sequencing (sc/snRNA-seq) data analysis, immunohistochemistry, and primary macrophage studies, we have identified pathogenic macrophages characterized by TET3 overexpression (Toe-Macs) in three major human diseases associated with chronic inflammation: metabolic dysfunction-associated steatohepatitis (MASH), non-small cell lung cancer (NSCLC), and endometriosis. These macrophages are induced by common factors present in the disease microenvironment (DME). Crucially, the universal reliance on TET3 overexpression among these macrophages enables their selective elimination as a single population, irrespective of heterogeneity in other molecular markers. In mice, depleting these macrophages via myeloid-specific Tet3 knockout markedly mitigates disease progression and the therapeutic effects are recapitulated pharmacologically using a TET3-specific small molecule degrader. Through an unexpected mode of action, TET3 epigenetically regulates expression of multiple genes key to the generation and maintenance of an inflammatory/immunosuppressive DME. We propose that Toe-Macs are a unifying feature of pathogenic macrophages that could be therapeutically targeted to treat MASH, NSCLC, endometriosis, and potentially other chronic inflammatory diseases.
Authors
Beibei Liu, Yangyang Dai, Zixin Wang, Jiahui Song, Yushu Du, Haining Lv, Stefania Bellone, Yang-Hartwich Yang, Andrew Kennedy, Songying Zhang, Muthukumaran Venkatachalapathy, Yulia V. Surovtseva, Penghua Wang, Gordon G. Carmichael, Hugh S. Taylor, Xuchen Zhang, Da Li, Yingqun Huang
Abstract
Acute ischemic organ diseases such as acute myocardial infarction and acute kidney injury often result in irreversible tissue damage and progress to chronic heart failure (CHF) and chronic kidney disease (CKD), respectively. However, the molecular mechanisms underlying the development of CHF and CKD remain incompletely understood. Here, we show that mice deficient in CD300a, an inhibitory immunoreceptor expressed on myeloid cells, showed enhanced efferocytosis by tissue-resident macrophages and decreased damage-associated molecular patterns and pathogenic SiglecFhi neutrophils, resulting in milder inflammation-associated tissue injury than wild-type mice after ischemia and reperfusion (IR). Notably, we uncovered that CD300a-deficiency on SiglecFlo neutrophils increased the signal transducer and activator of transcription 3-mediated production of pro-angiogenic and anti-fibrotic factors, resulting in milder adverse remodeling after IR. Our results demonstrated that CD300a plays an important role in the pathogenesis of ischemic tissue injury and adverse remodeling in the heart and kidney.
Authors
Nanako Nishiyama, Hitoshi Koizumi, Chigusa Nakahashi-Oda, Satoshi Fujiyama, Xuewei Ng, Hanbin Lee, Fumie Abe, Jinao Li, Yan Xu, Takehito Sugasawa, Kazuko Tajiri, Taketaro Sadahiro, Masaki Ieda, Keiji Tabuchi, Kazuko Shibuya, Akira Shibuya
Abstract
Group 3 innate lymphoid cells (ILC3s) have emerged as an important player in the pathogenesis of neutrophilic asthma. However, the regulatory mechanism supporting ILC3 responses in lung remains largely unclear. Here, we demonstrated that stem cell factor (SCF) expression is significantly increased and positively correlated with IL-17A and MPO expression in asthmatic patients. Notably, we identified ILC3 as a major IL-17A-producing responder to SCF in lung. In mice, SCF synergized with IL-1β/IL-23 to enhance pulmonary ILC3 activation and neutrophilic inflammation. Mechanistically, SCF promoted ILC3 proliferation and cytokine production. Transcriptomic analysis revealed that SCF treatment upregulated the genes related to proliferation and Th17 differentiation, associated with increased AKT and STAT3 signaling. In contrast, deficiency of SCF receptor, c-Kit, reduced ILC3 proliferation and IL-17A production, resulting in the amelioration of airway hyperreactivity (AHR) and neutrophilic inflammation in mouse neutrophilic asthma model. Furthermore, genetic deletion of SCF in fibroblasts revealed fibroblasts as the primary source of SCF for ILC3 activation in lung. Moreover, administration of imatinib, a c-Kit inhibitor, alleviated LPS, air pollution or ovalbumin/LPS-induced AHR and neutrophilic inflammation. Our findings elucidated a positive modulatory role of SCF/c-Kit signaling in ILC3 responses during neutrophilic inflammation, offering a potential therapeutic target for neutrophilic asthma.
