BACKGROUND. Obesity is a multi-factorial disease with adverse health implications including insulin resistance (IR). In patients with obesity, the presence of high circulating levels of leptin, deemed hyperleptinemia, is associated with IR. Recent data in mice with diet-induced-obesity (DIO) shows a partial reduction in leptin levels improves IR. Additional animal studies demonstrate IL-4 decreases leptin levels. In rodents, resident adipose tissue (AT) eosinophils (EOS) are the main source of IL-4 and are instrumental in maintaining metabolic homeostasis. A marked reduction in AT-EOS content is observed in animal models of DIO. These observations have not been explored in humans. METHODS. We analyzed AT from individuals with obesity and age-matched lean counterparts for AT-EOS content, IL-4, circulating leptin levels and measures of IR. RESULTS. Our results showed that individuals with obesity (n=15) had a significant reduction in AT-EOS content (P<0.01), decreased AT-IL-4 gene expression (P=0.02), and decreased IL-4 plasma levels (P<0.05) in addition to expected IR (P<0.001) and hyperleptinemia (P<0.01) compared to lean subjects (n=15). AT-EOS content inversely correlated with BMI (P=0.002) and IR (P=0.005). Ex vivo AT explants and in vitro cell culture of primary, human mature adipocytes exposed to either IL-4 or EOS conditioned media produced less leptin (P<0.05). CONCLUSIONS. Our results suggested for IL-4 to act as a link between EOS, AT, and leptin production. Future studies exploring this interaction may identify a new avenue for the treatment of obesity and its complications through amelioration of hyperleptinemia. TRIAL REGISTRATION. Clinicaltrials.gov NCT02378077 & NCT04234295. FUNDING. Dr. Eleanna De Filippis received support by Arizona Department of Health Services, Arizona Biomedical Research Commission (ABRC) (ADHS14-00003606), the Katryn H. and Roger Penske Career Development Award in Endocrinology in Honor of Dr. Ian Hay, and Mayo Foundation, KL2 TR002379-02-01 CTSA UL1 TR002377 NCATS/NIH. Dr. Elizabeth A. Jacobsen received support from NIAID AI132840 and Mayo Foundation
James D. Hernandez, Ting Li, Hamza Ghannam, Cassandra M. Rau, Mia Y. Masuda, James A. Madura, Elizabeth A. Jacobsen, Eleanna De Filippis
Intrahepatic macrophages in nonalcoholic steatohepatitis (NASH) are heterogenous and include proinflammatory recruited monocyte derived macrophages. The receptor for advanced glycation end products (RAGE) is expressed on macrophages and can be activated by damage associated molecular patterns (DAMPs) upregulated in NASH, yet the role of macrophage-specific RAGE signaling in NASH is unclear. Therefore, we hypothesized that RAGE expressing macrophages are proinflammatory and mediate liver inflammation in NASH. Compared to healthy controls, RAGE expression was increased in liver biopsies from human NASH patients. In a high -fat, -fructose, and -cholesterol (FFC)-induced murine model of NASH, RAGE expression was increased, specifically on recruited macrophages. FFC mice that received a pharmacological inhibitor of RAGE (TTP488), and myeloid-specific RAGE knockout mice (RAGE-MKO) had attenuated liver injury associated with a reduced accumulation of RAGE+ recruited macrophages. Transcriptomic analysis suggested that pathways of macrophage and T-cell activation were upregulated by FFC diet, inhibited by TTP488 treatment, and reduced in RAGE-MKO mice. Correspondingly, the secretome of ligand-stimulated bone marrow derived macrophages from RAGE-MKO mice had an attenuated capacity to activate CD8+ T cells. Our data implicate RAGE as what we propose to be a novel and potentially targetable mediator of the proinflammatory signaling of recruited macrophages in NASH.
