Inflammation
Abstract
SOCS3 is the main inhibitor of the JAK/STAT3 pathway. This pathway is activated by interleukin 6 (IL-6), a major mediator of the cytokine storm during shock. To determine its role in the vascular response to shock, we challenged mice lacking SOCS3 in the adult endothelium (SOCS3iEKO) with a non-lethal dose of lipopolysaccharide (LPS). SOCS3iEKO mice died 16-24 hours post-injection after severe kidney failure. Loss of SOCS3 led to an LPS-induced type I interferon-like program, and high expression of pro-thrombotic and pro-adhesive genes. Consistently, we observed intraluminal leukocyte adhesion and NETosis, as well as retinal venular leukoembolization. Notably, heterozygous mice displayed an intermediate phenotype, suggesting a gene dose effect. In vitro studies were performed to study the role of SOCS3 protein levels in the regulation of the inflammatory response. In HUVEC, pulse-chase experiments showed that SOCS3 protein has a half-life below 20 minutes. Inhibition of SOCS3 ubiquitination and proteasomal degradation leads to protein accumulation and a stronger inhibition of IL-6 signaling and barrier function loss. Together, our data demonstrates that the regulation of SOCS3 protein levels is critical to inhibit IL-6-mediated endotheliopathy during shock and provides a promising new therapeutic avenue to prevent MODS though stabilization of endothelial SOCS3.
Authors
Nina Martino, Ramon Bossardi Ramos, Shuhan Lu, Kara Leyden, Lindsay Tomaszek, Sudeshna Sadhu, Gabrielle Fredman, Ariel Jaitovich, Peter A. Vincent, Alejandro P. Adam
Abstract
TIGIT is a recently identified coinhibitory receptor that is upregulated in the setting of cancer and functionally contributes to the impairment of antitumor immunity. However, its role during sepsis is unknown. Because patients with cancer are 10 times more likely to die of sepsis than previously healthy (PH) patients with sepsis, we interrogated the role of TIGIT during sepsis in the context of preexistent malignancy. PH mice or cancer (CA) mice inoculated with lung carcinoma cells were made septic by cecal ligation and puncture (CLP). We found that sepsis induced TIGIT upregulation predominantly on Tregs and NK cells in both PH and CA mice. Anti-TIGIT Ab improved the 7-d survival of CA septic mice but not PH mice after CLP. Treatment of CA septic animals but not PH septic animals with anti-TIGIT mAb significantly reversed sepsis-induced loss of CD4+ T cells, CD8+ T cells, Foxp3+ Treg, and CD19+ B cells in the spleen, which was the result of decreased caspase-3+ apoptotic cells. In sum, we found that anti-TIGIT Ab reversed sepsis-induced T cell apoptosis in CA septic mice and led to a significant survival benefit, suggesting its use as a potential immunotherapy to improve outcomes in septic patients with cancer.
Authors
Wenxiao Zhang, Jerome C. Anyalebechi, Kimberly M. Ramonell, Ching-wen Chen, Jianfeng Xie, Zhe Liang, Deena B. Chihade, Shunsuke Otani, Craig M. Coopersmith, Mandy L. Ford
Abstract
The omega-3 fatty acid docosahexaenoic acid (DHA) inversely relates to neurological impairments with aging; however, limited nondietary models manipulating brain DHA have hindered a direct linkage. We discovered that loss of long-chain acyl-CoA synthetase 6 in mice (Acsl6–/–) depletes brain membrane phospholipid DHA levels, independent of diet. Here, Acsl6–/– brains contained lower DHA compared with controls across the life span. The loss of DHA- and increased arachidonate-enriched phospholipids were visualized by MALDI imaging predominantly in neuron-rich regions where single-molecule RNA in situ hybridization localized Acsl6 to neurons. ACSL6 is also astrocytic; however, we found that astrocyte-specific ACSL6 depletion did not alter membrane DHA because astrocytes express a non–DHA-preferring ACSL6 variant. Across the life span, Acsl6–/– mice exhibited hyperlocomotion, impairments in working spatial memory, and increased cholesterol biosynthesis genes. Aging caused Acsl6–/– brains to decrease the expression of membrane, bioenergetic, ribosomal, and synaptic genes and increase the expression of immune response genes. With age, the Acsl6–/– cerebellum became inflamed and gliotic. Together, our findings suggest that ACSL6 promotes membrane DHA enrichment in neurons, but not in astrocytes, and is important for neuronal DHA levels across the life span. The loss of ACSL6 impacts motor function, memory, and age-related neuroinflammation, reflecting the importance of neuronal ACSL6-mediated lipid metabolism across the life span.
