Inflammation
Abstract
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.
Authors
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
Abstract
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.
Authors
Qintao Wang, Taijie Jin, Shan Jian, Xu Han, Hongmei Song, Qing Zhou, Xiaomin Yu
Abstract
Eosinophilic esophagitis (EoE) is an esophageal immune-mediated disease characterized by eosinophilic inflammation and epithelial remodeling, including basal cell hyperplasia (BCH). Although BCH is known to correlate with disease severity and with persistent symptoms in patients in histological remission, the molecular processes driving BCH remain poorly defined. Here, we demonstrated that BCH is predominantly characterized by an expansion of non-proliferative suprabasal cells that are still committed to early differentiation. Furthermore, we discovered that suprabasal and superficial esophageal epithelial cells retain progenitor identity programs in EoE, which was evidenced by increased quiescent cell identity scoring and the enrichment of signaling pathways regulating stem cell pluripotency. Enrichment and trajectory analyses identified SOX2 and KLF5 as potential drivers of the increased quiescent identity and epithelial remodeling observed in EoE. Notably, these alterations were not observed in GERD. These findings provide additional insights into the differentiation process in EoE and highlight the distinct characteristics of suprabasal and superficial esophageal epithelial cells in the disease.
Authors
Margarette H. Clevenger, Adam L. Karami, Dustin A. Carlson, Peter J. Kahrilas, Nirmala Gonsalves, John E. Pandolfino, Deborah R. Winter, Kelly A. Whelan, Marie-Pier Tétreault
Abstract
Tumor necrosis factor receptor (TNF)-associated factor 4 (TRAF4) is an important regulator of type 2 responses in the airway; however, the underlying cellular and molecular mechanisms remain elusive. Herein, we generated T cell-specific TRAF4-deficient (CD4cre-Traf4fl/fl) mice and investigated the role of TRAF4 in interleukin (IL)-33 receptor (ST2, suppression of tumorigenicity 2)-expressing memory Th2 cells (ST2+ mTh2) in IL-33-mediated type 2 airway inflammation. We found that in vitro polarized TRAF4-deficient (CD4cre-Traf4fl/fl) ST2+ mTh2 cells exhibited decreased IL-33-induced proliferation as compared with TRAF4-sufficient (Traf4fl/fl) cells. Moreover, CD4cre-Traf4fl/fl mice showed less ST2+ mTh2 cell proliferation and eosinophilic infiltration in the lungs than Traf4fl/fl mice in the preclinical models of IL-33-mediated type 2 airway inflammation. Mechanistically, we discovered that TRAF4 was required for the activation of AKT/mTOR and ERK1/2 signaling pathways as well as the expression of transcription factor Myc and nutrient transporters (Slc2a1, Slc7a1, and Slc7a5), signature genes involved in T cell growth and proliferation, in ST2+ mTh2 cells stimulated by IL-33. Taken together, the current study reveals a previously unappreciated role of TRAF4 in ST2+ mTh2 cells in IL-33-mediated type 2 pulmonary inflammation, opening up avenues for the development of new therapeutic strategies.
Authors
Jianxin Xiao, Xing Chen, Weiwei Liu, Wen Qian, Katarzyna Bulek, Lingzi Hong, William Miller-Little, Xiaoxia Li, Caini Liu
Abstract
IgG4-related disease (IgG4-RD) is a systemic autoimmune disease with unclear pathogenesis. We performed single-cell RNA-seq and surface proteome analyses on 61,379 PBMCs from 9 treatment-naïve IgG4-RD patients and 7 age- and sex-matched healthy controls. Integrative analyses were performed for altered gene expression in IgG4-RD, and flow cytometry and immunofluorescence were used for validation. We observed expansion of plasmablasts with enhanced protein processing and activation, which correlated with number of involved organs in IgG4-RD. Increased proportions of CD4+ cytotoxic T lymphocytes (CTLs), CD8+ CTLs-GNLY (granulysin) and γδT cells with enhanced chemotaxis and cytotoxicity but with suppressed inhibitory receptors characterize IgG4-RD. Prominent infiltration of lymphocytes with distinct compositions were found in different organs of IgG4-RD patients. Transcription factors (TFs) including PRDM1/XBP1 and RUNX3 were upregulated in IgG4-RD, promoting the differentiation of plasmablasts and CTLs, respectively. Monocytes in IgG4-RD have stronger expression of genes related to cell adhesion and chemotaxis, which may give rise to profibrotic macrophages in lesions. The gene activation pattern in peripheral immune cells indicated activation of multiple interaction pathways between cell types, in part through chemokines or growth factors and their receptors. Specific upregulation of TFs and expansion of plasmablasts and CTLs may be involved in the pathogenesis of IgG4-RD, and each of these populations are candidate targets for therapeutic interventions in this disease.
