Inflammation
Abstract
Fibroblasts are central to pathogenesis of systemic sclerosis (SSc). However, studies of conventional explant fibroblast cultures incompletely reflect disease biology and treatment response. We isolated a second non-migratory “resident” population of fibroblasts from skin biopsies after outgrowth of explant “migratory” cells. These non-motile resident fibroblasts were compared with migratory cells from the same biopsy, using functional studies, bulk and scRNAseq, and localised in situ by multichannel immunofluorescence. Migratory and resident fibroblast populations in SSc showed distinct pro-fibrotic characteristics and gene expression for pathogenic pathways differing by stage and autoantibody subgroup. TGFβ signalling was highly active in migratory fibroblasts in early stage dcSSc. Conversely, resident fibroblasts had less upregulated TGFβ signalling, especially in late dcSSc. Increased chemokine expression was a hallmark of resident fibroblasts at all stages. In vitro studies confirmed differential response to TGFβ1 and CCL2 between migratory and resident cells. We suggest that migratory fibroblasts are especially important in early skin disease whereas non-migratory fibroblasts may have a regulatory role and contribute more to fibrosis in later stage disease. Thus, we have identified a pathogenic fibroblast population in SSc, not isolated by conventional explant culture, that could play an important role in fibrosis and be targeted therapeutically.
Authors
Kristina E.N. Clark, Shiwen Xu, Moustafa Attar, Voon H. Ong, Christopher D. Buckley, Christopher P. Denton
Citation Information: JCI Insight. 2025. https://doi.org/10.1172/jci.insight.189794.
Abstract
Authors
Junping Yin, Melanie Eichler, Clivia Lisowski, Jian Li, Sibylle von Vietinghoff, Natalio Garbi, Qi Mei, Anne-Kathrin Gellner, Christian Kurts
Abstract
The inflammatory response after myocardial infarction (MI) is a precisely regulated process that greatly affects subsequent wound healing and remodeling. However, the understood about the process are still limited. Macrophages are critically involved in inflammation resolution after MI. Krüppel-like factor 9 (Klf9) is a C2H2 zinc finger-containing transcription factor that has been implicated in glucocorticoid regulation of macrophages. However, the contribution of Klf9 to macrophage phenotype and function in the context of MI remains unclear. Our study revealed that KLF9 deficiency results in higher mortality and cardiac rupture rate, as well as a considerable exacerbation in cardiac function. Single-cell RNA sequencing and flow cytometry analyses reveals that, compared to WT mice, Klf9-/- mice display excessive neutrophil infiltration, insufficient macrophage infiltration, and a reduced proportion of Monocyte-derived CD206+ macrophages post-MI. Moreover, the expression of IFN-γ-STAT1 pathway genes in Klf9-/- cardiac macrophages is dysregulated, characterized by insufficient expression at 1 day post-MI and excessive expression at day 3 post-MI. Mechanistically, Klf9 directly binds to the promoters of Stat1 gene, regulating its transcription. Overall, these findings indicates that Klf9 beneficially influences wound healing after MI through modulating macrophage recruitment and differentiation by regulating the IFN-γ-STAT1 signal pathway.
Authors
Sheng Xu, Hao Li, Jun Han, Yawei Xu, Niannian Li, Wenliang Che, Feng Liu, Wenhui Yue
Citation Information: JCI Insight. 2025. https://doi.org/10.1172/jci.insight.191098.
Abstract
Type 2 inflammatory diseases are common in cystic fibrosis (CF) including asthma, sinusitis, and allergic bronchopulmonary aspergillosis. CD4+ T helper 2 (Th2) cells promote these diseases through secretion of IL-4, IL-5, and IL-13. Whether the cystic fibrosis transmembrane conductance regulator (CFTR), the mutated protein in CF, has a direct effect on Th2 development is unknown. Using murine models of CFTR deficiency and human CD4+ T cells, we show CD4+ T cells expressed Cftr transcript and CFTR protein following activation. Loss of T cell CFTR expression increased Th2 cytokine production compared to control cells. Mice with CFTR-deficient T cells developed increased allergic airway disease to Alternaria alternata extract compared to control mice. Culture of CFTR-deficient Th2 cells demonstrated increased IL-4Rα expression and increased sensitivity to IL-4 with greater induction of GATA3 and IL-13 compared to control Th2 cell cultures. The CFTR potentiator ivacaftor reduced allergic inflammation and type 2 cytokine secretion in bronchoalveolar lavage of “humanized” CFTR mice following Alternaria alternata extract challenge and decreased Th2 development in human T cell culture. Together, these data support a direct role of CFTR in regulating T cell sensitivity to IL-4 and demonstrate a potential CFTR-specific therapeutic strategy for Th2 cell-mediated allergic disease.
