Inflammation
Abstract
Background & Aims Liver cirrhosis is characterized by chronic inflammation and fibrosis, with Th17 cells playing a crucial role in its progression. Recent evidence suggests that dietary salt influences immune diseases by modulating Th17 differentiation. This study assessed the impact of dietary salt on Th17-driven inflammation in patients with compensated cirrhosis and explored its effects on liver injury in mouse models. Methods A non-drug, open-label, non-randomized study involved 37 patients with compensated cirrhosis, who were given personalized guidelines to reduce salt intake over three months. Changes in Th17-driven inflammation and liver function markers were assessed at baseline and after salt restriction. In parallel, the impact of a high-salt diet on hepatic CD4+ T cells was analyzed in mouse models of acute liver injury and fibrosis. Results High salt intake was associated with Th17-mediated inflammation and correlated with markers of impaired liver function in these patients. Importantly, moderating salt intake through a personalized nutritional intervention was sufficient to reduce CD4+ T cell- mediated inflammation. Furthermore, analysis of RNA-seq data revealed enrichment of salt-induced Th17 gene signatures in both liver tissue and peripheral cells from patients with liver disease. Similarly, mice fed a high salt diet showed hepatic enrichment of Th17 cells and exacerbated liver fibrosis upon injury. Mechanistic studies revealed that high sodium conditions activated NF-κB and induced IL-6 production in hepatocytes, which may promote Th17 responses. Conclusion Dietary salt exacerbates Th17-driven inflammation and contributes to cirrhosis progression. Salt reduction may represent a viable therapeutic approach to manage inflammation in compensated cirrhosis.
Authors
Amalia Tzoumpa, Beatriz Lozano-Ruiz, Yin Huang, Joanna Picó, Alba Moratalla, María Teresa Pomares, Iván Herrera, Juanjo Lozano, María Rodríguez-Soler, Cayetano Miralles, Pablo Bellot, Paula Piñero, Fabián Tarín, Pedro Zapater, Sonia Pascual, José Manuel González-Navajas
Abstract
Psoriasis is a chronic autoimmune skin disease characterized by abnormal keratinocyte proliferation and immune dysregulation. Altered lipid metabolism has been implicated in its pathogenesis, but the underlying mechanisms remain unclear. In this study, we generated an keratinocyte-specific Sprouty RTK signaling antagonist 1 (SPRY1) knockout (Spry1ΔEpi) mouse model, which exhibits psoriasis-like symptoms. Using both psoriasis patient samples and Spry1ΔEpi mice, we investigated the role of diacylglycerol acyltransferase 2 (DGAT2) in psoriasis. Our results show that DGAT2 expression is reduced, and glycerides metabolism is disrupted in psoriatic lesions in both psoriasis patients and Spry1ΔEpi mice. Lipidomic analysis reveals significant alterations in glycerides, glycerophospholipids, sphingolipids, and fatty acids in Spry1ΔEpi mice. At the cellular level, DGAT2 downregulation and lipid dysregulation enhance Toll-like receptor 3 (TLR3)-mediated inflammatory signaling in keratinocytes. Furthermore, increased DGAT2 secretion from keratinocytes promotes CD8⁺ T cell activation, proliferation and survival, amplifying psoriatic inflammation. These findings highlight the role of DGAT2 and lipid metabolism in the pathogenesis of psoriasis and reveal their interaction with immune responses in psoriasis.