Authors
Chenyang Lu, Shasha Li, Pingying Qing, Qiuping Zhang, Xing Ji, Zhigang Tang, Chunyan Chen, Tong Wu, Yidan Hu, Yi Zhao, Xiaohui Zhang, Qi He, David A. Fox, Chunyu Tan, Yubin Luo, Yi Liu
Abstract
Rationale: Femoral atherosclerotic plaques are less inflammatory than carotid plaques histologically, but limited cell-level data exist regarding comparative immune landscapes and polarization at these sites. Objectives: We investigated intraplaque leukocyte phenotypes and transcriptional polarization in 49 total patients undergoing femoral (N=23) or carotid (N=26) endarterectomy using single-cell ribonucleic acid sequencing (scRNA-seq; N=13), flow cytometry (N=24), and immunohistochemistry (N=12). Findings: Comparative scRNA-seq of CD45 positive-selected leukocytes from femoral (N=9; 35265 cells) and carotid (N=4; 30655 cells) plaque revealed distinct transcriptional profiles. Inflammatory foam cell-like macrophages and monocytes comprised 2.5- to 4-fold higher proportions of myeloid cells in carotid plaques, whereas non-inflammatory foam cell-like macrophages and LYVE1-overexpressing resident-like macrophages comprised 3.5- to 9-fold higher proportions of myeloid cells in femoral plaque (p<0.001 for all). A significant comparative excess of CCR2+ macrophages in carotid versus femoral plaque was observed by flow cytometry in a separate validation cohort. B cells were more prevalent and exhibited a comparatively anti-inflammatory profile in femoral plaque, whereas cytotoxic CD8+ T cells were more prevalent in carotid plaque. Conclusion: Human femoral plaques exhibit distinct macrophage profiles and diminished CD8+ T cell populations compared with carotid plaques. Experimental models elucidating determinants of plaque site-specific cell polarization cues are warranted.
Authors
Joshua Slysz, Arjun Sinha, Matthew DeBerge, Shalini Singh, Harris Avgousti, Inhyeok Lee, Kristofor Glinton, Reina Nagasaka, Prarthana J. Dalal, Shaina J. Alexandria, Ching Man Wai, Ricardo Tellez, Mariavittoria Vescovo, Ashwin Sunderraj, Xinkun Wang, Matthew J. Schipma, Ryan K Sisk, Rishab Gulati, Jenifer Vallejo, Ryosuke Saigusa, Donald M. Lloyd-Jones, Jon Lomasney, Samuel E. Weinberg, Karen J. Ho, Klaus Ley, Chiara Giannarelli, Edward B. Thorp, Matthew J. Feinstein
Abstract
Pansclerotic morphea (PSM) is a rare, devastating disease characterized by extensive soft tissue fibrosis, secondary contractions, and significant morbidity. PSM pathogenesis is unknown, and aggressive immunosuppressive treatments rarely slow disease progression. We aimed to characterize molecular mechanisms driving PSM and identify therapeutically targetable pathways by performing single-cell and spatial RNA-sequencing on lesional and non-lesional skin biopsies of a PSM patient 12-months apart and 6 healthy controls. We then validated using immunostaining and in vitro approaches.Fibrotic skin was characterized by prominent type-II IFN response, accompanied by infiltrating myeloid, B-cells, and T-cells, which were the main IFN-γ source. We identified unique CXCL9+ fibroblasts enriched in PSM, characterized by increased chemokine expression, including CXCL9, CXCL10, and CCL2. CXCL9+ fibroblasts were related to profibrotic COL8A1+ myofibroblasts, which had enriched TGF-β response. In vitro, TGF-β and IFN-γ synergistically increased CXCL9 and CXCL10 expression, contributing to the perpetuation of IFN-γ responses. Further, cell-cell interaction analyses revealed cDC2B dendritic cells as a key communication hub between CXCL9+ fibroblasts and COL8A1+ myofibroblasts. These results define PSM as an inflammation-driven condition centered on type-II IFN responses. This work identified key pathogenic circuits between T-cells, cDC2Bs, and myofibroblasts, and suggests JAK1/2 inhibition is a potential therapeutic option in PSM.
