Inflammation
Abstract
Heat stroke (HS) is the most severe heat-related emergency, and its pathophysiology remains largely unknown, especially for exertional HS (EHS), which affects younger populations, athletes, and manual workers. Herein, we performed single-cell-transcriptomics, T cell receptor sequencing, and flow cytometry of PBMCs from 9 healthy control participants, 9 patients with heat exhaustion, and 9 patients with EHS to explore complex immunological responses associated with HS pathobiology. We showcased that granzyme-positive T cells and CD56dim NK cells with high cytotoxicity features and IL-1B+NLRP3+ monocytes with high inflammation and pyroptosis scores were enriched in HS, while the CD161+ T cells with innate immune-like, low cytotoxicity, and clonal expansion features were reduced in HS. Importantly, elevated granzyme-positive T and NK cells might interact with monocytes to induce pyroptosis of hepatic and renal cells and target organ injuries, and blocking the NLRP3 inflammasome pathway prior to the induction could alleviate organ injury in HS. This study offers deeper insights into the pathogenesis of HS, supporting the development of optimal treatment strategies.
Authors
Min Zhang, Bin Wang, Ding Sun, Xizhao Chen, Yena Zhou, Jin Yao, Liwen Du, Zehao Zhang, Hao Li, Zeyu Qu, Lu Chen, Qing Luo, Jie Zhang, Xinye Jin, Xiaowei Cheng, Jingxue Niu, Qinrui Xing, Xuezeng Tan, Tao Wang, Jie Liu, Lei Li, Qing Song, Xiangmei Chen, Yizhi Chen
Abstract
Authors
Robert Lakin, Xueyan Liu, Dana Sherrard, Mihir Parikh, Ryan Debi, Nazari Polidovitch, Markus J. Duncan, Jian Wu, Peter H. Backx
Abstract
Cutaneous radiation injury is an unintended consequence of radiotherapy for many common cancers and can progress to debilitating radiation-induced skin fibrosis (RISF). Existing radiation injury models do not fully capture the skin toxicities observed in patients, contributing to the lack of efficacious therapies to mitigate RISF. To address this, we developed an ex vivo human skin model that recapitulates the temporal radiation injury and RISF response. Human skin explants (N=12) subjected to ionizing radiation demonstrated DNA double-strand breaks and robust p53-driven transcriptional programming of cell cycle arrest, apoptosis, and senescence compared to non-irradiated controls. Irradiated skin also exhibited induction of pro-inflammatory cytokines, epithelial-mesenchymal transition, pro-fibrotic TGF-beta1 (TGFB1)-mediated signaling, and thickened collagen over time. P53 regulators murine double minute 2 (MDM2) and microRNA (miR)-34a were induced post-irradiation and may be leveraged to modulate injury response. Notably, RNA-sequencing of breast skin from mastectomy patients post-radiotherapy showed similar p53, inflammatory, and TGFB1 signatures as the ex vivo model, supporting its translational relevance. Together, this model provides a platform for identifying biomarkers and testing therapies to prevent or mitigate cutaneous radiation toxicities. Targeting the dynamic p53-driven pro-fibrotic radiation response represents a new therapeutic avenue to improve post-radiotherapy quality of life for cancer survivors.
Authors
Caroline Dodson, Sophie M. Bilik, Gabrielle DiBartolomeo, Hannah Pachalis, Lindsey G. Siegfried, Jordan A. K. Johnson, Seth R. Thaller, Irena Pastar, Marjana Tomic-Canic, Anthony J. Griswold, Rivka C. Stone
Abstract
The lung alveoli are continually exposed to inhaled pathogens and environmental hazards and rely on coordinated communication between alveolar macrophages and type 2 alveolar epithelial cells (AT2s) to maintain homeostasis. Disruption of these interactions can impair immunity and repair, contributing to acute and chronic respiratory diseases. To better define these mechanisms and support therapeutic discovery, we established a human iPSC-derived air-liquid interface platform that captures key features of AT2-macrophage crosstalk. Using this system, we show that coculture enhances AT2-specific transcriptional programs including lipid synthesis, while macrophages actively phagocytose AT2-derived surfactant. iPSC-derived macrophages adopt an alveolar macrophage-like phenotype and respond to AT2-derived M-CSF. During respiratory infection, macrophages played a crucial role in modulating epithelial inflammatory responses, augmenting antiviral immunity, and limiting viral replication. We further identify a previously unrecognized role for macrophages in epithelial repair, where VEGF-mediated signaling to macrophages increases epithelial permeability during viral infection. Together, these findings reveal dimensions of AT2-macrophage cooperation in homeostasis, infection, and repair, and demonstrate how this iPSC-derived platform can be used to dissect mechanisms that may initiate or drive the progression of respiratory diseases.