Authors
Jheng-Syuan Shao, Alan C. Lai, Wei-Chang Huang, Ko-Chien Wu, Po-Yu Chi, Yao-Ming Chang, Ya-Jen Chang
Abstract
While weight loss is highly recommended for those with obesity, >60% will regain their lost weight. This weight cycling is associated with elevated risk of cardiovascular disease, relative to never having lost weight. How weight loss/regain directly influence atherosclerotic inflammation is unknown. Thus, we studied short-term caloric restriction (stCR) in obese hypercholesterolemic mice, without confounding effects from changes in diet composition. Weight loss was found to promote atherosclerosis resolution independent of plasma cholesterol. From single-cell RNA-sequencing and subsequent mechanistic studies, this can be partly attributed to a unique subset of macrophages accumulating with stCR in epididymal white adipose tissue (eWAT) and atherosclerotic plaques. These macrophages, distinguished by high expression of Fcgr4, help to clear necrotic cores in atherosclerotic plaques. Conversely, weight regain (WR) following stCR accelerated atherosclerosis progression with disappearance of Fcgr4+ macrophages from eWAT and plaques. Furthermore, WR caused reprogramming of immune progenitors, sustaining hyper-inflammatory responsiveness. In summary, we have developed a model to investigate the inflammatory effects of weight cycling on atherosclerosis and the interplay between adipose tissue, bone marrow, and plaques. The findings suggest potential approaches to promote atherosclerosis resolution in obesity and weight cycling through induction of Fcgr4+ macrophages and inhibition of immune progenitor reprogramming.
Authors
Bianca Scolaro, Franziska Krautter, Emily J. Brown, Aleepta Guha Ray, Rotem Kalev-Altman, Marie Petitjean, Sofie Delbare, Casey Donahoe, Stephanie Pena, Michela L. Garabedian, Cyrus A. Nikain, Maria Laskou, Ozlem Tufanli, Carmen Hannemann, Myriam Aouadi, Ada Weinstock, Edward A. Fisher
Abstract
Authors
Macee C. Owen, Vinay R. Penna, Hao Dun, Wenjun Li, Benjamin J. Kopecky, Kenneth M. Murphy, Daniel Kreisel, Kory J. Lavine
Abstract
Chagas disease, caused by Trypanosoma cruzi, is endemic to Latin America and is characterized by chronic inflammation of cardiac tissues due to parasite persistence. Hypoxia within infected tissues may trigger the stabilization of HIF-1 and be linked to ATP release. Extracellular ATP exhibits microbicidal effects but is scavenged by CD39 and CD73 ectonucleotidases, which ultimately generate adenosine (ADO), a potent immunosuppressor. Here, we comprehensively study the importance of HIF-1 stabilization and the CD39/CD73/ADO axis, on CD4+ T cells with the cytotoxic phenotype, in facilitating the persistence of T. cruzi. Myocardial infection induces prominent areas of hypoxia, which is concomitant with HIF-1α stabilization in T cells and linked to early expansion of CD39+CD73+CD4+ T cell infiltrating population. Functional assays further demonstrate that HIF-1 stabilization and CD73 activity are associated with impaired CD4+ T cell cytotoxic potential. RNA-Seq analysis reveals that HIF-1 and purinergic signaling pathways are overrepresented in cardiac tissues of patients with end-stage Chagas disease. The findings highlight a major effect of purinergic signaling on CD4+ T cells with potential cytotoxic capacity in the setting of T. cruzi infection and have translational implications for therapy.
Authors
Gastón Bergero, Yanina L. Mazzocco, Sebastian Del Rosso, Ruining Liu, Zoé M. Cejas Gallardo, Simon C. Robson, Martin Rottenberg, Maria P. Aoki
Abstract
Authors
James G. Krueger, Mrinal K. Sarkar, Mark G. Lebwohl, Akimichi Morita, Kenneth Gordon, Rachael Bogle, Christopher Cole, Anthony Coon, Richard G. Langley, Richard B. Warren, Arash Mostaghimi, Bruce Strober, A. David Burden, Min Zheng, Aaron R. Mangold, Milan J. Anadkat, Jonathan N. Barker, Joseph F. Merola, Lam C. Tsoi, Ming Tang, Kolja Becker, Denis Delic, Christian Thoma, Johann E. Gudjonsson
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ISSN: 0021-9738 (print), 1558-8238 (online)