Authors
Mark Rusznak, Christopher M. Thomas, Jian Zhang, Shinji Toki, Weisong Zhou, Masako Abney, Danielle M. Yanda, Allison E. Norlander, Craig A. Hodges, Dawn C. Newcomb, Mark H. Kaplan, R. Stokes Peebles Jr., Daniel P. Cook
Abstract
RESULTS. Participants with CAD (n = 723) had 12% higher mean relative levels of nHDLox compared with those with invasively excluded CAD (n = 502, P < 0.001). Patients presenting with symptoms of an ACS had the highest nHDLox values when compared with the elective cohort (median 1.35, IQR 0.97 to 1.85, P < 0.001). In multivariate analysis adjusted for age, sex, body mass index, and hypertension, nHDLox was a strong independent predictor of ACS (P < 0.001) but not of CAD (P > 0.05).CONCLUSION. HDL antioxidant function is reduced in patients with CAD. nHDLox is strongly associated with ACS. TRIAL REGISTRATION. German Clinical Trials Register DRKS00014037. FUNDING. Brandenburg Medical School Theodor Fontane, the BIOX Stiftung, and NIH grants R01AG059501 and R03AG059462. BACKGROUND. High-density lipoprotein (HDL) function rather than its concentration plays an important role in the pathogenesis of coronary artery disease (CAD). The aim of the present study was to determine whether reduced antioxidant function of HDL is associated with the presence of a stable CAD or acute coronary syndrome (ACS).METHODS. HDL function was measured in 2 cohorts: 1225 patients admitted electively for coronary angiography and 196 patients with ACS. A validated cell-free biochemical assay was used to determine reduced HDL antioxidant function, as assessed by increased HDL-lipid peroxide content (HDLox), which was normalized by HDL-C levels and the mean value of a pooled serum control from healthy participants (nHDLox; unitless). Results are expressed as median with interquartile range (IQR).
Authors
Benjamin Sasko, Linda Scharow, Rhea Mueller, Monique Jaensch, Werner Dammermann, Felix S. Seibert, Philipp Hillmeister, Ivo Buschmann, Martin Christ, Oliver Ritter, Nazha Hamdani, Christian Ukena, Timm H. Westhoff, Theodoros Kelesidis, Nikolaos Pagonas
Citation Information: JCI Insight. 2025. https://doi.org/10.1172/jci.insight.189362.
Abstract
Urinary tract infections (UTIs) are one of the most commonly encountered infections in clinical practice, in which psychological stress is a critical pathological contributor to modulate immune function. However, mechanistic pathways linking stress networks in the brain to bladder infection remain poorly understood. In this study, we discovered that acute stress treatment suppressed bladder inflammation in mice with UTIs, and a significant number of neurons showing overlap between inflammation-associated markers and retrograde labeling were observed in the paraventricular nucleus (PVN) brain region of these mice. Activation of PVN alleviated UPEC-induced bladder inflammatory response. Moreover, blocked hypothalamic-pituitary-adrenal (HPA) axis reversed the anti-inflammatory reflex mediated by acute stress, suggesting that the potential of glucocorticoids levels through the brain-body circuits to ameliorate UTIs. Single cell-RNAseq of bladder immune cells revealed that type 2 innate lymphoid cells (ILC2) expressed abundant levels of glucocorticoid receptor (GR). The activation of PVN effectively inhibited the expression of the proinflammatory cytokine Csf2 by ILC2 through direct regulation of cell-intrinsic glucocorticoids signaling. Ultimately, our study has implications for the positioning of brain-body circuit for UTIs treatment.
Authors
Yaxiao Liu, Jinhua Wang, Junyang Lin, Dingqi Sun, Kejia Zhu, Tongxiang Diao, Qiang Fu, Qingyu Ren
Citation Information: JCI Insight. 2025. https://doi.org/10.1172/jci.insight.179875.