Authors
Declan L. Turner, Hannah Baric, Katelyn Patatsos, Sahel Amoozadeh, Michael See, Kathleen A. Strumila, Jack T. Murphy, Jeremy J. Wiyana, Liam Gubbels, Elizabeth S. Ng, Andrew G. Elefanty, Melanie R. Neeland, Shivanthan Shanthikumar, Sarah L. Londrigan, Mirana Ramialison, Fernando J. Rossello, Edouard G. Stanley, Rhiannon B. Werder
Abstract
Glucagon-like peptide-1 (GLP-1) and glucose-induced insulinotropic polypeptide (GIP) receptor agonists have revolutionized obesity therapy but causes for obesity-associated dysregulation of endogenous incretin production remain incompletely understood. Here we show that intestinal transmembrane serine protease 2 (TMPRSS2) plays a pivotal role in deregulating anti-diabetic GLP-1 production in obesity. TMPRSS2 is widely co-expressed in intestinal epithelial cells (IEC) along with its signaling target protease activated receptor 2 (PAR2). In addition to its role in regulating coagulation protease-mediated adipose tissue inflammation, PAR2 signaling in the gut controls postprandial GIP secretion. TMPRSS2, but not the epithelial-expressed proteases FXa or matriptase, activates PAR2 and thereby promotes postprandial GIP release. Accordingly, a PAR2 mutant mouse resistant to TMPRSS2 cleavage is protected from GIP upregulation and diet induced obesity. In the context of obesity, TMPRSS2 also attenuates bioavailability of ghrelin pathway and thereby suppresses GLP-1-mediated control of glucose homeostasis. Pharmacological inhibition or genetic deletion of TMPRSS2 restores ghrelin signaling dependent GLP-1 secretion and GLP-1’s anti-diabetic effects on nutritional glucose homeostasis. Thus, epithelial cell-expressed TMPRSS2, which critically contributes to the lung pathology in SARS-CoV-2 infection, emerges as an intestinal incretin regulator and a potential link between infection and chronic cardiometabolic diseases.
Authors
Dilraj Kaur, Sagarika Chakrabarty, Claudius Witzler, Hongjie Wang, Mengwen Wang, Romina Wolz, Petra Wilgenbus, Jens J.N. Posma, P. Sivaramakrishna Rachakonda, Federico Marini, Valeriya V. Zinina, Sabine Reyda, Rajinikanth Gogiraju, Claudine Graf, Fahumiya Samad, Katrin Schäfer, Christoph Reinhardt, Natalia Soshnikova, Wolfram Ruf, Thati Madhusudhan
Abstract
Vaso-occlusive episodes (VOEs) or acute pain events, involving complex interactions between sickle erythrocytes and other blood cells, are a hallmark of sickle cell disease (SCD). In this study, we analyzed changes in peripheral blood transcriptomes between steady state and VOEs in individuals with SCD. We followed a cohort of 174 individuals with SCD with or without chronic pain and collected peripheral blood at clinic visits (steady state) and during hospitalizations (VOEs). We performed RNA-Seq profiling of CD45+ leukocytes and CD71+ erythroid cells. Pathways linked to complement activation, coagulation, and IL-6/JAK/STAT3 signaling were enriched during VOEs in the CD45+ cells. Contrastingly, the CD71+ cells showed an enrichment of pathways related to the cell cycle, such as mTORC1 signaling and the G2M checkpoint during VOEs. We then analyzed the expression changes of genes in patients with longitudinal data to determine potential biomarkers for VOEs. Expression of 4 genes — FAM20A, IL1B, MS4A4A, and SERPINB2 — was elevated during VOEs compared with steady state in the majority of patients. Furthermore, our results indicate that patients experiencing chronic pain exhibited 44% increased enrichment of significant pathways during VOEs when compared with patients without chronic pain.
Authors
Varsha Bhat, Justin J. Yoo, Srija Ponna, Alka A. Potdar, Ashwin P. Patel, G. Karen Yu, Greg Gibson, Vivien A. Sheehan
Abstract
Next-generation sequencing technologies are increasingly used to diagnose genetic disorders, particularly immunological diseases with broad and overlapping immune dysregulation. Cryopyrin-associated periodic syndromes (CAPS) are caused by gain-of-function mutations in NLRP3 and include 3 autoinflammatory diseases spanning a continuum of severity: familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID). Linking NLRP3 variants to protein dysfunction and clinical phenotype remains challenging because of genetic modifiers and environmental factors. We report the generation and phenotyping of 5 mouse lines expressing either the common human NLRP3 allele or 1 of 4 CAPS mutations spanning the disease spectrum from FCAS to NOMID. In these lines, the murine Nlrp3 locus is replaced by syntenic integration of the human NLRP3 locus, yielding 1 line with the common allele and 4 lines each carrying a distinct CAPS mutation. Unlike models in which a human mutation is introduced into the mouse protein, these lines recapitulate the spectrum of disease severity observed in humans. These findings support a model in which evaluation of nonsynonymous mutations in mice is optimized when introduced in the context of the human gene. This suggests that species-specific regulation and/or intramolecular epistasis may impact modeling of disease-associated variants.