Authors
Ying-Ying Li, Li-Ran Ye, Ying-Zhe Cui, Fan Xu, Xi-Bei Chen, Feng-Fei Zhang, Yi Lu, Yu-Xin Zheng, Xiao-Yong Man
Abstract
Hematopoietic stem cell transplantation (HCT) is a potentially life-saving therapy but can lead to lung injury due to chemoradiation toxicity, infection, and immune dysregulation. We previously showed that bronchoalveolar lavage (BAL) transcriptomes representing pulmonary inflammation and cellular injury can phenotype post-HCT lung injury and predict mortality. To test whether peripheral blood might be a suitable surrogate for BAL, we compared 210 paired BAL and blood transcriptomes obtained from 166 pediatric HCT patients at 27 hospitals. BAL and blood RNA abundance showed minimal correlation at the level of individual genes, gene set enrichment scores, imputed cell fractions, and T- and B-cell receptor clonotypes. Instead, we identified significant site-specific transcriptional programs. In BAL, pathways related to immunity, hypoxia, and epithelial mesenchymal transition were tightly co-expressed and linked to mortality. In contrast, in blood, expression of endothelial injury, DNA repair, and cellular metabolism pathways was associated with mortality. Integration of paired BAL and blood transcriptomes dichotomized patients into two groups with significantly different rates of hypoxia and clinical outcomes within 1 week of BAL. These findings reveal a compartmentalized injury response, where BAL and blood transcriptomes provide distinct but complementary insights into local and systemic mechanisms of post-HCT lung injury.
Authors
Emma M. Pearce, Erica Evans, Madeline Y. Mayday, Gustavo Reyes, Miriam R. Simon, Jacob Blum, Hanna Kim, Jessica Mu, Peter J. Shaw, Courtney M. Rowan, Jeffery J. Auletta, Paul L. Martin, Caitlin Hurley, Erin M. Kreml, Muna Qayed, Hisham Abdel-Azim, Amy K. Keating, Geoffrey D.E. Cuvelier, Janet R. Hume, James S. Killinger, Kamar Godder, Rabi Hanna, Christine N. Duncan, Troy C. Quigg, Paul Castillo, Nahal R. Lalefar, Julie C. Fitzgerald, Kris M. Mahadeo, Prakash Satwani, Theodore B. Moore, Benjamin Hanisch, Aly Abdel-Mageed, Dereck B. Davis, Michelle P. Hudspeth, Greg A. Yanik, Michael A. Pulsipher, Christopher C. Dvorak, Joseph L. DeRisi, Matt S. Zinter
Abstract
Tumor immunosuppression impacts survival and treatment efficacy. Tumor NOS2/COX2 coexpression strongly predicts poor outcome in ER– breast cancer by promoting metastasis, drug resistance, cancer stemness, and immune suppression. Herein, a spatially distinct NOS2/COX2 and CD3+CD8+PD1– T effector (TEff) cell landscape correlated with poor survival in ER– tumors. NOS2 was primarily expressed at the tumor margin, whereas COX2 together with B7H4 was associated with immune desert regions lacking TEff cells, where a higher ratio of tumor NOS2 or COX2 to TEff cells predicted poor survival. Also, PDL1/PD1, regulatory T cells (TReg) and IDO1 were primarily associated with stroma restricted TEff cells. Regardless of the survival outcome, CD4+ T cells and macrophages were primarily in stromal lymphoid aggregates. Finally, in a 4T1 model, COX2 inhibition led to increased CD8+ TEff/CD4+ TReg ratio and CD8+ TEff infiltration while Nos2 deficiency had no significant effect, thus reinforcing our observations that COX2 is an essential component of immunosuppression through CD8+ TEff cell exclusion from the tumor. Our study indicates that tumor NOS2/COX2 expression plays a central role in tumor immune evasion, suggesting that strategies combining clinically available NOS2/COX2 inhibitors with immune therapy could provide effective options for the treatment of aggressive and drug-resistant ER– breast tumors.