Authors
Regina F. Fernandez, Andrea S. Pereyra, Victoria Diaz, Emily S. Wilson, Karen A. Litwa, Jonatan Martínez-Gardeazabal, Shelley N. Jackson, J. Thomas Brenna, Brian P. Hermann, Jeffrey B. Eells, Jessica M. Ellis
Abstract
The small GTPase RhoA and its downstream effectors are critical regulators in the pathophysiological pro¬cesses of asthma. The underlying mechanism, however, remains undetermined. Here, we generated asthma mouse model with RhoA conditional knockout mice (Sftpc-cre;RhoAf/f) in type II alveolar epithelial cells (AT2) and demonstrated that AT2 cell specific deletion of RhoA leads to exacerbation of allergen-induced airway hyper-responsiveness and airway inflammation with elevated Th2 cytokines in bronchoalveolar lavage fluid (BALF). Notably, Sftpc-cre;RhoAf/f mice showed a significant reduction in TGF-β1 levels in BALFs and lung tissues, and administration of recombinant TGF-β1 to the mice rescued TGF-β1 and alleviated the increased allergic airway inflammation observed in Sftpc-cre;RhoAf/f mice. Using RNA-seq technology, we identified Slc26a4 (pendrin), a transmembrane anion exchange, as the most up-regulated gene in RhoA-deficient AT2 cells. The up-regulation of SLC26A4 was further confirmed in AT2 cells of asthmatic patients and mouse model and in human airway epithelial cells expressing dominant- negative RhoA (RhoA-N19). SLA26A4 was also elevated in serum from asthmatic patients and negatively associated with FEV1%. Furthermore, SLC26A4 inhibitor promoted epithelial TGF-β1 release and attenuated allergic airway inflammation. Our study reveals a previously undefined RhoA-SLC26A4 axis in AT2 cells that functions as a protective mechanism against allergic airway inflammation.
Authors
Danh C. Do, Yan Zhang, Wei Tu, Xinyue Hu, Xiaojun Xiao, Jingsi Chen, Haiping Hao, Zhigang Liu, Jing Li, Shau-Ku Huang, Mei Wan, Peisong Gao
Abstract
T cell receptor (TCR) stimulation leads to expression of the transcription factor TOX. Prolonged TCR signaling, such as encountered during chronic infections or in tumors, leads to sustained TOX expression, which is required for the induction of a state of exhaustion or dysfunction. While CD8 memory T cells (Tmem) in mice typically do not express TOX at steady state, some human Tmem express TOX, but appear fully functional. This seeming discrepancy between mouse and human T cells has led to the speculation that TOX is differentially regulated between these species, which could complicate the interpretation of pre-clinical mouse model studies. We report here that similarly to TCR-mediated signals, inflammatory cytokines are also sufficient to increase TOX expression in human and mouse Tmem. Thus, TOX expression is controlled by the environment, which provides an explanation for the different TOX expression patterns encountered in T cells isolated from specific pathogen free laboratory mice versus humans. Finally, we report that TOX is not necessary for cytokine-driven expression of PD-1. Overall, our data highlight that the mechanisms regulating TOX expression are conserved across species and indicate that TOX expression reflects a T cell’s activation state, and does not necessarily correlate with T cell dysfunction.