Gopanandan Parthasarathy, Amy S. Mauer, Naresh Golla, P. Vineeth Daniel, Lily H. Kim, Guneet S. Sidhu, George W. Marek 3rd, Emilien Loeuillard, Anuradha Krishnan, Hyun Se Kim Lee, Kevin D. Pavelko, Michael Charlton, Petra Hirsova, Sumera I. Ilyas, Harmeet Malhi
Gout commonly manifests as a painful, self-limiting inflammatory arthritis. Nevertheless, the understanding of the inflammatory and immune responses underlying gout flares and remission remains ambiguous. Here, based on single-cell RNA-Seq and an independent validation cohort, we identified the potential mechanism of gout flare, which likely involves the upregulation of HLA-DQA1+ nonclassical monocytes and is related to antigen processing and presentation. Furthermore, Tregs also play an essential role in the suppressive capacity during gout remission. Cell communication analysis suggested the existence of altered crosstalk between monocytes and other T cell types, such as Tregs. Moreover, we observed the systemic upregulation of inflammatory and cytokine genes, primarily in classical monocytes, during gout flares. All monocyte subtypes showed increased arachidonic acid metabolic activity along with upregulation of prostaglandin-endoperoxide synthase 2 (PTGS2). We also detected a decrease in blood arachidonic acid and an increase in leukotriene B4 levels during gout flares. In summary, our study illustrates the distinctive immune cell responses and systemic inflammation patterns that characterize the transition from gout flares to remission, and it suggests that blood monocyte subtypes and Tregs are potential intervention targets for preventing recurrent gout attacks and progression.
Hanjie Yu, Wen Xue, Hanqing Yu, Yaxiang Song, Xinying Liu, Ling Qin, Shu Wang, Hui Bao, Hongchen Gu, Guangqi Chen, Dake Zhao, Yang Tu, Jiafen Cheng, Liya Wang, Zisheng Ai, Dayong Hu, Ling Wang, Ai Peng
Cachexia is a debilitating skeletal muscle wasting condition for which we currently lack effective treatments. In the context of cancer, certain chemotherapeutics cause DNA damage and cellular senescence. Senescent cells exhibit chronic activation of the transcription factor nuclear factor (NF)-κB, a known mediator of the pro-inflammatory senescence-associated secretory phenotype (SASP) and skeletal muscle atrophy. Thus, targeting NF-κB represents a logical therapeutic strategy to alleviate unintended consequences of genotoxic drugs. Herein, we show that treatment with the IKK/NF-κB inhibitor SR12343 during a course of chemotherapy reduces markers of cellular senescence and the SASP in liver, skeletal muscle, and circulation and, correspondingly, attenuates features of skeletal muscle pathology. Lastly, we demonstrate SR12343 mitigates chemotherapy-induced reductions in body weight, lean mass, fat mass, and muscle strength. These findings support senescent cells as a promising druggable target to counteract the SASP and skeletal muscle wasting in the context of chemotherapy.
Davis A. Englund, Alyssa M. Jolliffe, Gabriel J. Hanson, Zaira Aversa, Xu Zhang, Xinyi Jiang, Thomas A. White, Lei Zhang, David G. Monroe, Paul D. Robbins, Laura J. Niedernhofer, Theodore M. Kamenecka, Sundeep Khosla, Nathan K. LeBrasseur
Plasma cell-free DNA (cfDNA), a marker of disease severity in sepsis, is a recognized driver of thromboinflammation and a potential therapeutic target. In sepsis, plasma cfDNA is mostly derived from neutrophil extracellular trap (NET) degradation. Proposed NET-directed therapeutic strategies include preventing NET formation or accelerating NET degradation. However, NET digestion liberates pathogens and releases cfDNA that promote thrombosis and endothelial cell injury. We propose an alternative strategy of cfDNA and NET stabilization with chemokine platelet factor 4 (PF4, CXCL4). We previously showed that human PF4 (hPF4) enhances NET-mediated microbial entrapment. We now show that hPF4 interferes with thrombogenicity of cfDNA and NETs by preventing their cleavage to short-fragment and single-stranded cfDNA that more effectively activates the contact pathway of coagulation. In vitro, hPF4 also inhibits cfDNA-induced endothelial tissue factor surface expression and von Willebrand factor release. In vivo, hPF4 expression reduced plasma thrombin-antithrombin (TAT) levels in animals infused with exogenous cfDNA. Following lipopolysaccharide challenge, Cxcl4–/– mice had significant elevation in plasma TAT, cfDNA, and cystatin C levels, effects prevented by hPF4 infusion. These results show that hPF4 interacts with cfDNA and NETs to limit thrombosis and endothelial injury, an observation of potential clinical benefit in the treatment of sepsis.