Authors
Lisa A. Ridnour, Robert Y.S. Cheng, William F. Heinz, Milind Pore, Ana L. Gonzalez, Elise L. Femino, Rebecca L. Moffat, Adelaide L. Wink, Fatima Imtiaz, Leandro L. Coutinho, Donna Butcher, Elijah F. Edmondson, M. Cristina Rangel, Stephen T.C. Wong, Stanley Lipkowitz, Sharon A. Glynn, Michael P. Vitek, Daniel W. McVicar, Xiaoxian Li, Stephen K. Anderson, Nazareno Paolocci, Stephen M. Hewitt, Stefan Ambs, Timothy R. Billiar, Jenny C. Chang, Stephen J. Lockett, David A. Wink
Abstract
Extracellular DNA (ecDNA) released from injured and dying cells powerfully induces injurious inflammation. In this study we define the role of ecDNA in systemic vasculitis affecting the kidney, using human kidney biopsies and murine models of myeloperoxidase anti-neutrophil cytoplasmic antibody-associated glomerulonephritis (MPO-ANCA GN). Twice daily administration of intravenous DNase I (ivDNase I) in two models of anti-MPO GN reduced glomerular deposition of ecDNA, histological injury, leukocyte infiltration and NETosis. Comprehensive investigation into DNase I modes of action revealed that after exposure to MPO, DNase I reduced lymph node DC numbers and their activation status, resulting in decreased frequency of MPO-specific CD4 effector T cells (IFN-, and IL-17A producing), and reductions in dermal anti-MPO delayed type hypersensitivity responses. To overcome the translational obstacle of the short half-life of DNase I (<5 hours), we tested an adeno-associated viral vector encoding DNase I (vec-DNase I). The method of DNase I delivery was more effective, as in addition to the histological and anti-inflammatory changes described above, a single vector treatment also reduced circulating MPO-ANCA titers and albuminuria. These results indicate ecDNA is a potent driver of anti-MPO GN and that DNase I is a potential therapeutic that can be delivered using gene technology
Authors
Anne Cao Le, Virginie Oudin, Jonathan Dick, Maliha A. Alikhan, Timothy A. Gottschalk, Lu Lu, Kate E. Lawlor, Daniel Koo Yuk Cheong, Mawj Mandwie, Ian E. Alexander, A R. Kitching, Poh-Yi Gan, Grant J. Logan, Kim M. O'Sullivan
Abstract
ADAR1 edits double-stranded RNAs (dsRNAs) by deaminating adenosines into inosines, preventing aberrant activation of innate immunity by endogenous dsRNAs, which may resemble viral structures. Several tumors exploit ADAR1 to evade immune surveillance; indeed, its deletion reduces tumor viability and reshapes infiltrating leukocytes. Here we investigated the role of ADAR1 in immune evasion mechanisms during cervical cancer (CC) progression. Patients’ biopsy samples showed higher ADAR1 expression already in premalignant lesions (squamous intraepithelial lesions [SIL]) and a substantially reduced percentage of infiltrating CD7+ innate cells in in situ and invasive carcinomas compared with normal mucosa, with CD56+ NK cells showing phenotypic alterations that may have affected their functional responses. In CC-derived cell lines (SiHa, CaSki), ADAR1 silencing reduced cell proliferation, an effect further enhanced by exogenous IFN-β administration. It also induced proinflammatory gene expression, as demonstrated by RNA-Seq analysis, and conditioned supernatants collected from these cells activated several NK cell effector functions. NK cell infiltration and activation were also confirmed in organotypic 3D tissue models of SiHa cells knocked out for ADAR1. In conclusion, ADAR1 expression increased with CC progression and was accompanied by alterations in tumor-infiltrating NK cells, but its silencing in CC-derived cell lines potentiated antitumor NK cell activities. Thus, ADAR1 inhibition may represent a therapeutic perspective for CC and possibly other malignancies.