Authors
Nicholas J. Maurice, Jacqueline Berner, Alexis K. Taber, Dietmar Zehn, Martin Prlic
Abstract
The fact that the COVID-19 fatality rate varies by sex and age is poorly understood. Notably, the outcome of SARS-CoV-2 infections mostly depends on the control of cytokine storm and the increasingly recognized pathological role of uncontrolled neutrophil activation. Here, we used an integrative approach with publicly available RNA-Seq data sets of nasopharyngeal swabs and peripheral blood leukocytes from patients with SARS-CoV-2, according to sex and age. Female and young patients infected by SARS-CoV-2 exhibited a larger number of differentially expressed genes (DEGs) compared with male and elderly patients, indicating a stronger immune modulation. Among them, we found an association between upregulated cytokine/chemokine- and downregulated neutrophil-related DEGs. This was correlated with a closer relationship between female and young subjects, while the relationship between male and elderly patients was closer still. The association between these cytokine/chemokines and neutrophil DEGs is marked by a strongly correlated interferome network. Here, female patients exhibited reduced transcriptional levels of key proinflammatory/neutrophil-related genes, such as CXCL8 receptors (CXCR1 and CXCR2), IL-1β, S100A9, ITGAM, and DBNL, compared with male patients. These genes are well known to be protective against inflammatory damage. Therefore, our work suggests specific immune-regulatory pathways associated with sex and age of patients infected with SARS-CoV-2 and provides a possible association between inverse modulation of cytokine/chemokine and neutrophil transcriptional signatures.
Authors
Paula P. Freire, Alexandre H.C. Marques, Gabriela C. Baiocchi, Lena F. Schimke, Dennyson L.M. Fonseca, Ranieri C. Salgado, Igor S. Filgueiras, Sarah M.S. Napoleao, Desirée R. Plaça, Karen T. Akashi, Thiago Dominguez Crespo Hirata, Nadia El Khawanky, Lasse M. Giil, Gustavo Cabral-Miranda, Robson F. Carvalho, Luis Carlos S. Ferreira, Antonio Condino-Neto, Helder I. Nakaya, Igor Jurisica, Hans D. Ochs, Niels Olsen Saraiva Camara, Vera Lúcia G. Calich, Otavio Cabral-Marques
Abstract
Cigarette smoke (CS) is the main etiological factor in the pathogenesis of emphysema/Chronic Obstructive Pulmonary Disease (COPD), which is associated with abnormal epithelial-mesenchymal-transition (EMT). Previously, we have shown an association between circadian rhythms and CS-induced lung inflammation, and nuclear-heme-receptor α (REV-ERBα) acting as an anti-inflammatory target in both pulmonary epithelial cells and fibroblasts. We hypothesized that molecular clock REV-ERBα plays an important role in CS-induced circadian dysfunction and EMT alteration. C57BL/6J wild type (WT) and REV-ERBα heterozygous (Het) and knockout (KO) mice were exposed to CS for 30 days (sub-chronic) and 4 months (chronic), and WT mice were exposed to CS for 10 days with or without REV-ERBα agonist (SR9009) administration. Sub-chronic/chronic CS exposure caused circadian disruption and dysregulated EMT in the lungs of WT and REV-ERBα KO mice, both circadian and EMT dysregulation were exaggerated in REV-ERBα KO condition. REV-ERBα agonist, SR9009 treatment reduced acute CS-induced inflammatory response and abnormal EMT in the lungs. Further, REV-ERBα agonist (GSK4112) inhibited TGFβ/CS-induced fibroblast differentiation in human fetal lung fibroblast 1 (HFL-1).Thus, CS-induced circadian gene alterations and EMT activation are mediated through a Rev-erbα-dependent mechanism, which suggests activation of REV-ERBα as a novel therapeutic approach for smoking-induced chronic inflammatory lung diseases.
Authors
Qixin Wang, Isaac K. Sundar, Joseph H. Lucas, Thivanka Muthumalage, Irfan Rahman
Abstract
Epigenetic modifications of the genome, including DNA methylation, histone methylation/acetylation and noncoding RNAs, have been reported to play a fundamental role in regulating immune response during the progression of atherosclerosis. SETDB2 is a member of the KMT1 family of lysine methyltransferases and members of this family typically methylate histone H3 Lys9 (H3K9), an epigenetic mark associated with gene silencing and previous studies have shown SETDB2 is involved in innate and adaptive immunity, the pro-inflammatory response and hepatic lipid metabolism. Here we report that the expression of SETDB2 is markedly upregulated in human and murine atherosclerotic lesions. The upregulation of SETDB2 is observed in pro-inflammatory M1, but not anti-inflammatory M2 macrophages (MΦ). Notably, we found that genetic deletion of SETDB2 in hematopoietic cells promotes vascular inflammation and enhances the progression of atherosclerosis in bone marrow transfer studies in LDLR knockout mice. Single cell RNA-Seq analysis in isolated CD45+ cells from atherosclerotic plaques from mice with SETDB2 deficient bone marrow revealed a significant increase in inflammatory macrophage population and enhanced expression of genes involved in inflammation, myeloid cell recruitment and lipid metabolism. Additionally, we found that loss of SETDB2 in hematopoietic cells is associated with macrophage accumulation in atherosclerotic lesions, macrophage proliferation and attenuated efferocytosis. Overall, these studies identify SETDB2 as an important inflammatory cell regulator that controls macrophage activation in atherosclerotic plaques.