Authors
John N. Snouwaert, MyTrang Nguyen, Christopher A. Gabel, Ivona Aksentijevich, Jenny P.-Y. Ting, Beverly H. Koller
Abstract
Aberrant neutrophil (PMN) accumulation in the tissue induces chronic vascular diseases. Endothelial cells (ECs) regulate the access of PMNs into the tissue from the blood. However, the mechanisms that prevent PMNs from being activated and accumulating in the tissue, a hallmark of acute lung injury (ALI), remain elusive. We demonstrate that conditional deletion of Erg in ECs spontaneously alters the PMN transcriptome, which is enriched with genes that induce PMN recruitment, adhesion, activation, and 'do not eat me' signals due to impaired synthesis of the deubiquitinase, A20. Decreased A20 levels, in turn, activated the transcription factor NFκB and the secretion of MIP2α (human homolog of IL8) in ECs. EC-secreted MIP2α/IL8 engaged the CXCR2 cascade on PMNs, leading to their activation and inflammatory injury. These findings were recapitulated in the lungs and blood of PMNs from patients dying of ALI. Overexpression of the A20 gene in EC or pharmacological inhibition of CXCR2 on PMNs in iEC-Erg–/– mice rescued EC control of PMNs and tissue homeostasis, and enhanced mouse survival after pneumonia. Thus, the EC-Erg-A20 axis regulates PMN accumulation and hyperactivation in the lungs by inhibiting EC-mediated IL-8 activation of PMN-CXCR2, thereby providing a potential target for neutrophilic inflammatory vascular diseases.
Authors
Vigneshwaran Vellingiri, Vijay Avin Balaji Ragunathrao, Jagdish Chandra Joshi, Md Zahid Akhter, Mumtaz Anwar, Somenath Banerjee, Sayanti Datta, Viktor Pinneker, Steven M. Dudek, Yoshikazu Tsukasaki, Sandra Pinho, Dolly Mehta
Abstract
Immune checkpoint inhibitors (ICIs) can cause immune-related adverse events (irAEs), with acute interstitial nephritis (ICI-AIN) being the most common irAE. While the exact mechanism remains unclear, upregulation of interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) pathways has been implicated. This study used a humanized chimeric PD-1/PD-L1 mouse model to assess renal effects of ICIs, alone or combined with pro-inflammatory cytokines, and to test if selective TNF-α blockade could prevent ICI-AIN. Mice were randomly divided into four experimental groups: Control, ICI-Only, ICI-Cytokines (ICI-Cyt), and ICI-Block (ICI-TNF-α blockade). Renal function and cytokine profiles were assessed, while kidney tissue was analyzed using microscopy and single-cell RNA sequencing. Histology revealed increased renal infiltration of CD4⁺/CD8⁺ T cells in ICI-treated groups and decreased TNF-α expression following TNF-α blockade. Additionally, kidney tissue ELISA demonstrated reduced IFN-γ levels following TNF-α blockade. Plasma IL-6, MCP-1, and TNF-α were lower in ICI-Block mice. Single-cell RNA sequencing revealed shifts in immune cell populations and genes of interest including: Bcl2a1, Icos, Il18r1, Ccr2, and Jaml. This humanized model replicates ICI-AIN key features, revealing a synergistic role of ICIs and pro-inflammatory cytokines. TNF-α blockade demonstrated protective effects, supporting its potential role in mitigating the risk of ICI-AIN.
Authors
Victor D. Cuenca Narvaez, Coraima Nava Chavez, Omar Al Refai, Johanna E. J. Jacobs, Luis E. Gutierrez, Song Zhang, Xiaoyan Li, Jacob B. Hirdler, Michael F. Romero, Joerg Herrmann, Xiaogang Li, Haidong Dong, Alfonso Eirin, Sandra M. Herrmann
Abstract
This study provides a comprehensive evaluation of the cutaneous adipose tissue (CAT) transcriptome in psoriasis patients and investigates the effects of IL-17 blockade on CAT inflammation through a randomized placebo-controlled trial using secukinumab (ObePso-S study, NCT03055494). RNA sequencing analysis of CAT biopsies from 82 psoriasis patients revealed 2132 differentially expressed transcripts compared to healthy controls. Notably, significant gene dysregulation was observed in both lesional skin (LS)- 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 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 dependent on 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 F. Muscianisi, Jennifer Steadman, Andrew Blauvelt, James G. Krueger
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