Authors
Valentina Tassinari, Marta Kaciulis, Stefano Petrai, Helena Stabile, Angelina Pernazza, Martina Leopizzi, Valeria Di Maio, Francesca Belleudi, Danilo Ranieri, Vanessa Mancini, Innocenza Palaia, Federica Tanzi, Ludovica Lospinoso Severini, Silvia Ruggeri, Maria Emanuela Greco, Giovanni Bernardini, Alessandra Zingoni, Marco Cippitelli, Cristina Cerboni, Alessandra Soriani
Abstract
Males often experience worse cardiac outcomes than females in sepsis. This study identified pyruvate dehydrogenase kinase 4 (PDK4) as a key mediator of this disparity. PDK4 regulates glucose utilization by inhibiting pyruvate dehydrogenase (PDH) in mitochondria. In a mouse endotoxemia model, a sublethal dose of lipopolysaccharide (LPS, 5 mg/kg) significantly upregulated myocardial PDK4 and induced cardiac dysfunction in males but not females. Cardiac-specific PDK4 overexpression promoted this cardiac dysfunction in both sexes, whereas PDK4 knockout provided protection. In WT males, LPS reduced PDH activity and fatty acid oxidation (FAO) while increasing lactate levels, suggesting a shift toward glycolysis. These effects were exacerbated by PDK4 overexpression but attenuated by knockout. In females, metabolic changes were minimal, aside from reduced FAO in LPS-challenged females overexpressing PDK4. Additionally, a higher LPS dose (8 mg/kg) triggered cardiac dysfunction in females, accompanied by modest upregulation of PDK4, but without changes in PDH or lactate. Dichloroacetate (DCA), restraining PDK-mediated PDH inhibition, improved cardiac function in males but not females during endotoxemia. PDK4 overexpression also exacerbated cardiac mitochondrial damage, reduced mitophagy, and increased oxidative stress and inflammation during endotoxemia — effects that were prevented by PDK4 knockout. These findings suggest that PDK4 drives sex-specific cardiac responses in sepsis.
Authors
John Q. Yap, Azadeh Nikouee, Matthew Kim, Quan Cao, David J. Rademacher, Jessie E. Lau, Ananya Arora, Leila Y. Zou, Yuxiao Sun, Luke Szweda, Hesham Sadek, Sharon Elliot, Benjamin Roos, Marilyn K. Glassberg, Hong-Long Ji, Xiang Gao, Qunfeng Dong, Qun Sophia Zang
Abstract
Hematopoietic Protein-1 (Hem1) is a component of the WASP-family verprolin-homologous protein (WAVE) actin regulatory complex, which is activated downstream of multiple immune receptors. Mutations in the NCKAP1L gene encoding HEM1 have recently been found to result in severe Primary Immunodeficiency Disease (PID), characterized by recurrent respiratory infections, hyperinflammation, autoimmunity, and high mortality. However, how loss of Hem1 results in PID is unclear. To define the importance of Hem1 specifically in T cells, we generated constitutive and T cell specific Hem1 null mice. Hem1 deficient T cells exhibited an increased shift from naïve to memory T cells, and increased ratio of immunosuppressive regulatory to effector T cells. Loss of Hem1 resulted in hallmarks of T cell exhaustion including T cell lymphopenia, decreased activation and proliferation, increased expression of PD-1 and Tim3, and increased IL-10 production. In vitro TCR stimulation of CD4 T cells resulted in increased production of Th1 (IFN), Th2 (IL-5, IL-13), Th17 (IL-17, IL-22), and Treg (IL-10) cytokines. This correlated with reduced F-actin, increased expression of CD107a, and increased granzyme release indicative of increased granule membrane fusion and exocytosis. These results suggest that Hem-1 is critical for maintaining T cell activation, homeostasis and regulated cytokine production following antigen encounter.