Anh T.P. Ngo, Abigail Skidmore, Jenna Oberg, Irene Yarovoi, Amrita Sarkar, Nate Levine, Veronica Bochenek, Guohua Zhao, Lubica Rauova, M. Anna Kowalska, Kaitlyn Eckart, Nilam S. Mangalmurti, Ann Rux, Douglas B. Cines, Mortimer Poncz, Kandace Gollomp
Lung contusion and gastric aspiration (LC and GA) are major risk factors for developing acute respiratory distress following trauma. Hypoxia from lung injury is mainly regulated by hypoxia-inducible factor 1α (HIF-1α). Published data from our group indicate that HIF-1α regulation in airway epithelial cells (AEC) drives the acute inflammatory response following LC and GA. Metabolomic profiling and metabolic flux of Type II AEC following LC revealed marked increases in glycolytic and TCA intermediates in vivo and in vitro that were HIF-1α dependent. GLUT-1/4 expression was also increased in HIF-1α+/+ mice, suggesting that increased glucose entry may contribute to increased intermediates. Importantly, lactate incubation in vitro on Type II cells did not significantly increase the inflammatory byproduct IL-1β. Contrastingly, succinate had a direct proinflammatory effect on human small AEC by IL-1β generation in vitro. This effect was reversed by dimethylmalonate, suggesting an important role for succinate dehydrogenase in mediating HIF-1α effects. We confirmed the presence of the only known receptor for succinate binding, SUCNR1, on Type II AEC. These results support the hypothesis that succinate drives HIF-1α–mediated airway inflammation following LC. This is the first report to our knowledge of direct proinflammatory activation of succinate in nonimmune cells such as Type II AEC in direct lung injury models.
Madathilparambil V. Suresh, Sinan Aktay, George Yalamanchili, Sumeet Solanki, Dily Thazhath Sathyarajan, Manikanta Swamy Arnipalli, Subramaniam Pennathur, Krishnan Raghavendran
Abnormal macrophage polarization is generally present in autoimmune diseases. Overwhelming M1 macrophage activation promotes the continuous progression of inflammation, which is one of the vital reasons for the development of autoimmune diseases. However, the underlying mechanism is still unclear. Here we explore the function of RFX1 in macrophage polarization by constructing colitis and lupus-like mouse models. Both in vivo and in vitro experiments confirmed that RFX1 can promote M1 and inhibit M2 macrophage polarization. Besides, we also found that RFX1 promoted DNA demethylation of macrophage polarization-related genes by increasing APOBEC3A/Apobec3 expression. Noteworthily, we identified a potential RFX1 inhibitor, adenosine diphosphate (ADP), providing a potential strategy for treating autoimmune diseases.
Shuang Yang, Pei Du, Haobo Cui, Meiling Zheng, Wei He, Xiaofei Gao, Zhi Hu, Sujie Jia, Qianjin Lu, Ming Zhao
Modulation of the immune response to initiate and halt the inflammatory process occurs both at the site of injury as well as systemically. Due to the evolving role of cellular metabolism in regulating cell fate and function, tendon injuries which undergo normal and aberrant repair were evaluated by metabolic profiling to determine its impact on healing outcomes. Metabolomics revealed an increasing abundance of the immunomodulatory metabolite itaconate with the injury site. Subsequent single-cell RNA sequencing, molecular and metabolomic validation identified a highly mature neutrophil subtype, not macrophages, as the primary producers of itaconate following trauma. These mature itaconate-producing neutrophils were highly inflammatory, producing cytokines that promote local injury fibrosis before cycling back to the bone marrow. In the bone marrow, itaconate was shown to alter hematopoiesis, skewing progenitor cells down myeloid lineages, thereby regulating systemic inflammation. Therapeutically, exogenous itaconate was found to reduce injury site inflammation, promoting tenogenic differentiation and impairing aberrant vascularization with disease ameliorating effects. These results present an intriguing role for cycling neutrophils as a sensor of inflammation induced by injury, potentially regulating immune cell production in the bone marrow, through delivery of endogenously produced itaconate and demonstrate a therapeutic potential for exogenous itaconate following tendon injury.