Authors
Xinbo Zhang, Jonathan Sun, Alberto Canfrán-Duque, Binod Aryal, George Tellides, Ying Ju Chang, Yajaira Suárez, Timothy F. Osborne, Carlos Fernández-Hernando
Abstract
Trained immunity, induced by β-glucan in monocytes, is mediated by activating metabolic pathways that result in epigenetic rewiring of cellular functional programs; however, molecular mechanisms underlying these changes remain unclear. Here, we report a key immunometabolic and epigenetic pathway mediated by the miR–9-5p-isocitrate dehydrogenase 3α (IDH3α) axis in trained immunity. We found that β-glucan–trained miR–9-5p–/– monocytes showed decreased IL-1β, IL-6, and TNF-α production after LPS stimulation. Trained miR–9-5p–/– mice produced decreased levels of proinflammatory cytokines upon rechallenge in vivo and had worse protection against Candida albicans infection. miR–9-5p targeted IDH3α and reduced α-ketoglutarate (α-KG) levels to stabilize HIF-1α, which promoted glycolysis. Accumulating succinate and fumarate via miR–9-5p action integrated immunometabolic circuits to induce histone modifications by inhibiting KDM5 demethylases. β-Glucan–trained monocytes exhibited low IDH3α levels, and IDH3α overexpression blocked the induction of trained immunity by monocytes. Monocytes with IDH3α variants from autosomal recessive retinitis pigmentosa patients showed a trained immunity phenotype at immunometabolic and epigenetic levels. These findings suggest that miR–9-5p and IDH3α act as critical metabolic and epigenetic switches in trained immunity.
Authors
Haibo Su, Zhongping Liang, ShuFeng Weng, Chaonan Sun, Jiaxin Huang, TianRan Zhang, Xialian Wang, Shanshan Wu, Zhi Zhang, Yiqi Zhang, Qing Gong, Ying Xu
Abstract
BACKGROUND. The chemokine system of ligands and receptors is implicated in the progression of Alcohol-associated hepatitis (AH). Finding upstream regulators could lead to novel therapies. MOTHODS. The coordinated expression of chemokines in livers of healthy controls (HC) and patients with AH in two distinct cohorts of patients with various chronic liver diseases. Studies in cultured hepatocytes and in tissue-specific knockouts were used for mechanistic insight into a potential upstream regulator of chemokine expression in AH. RESULTS. Selected C-X-C chemokine members of the Interleukin-8 (IL-8) chemokine family and C-C chemokine CCl20 were highly associated with AH compared to HC, but not in patients with liver diseases of other etiologies (NAFLD or HCV). Our previous studies implicate Macrophage migration inhibitory factor (MIF) as a pleiotropic cytokine/chemokine with the potential to coordinately regulate chemokine expression in AH. LPS-stimulated expression of multiple chemokines in cultured hepatocytes was dependent on MIF. Gao-binge ethanol feeding to mice induced a similar coordinated chemokine expression in livers of wild-type mice; this was prevented in hepatocyte-specific Mif knockout (MifΔHep) mice. CONCLUSIONS. This study demonstrates that patients with AH exhibit a specific, coordinately expressed chemokine signature and hepatocyte-derived MIF might drive this inflammatory response.
Authors
Kyle L. Poulsen, Xiude D. Fan, Christopher D. Kibler, Emily Huang, Xiaoqin Wu, Megan R. McMullen, Lin Leng, Richard Bucala, Meritxell Ventura-Cots, Josepmaria Argemi, Ramon Bataller, Laura E. Nagy
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