Authors
Alexandra Christodoulou, Nutthakarn Suwankitwat, Jacob T. Tietsort, Ryan Z. Culbert, Julia Y. Tsai, Fatima A. Tarbal, Chengsong Zhu, Brian M. Iritani
Abstract
Pulmonary fibrosis (PF) is a life-threatening disease that requires effective and well-tolerated therapeutic modalities. Previously, the distinct pathogenic roles of cannabinoid receptor 1 (CB1R) and inducible nitric oxide synthase (iNOS) in the lungs and their joint therapeutic targeting were highlighted in PF. However, the cell-specific role of CB1R in PF has not been explored. Here, we demonstrate that CB1R in alveolar macrophages (AMs) mediates the release of anandamide into the alveoli, which promotes PF by inducing profibrotic macrophages that are accessible to locally delivered antifibrotic therapy. A multitargeted therapy may improve therapeutic efficacy in PF. Pulmonary delivery of 0.5 mg/kg/day MRI-1867 (zevaquenabant), a peripherally acting hybrid CB1R/iNOS inhibitor, is as effective as systemic delivery of 10 mg/kg/day, and also matches the efficacy of nintedanib in mitigating bleomycin-induced PF. A systems pharmacology approach reveals that zevaquenabant and nintedanib treatments reverse pathologic changes in both distinct and shared PF-related pathways, which are conserved in human and mouse. Moreover, zevaquenabant treatment also attenuated fibrosis and profibrotic mediators in human precision-cut lung slices. These findings establish CB1R-expressing AMs as a therapeutic target and support local delivery of dual CB1R/iNOS inhibitor zevaquenabant by inhalation as an effective, well-tolerated, and safer strategy for PF.
Authors
Abhishek Basu, Muhammad Arif, Kaelin M. Wolf, Madeline Behee, Natalie L. Johnson, Lenny Pommerolle, Ricardo H. Pineda, John Sembrat, Charles N. Zawatsky, Szabolcs Dvorácskó, Nathan J. Coffey, Joshua K. Park, Seray B. Karagoz, Grzegorz Godlewski, Tony Jourdan, Judith Harvey-White, Melanie Königshoff, Malliga R. Iyer, Resat Cinar
Abstract
Pancreatic ductal adenocarcinoma (PDAC) has a poor survival rate due to late detection. PDAC arises from precursor microscopic lesions, termed pancreatic intraepithelial neoplasia (PanIN), that develop at least a decade before overt disease––this provides an opportunity to intercept PanIN–to–PDAC progression. However, immune interception strategies require full understanding of PanIN and PDAC cellular architecture. Surgical specimens containing PanIN and PDAC lesions from a unique cohort of five treatment-naïve patients with PDAC were surveyed using spatial-omics (proteomic and transcriptomic). Findings were corroborated by spatial proteomics of PanIN and PDAC from tamoxifen-inducible KPC (tiKPC) mice. We uncovered the organization of lymphoid cells into tertiary lymphoid structures (TLSs) adjacent to PanIN lesions. These TLSs lacked CD21+CD23+ B cells compared to more mature TLSs near the PDAC border. PanINs harbored mostly CD4+ T cells with fewer Tregs and exhausted T cells than PDAC. Peri-tumoral space was enriched with naïve CD4+ and central memory T cells. These observations highlight the opportunity to modulate the immune microenvironment in PanINs before immune exclusion and immunosuppression emerge during progression into PDAC.
Authors
Melissa R. Lyman, Jacob T. Mitchell, Sidharth Raghavan, Luciane T. Kagohara, Amanda L. Huff, Saurav D. Haldar, Sarah M. Shin, Samantha Guinn, Benjamin Barrett, Gabriella Longway, Alexei Hernandez, Erin M. Coyne, Xuan Yuan, Lalitya Andaloori, Jiaying Lai, Yun Zhou Liu, Rachel Karchin, Anuj Gupta, Ashley L. Kiemen, André Forjaz, Denis Wirtz, Pei-Hsun Wu, Atul Deshpande, Jae W. Lee, Todd D. Armstrong, Nilofer S. Azad, Jacquelyn W. Zimmerman, Laura D. Wood, Robert A. Anders, Elizabeth D. Thompson, Elizabeth M. Jaffee, Elana J. Fertig, Won Jin Ho, Neeha Zaidi
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