Janna l. Crossley, Sonya Ostashevskaya-Gohstand, Stefano Comazzetto, Jessica S. Hook, Lei Guo, Neda Vishlaghi, Conan Juan, Lin Xu, Alexander R. Horswill, Gerta Hoxhaj, Jessica G. Moreland, Robert J. Tower, Benjamin Levi
BACKGROUND. Oxidized ApoB (oxLDL) and other oxidation-modified lipoproteins (OMLs), such as oxidized ApoA-I (oxHDL), are known pro-atherogenic factors. However, OMLs prognostic value for assessing high-risk coronary plaques by coronary computed tomography angiography (CCTA) has not been fully evaluated. METHODS. In a prospective, observational study, 306 participants with known cardiovascular disease (CVD) had extensive lipoprotein profiling, including plasma OMLs and HDL function measured. Proteomics analysis was performed on oxHDL isolated by anti-oxApoA-I antibody. Atherosclerotic plaque assessment was accomplished by quantitative CCTA (QAngio, Medis). RESULTS. Patients were predominantly white, overweight males (58.5%) on statin therapy (43.5%). Significant increases in LDL-C, ApoB, LDL-TG, sdLDL-C (P<0.001 for all), and TGs (P=0.03) were observed in high oxLDL group, accompanied by less efficient HDL function. High oxLDL was associated with necrotic (NB) (β=0.20; P<0.0001) and fibro-fatty (FFB) burdens (β=0.15; P=0.001) after multivariate adjustment. Low oxHDL had a significant reverse association with these plaque characteristics. Plasma oxHDL levels better predicted NB and FFB after adjustment (2.22, 1.27-3.88 and 2.80, 1.71-4.58) (ORs, 95% CIs) compared to oxLDL and HDL-C. Interestingly, oxHDL was associated with fibrous burden (FB) change over 3.3 years of follow-up (rho=0.535; P=0.033), when compared to oxLDL. Finally, combined Met(136) monooxidation and Trp(132) dioxidation of HDL showed the most evident association with CAC score (r=0.786; P<0.001) and FB (r=0.539; P=0.012) in high oxHDL, whereas Met(136) monooxidation significantly associated with high-risk plaque in low oxHDL. CONCLUSION. Our findings suggest that the investigated OMLs are associated with high-risk coronary plaque features and progression over time in CVD patients. TRIAL REGISTRATION. URL: https://www.clinicaltrials.gov. Unique identifier: NCT01621594. FUNDING. This work was supported by the National Heart, Lung and Blood Institute (NHLBI) at the National Institutes of Health Intramural Research Program. The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Alexander V. Sorokin, Christin G. Hong, Angel M. Aponte, Elizabeth M. Florida, Jingrong Tang, Nidhi Patel, Irina N. Baranova, Haiou Li, Philip M. Parel, Vicky Chen, Sierra R. Wilson, Emily L. Ongstad, Anna Collén, Martin P. Playford, Thomas L. Eggerman, Marcus Y. Chen, Kazuhiko Kotani, Alexander V. Bocharov, Alan T. Remaley
Pyrin, a protein encoded by the MEFV gene, plays a vital role in innate immunity by sensing modifications in Rho GTPase and assembling the pyrin inflammasome, which in turn activates downstream immune responses. We identified a novel and de novo MEFV p.E583A dominant variant in three patients from a family, distinct from the previously reported S242 and E244 sites. These patients exhibited a phenotype that diverged from those resulting from classical MEFV gene mutations, characterized by the absence of recurrent fever but the presence of recurrent chest and abdominal pain. Colchicine effectively controlled the phenotype, and the mutation was found to induce pyrin inflammasome assembly and activation in patients' peripheral blood mononuclear cells (PBMCs) and cell lines. Mechanistically, truncation experiments revealed that the E583A variant impacted the autoinhibitory structure of pyrin. Our study offers new insights into the mechanisms underlying pyrin inflammasome activation.
Qintao Wang, Taijie Jin, Shan Jian, Xu Han, Hongmei Song, Qing Zhou, Xiaomin Yu
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