Abstract
Skin inflammation in juvenile dermatomyositis (JDM) can signal disease onset or flare, and the persistence of cutaneous disease can prevent complete disease remission. The non-invasive study of cutaneous expression signatures through tape stripping (TS) holds the potential to reveal mechanisms underlying disease heterogeneity and organ-specific inflammation. The objectives of this study were to 1) define TS expression signatures in lesional and non-lesional JDM skin, 2) analyze TS signatures to identify JDM disease endotypes and 3) compare TS and blood signatures. While JDM lesional skin demonstrated interferon signaling as the top upregulated pathway, non-lesional skin uniquely highlighted pathways involved in metabolism, angiogenesis and calcium signaling. Both lesional and non-lesional skin shared inflammasome pathway dysregulation. Using unsupervised clustering of skin expression data, we identified a treatment-refractory JDM subgroup distinguished by upregulation of genes associated with mitochondrial dysfunction. The treatment-refractory JDM subgroup also demonstrated higher interferon, angiogenesis and innate immune expression scores in skin and blood, although scores were more pronounced in skin as compared to blood. Tape-stripping expression signatures in JDM provided insight into disease mechanisms and molecular subgroups. Skin, as compared to blood, transcriptional profiles served as more sensitive markers to classify disease subgroups and identify candidate treatment targets.
Authors
Jessica L. Turnier, Sarah M.H. Vandenbergen, Madison E. McClune, Christine Goudsmit, Sophia Matossian, Meredith Riebschleger, Nadine Saad, Jacqueline A. Madison, Smriti Mohan, Johann E. Gudjonsson, Lam C. Tsoi, Celine C. Berthier, J. Michelle Kahlenberg
Abstract
Authors
Máté Sándor, Balázs Csaba Németh, Alexandra Demcsák, Miklós Sahin-Tóth
Citation Information: JCI Insight. 2025;10(5):e187172. https://doi.org/10.1172/jci.insight.187172.
Abstract
Idiopathic pulmonary fibrosis (IPF) causes remodeling of the distal lung. Pulmonary remodeling is histologically characterized by fibrosis, as well as appearance of basal cells; however, the involvement of basal cells in IPF remains unclear. Here, we focus on the long noncoding RNA MIR205HG, which is highly expressed in basal cells, using RNA sequencing. Through RNA sequencing of genetic manipulations using primary cells and organoids, we discovered that MIR205HG regulates IL-33 expression. Mechanistically, the AluJb element of MIR205HG plays a key role in IL-33 expression. Additionally, we identified a small molecule that targets the AluJb element, leading to decreased IL-33 expression. IL-33 is known to induce type 2 innate lymphoid cells (ILC2s), and we observed that MIR205HG expression was positively correlated with the number of ILC2s in patients with IPF. Collectively, these findings provide insights into the mechanisms by which basal cells contribute to IPF and suggest potential therapeutic targets.
Authors
Tsuyoshi Takashima, Chao Zeng, Eitaro Murakami, Naoko Fujiwara, Masaharu Kohara, Hideki Nagata, Zhaozu Feng, Ayako Sugai, Yasue Harada, Rika Ichijo, Daisuke Okuzaki, Satoshi Nojima, Takahiro Matsui, Yasushi Shintani, Gota Kawai, Michiaki Hamada, Tetsuro Hirose, Kazuhiko Nakatani, Eiichi Morii
Citation Information: JCI Insight. 2025;10(5):e171783. https://doi.org/10.1172/jci.insight.171783.
Abstract
Crohn’s disease (CD) involves a complex intestinal microenvironment driven by chronic inflammation. While single-cell RNA sequencing has provided valuable insights into this biology, the spatial context is lost during single-cell preparation of mucosal biopsies. To deepen our understanding of the distinct inflammatory signatures of CD and overcome the limitations of single-cell RNA sequencing, we combined spatial transcriptomics of frozen CD surgical tissue sections with single-cell transcriptomics of ileal CD mucosa. Coexpressed genes and cell-cell communication from single-cell analyses and factorized genes from spatial transcriptomics revealed overlapping pathways affected in inflamed CD, like antigen presentation, phagosome activity, cell adhesion, and extracellular matrix. Within the pathways, early epithelial cells showed evidence of significant changes in gene expression and subtype composition, while spatial mapping revealed the location of the events, particularly antigen presentation from epithelial cells in the base of the crypt. Furthermore, we identified early epithelial cells as a potential mediator of the MHC class II pathway during inflammation, which we validated by spatial transcriptomics cell subtype deconvolution. Therefore, the inflammation from CD appears to change the types of interactions detectable between epithelial cells with immune and mesenchymal cells, likely promoting the conditions for more macrophage infiltration into these inflammatory microdomains.
Authors
Vasantha L. Kolachala, Sushma Chowdary Maddipatla, Shanta Murthy, Yeonjoo Hwang, Anne F. Dodd, Garima Sharma, Sachith Munasinghe, Ranjit Singh Pelia, Suresh Venkateswaran, Murugadas Anbazhagan, Tarun Koti, Navdeep Jhita, Gaurav N. Joshi, Chrissy A. Lopez, Duke Geem, Hong Yin, David J. Cutler, Peng Qiu, Jason D. Matthews, Subra Kugathasan
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