Authors
Enze Xing, Feiyang Ma, Rachael Wasikowski, Allison C. Billi, Mehrnaz Gharaee-Kermani, Jennifer Fox, Craig Dobry, Amanda Victory, Mrinal Sarkar, Xianying Xing, Olesya Plazyo, Henry W. Chen, Grant C. Barber, Heidi Jacobe, Pei-Suen Tsou, Robert L. Modlin, John Varga, J. Michelle Kahlenberg, Lam C. Tsoi, Johann E. Gudjonsson, Dinesh Khanna
Abstract
Intestinal mucins play an essential role in the defense against bacterial invasion and the maintenance of gut microbiota, which is instrumental in the regulation of host immune systems; hence, its dysregulation is a hallmark of metabolic disease and intestinal inflammation. However, the mechanism by which intestinal mucins control the gut microbiota as well as disease phenotypes remains nebulous. Herein, we report that N-acetylglucosamine (GlcNAc)-6-O-sulfation of O-glycans on intestinal mucins performs a protective role against obesity and intestinal inflammation. Chst4-/- mice, lacking GlcNAc-6-O-sulfation of the mucin O-glycans, showed significant weight gain and increased susceptibility to dextran sodium sulfate-induced colitis as well as colitis-associated cancer accompanied by significantly reduced immunoglobulin A (IgA) production caused by impaired T follicular helper cell-mediated IgA response. Interestingly, the protective effects of GlcNAc-6-O-sulfation against obesity and intestinal inflammation depend on the gut microbiota, evidenced by the modulation of the gut microbiota by co-housing or microbiota transplantation reversing disease phenotypes and IgA production. Collectively, our findings provide novel insight into the significance of host glycosylation, more specifically GlcNAc-6-O-sulfation on intestinal mucins, in protecting against obesity and intestinal inflammation via regulation of the gut microbiota.
Authors
Hirohito Abo, Aoi Muraki, Akihito Harusato, Tetsuya Imura, Maki Suzuki, Kohta Takahashi, Timothy L. Denning, Hiroto Kawashima
Abstract
Low Density Lipoprotein Receptor-related Protein-1 (LRP1) functions as a receptor for non-pathogenic cellular prion protein (PrPC), which is released from cells by ADAM proteases or in extracellular vesicles. This interaction activates cell-signaling and attenuates inflammatory responses. We screened 14-mer PrPC-derived peptides and identified a putative LRP1 recognition motif in the PrPC sequence spanning residues 98-111. A synthetic peptide (P3) corresponding to this region replicated the cell-signaling and biological activities of full-length shed PrPC. P3 blocked lipopolysaccharide (LPS)-elicited cytokine expression in macrophages and microglia and rescued the heightened sensitivity to LPS in mice in which the PrPC gene (Prnp) is deleted. P3 activated ERK1/2 and induced neurite outgrowth in PC12 cells. The response to P3 required LRP1 and the NMDA Receptor and was blocked by the PrPC-specific antibody, POM2. P3 has Lys residues, which are typically necessary for LRP1-binding. Converting Lys100 and Lys103 into Ala eliminated the activity of P3, suggesting that these residues are essential in the LRP1 binding motif. A P3 derivative in which Lys105 and Lys109 were converted into Ala retained activity. We conclude that the biological activities of shed PrPC, attributed to interaction with LRP1, are retained in synthetic peptides, which may be templates for therapeutics development.
Authors
Elisabetta Mantuano, Carlotta Zampieri, Pardis Azmoon, Cory B. Gunner, Kyle R. Heye, Steven L. Gonias
Abstract
ˆCCL24 is a pro-fibrotic, pro-inflammatory chemokine expressed in several chronic fibrotic diseases. In the liver, CCL24 plays a role in fibrosis and inflammation, and blocking CCL24 led to reduced liver injury in experimental models. We studied the role of CCL24 in primary sclerosing cholangitis (PSC) and evaluated the potential therapeutic effect of blocking CCL24 in this disease. Multidrug resistance gene 2–knockout (Mdr2–/–) mice demonstrated CCL24 expression in liver macrophages and were used as a relevant experimental PSC model. CCL24-neutralizing monoclonal antibody, CM-101, significantly improved inflammation, fibrosis, and cholestasis-related markers in the biliary area. Moreover, using spatial transcriptomics, we observed reduced proliferation and senescence of cholangiocytes following CCL24 neutralization. Next, we demonstrated that CCL24 expression was elevated under pro-fibrotic conditions in primary human cholangiocytes and macrophages, and it induced proliferation of primary human hepatic stellate cells and cholangiocytes, which was attenuated following CCL24 inhibition. Correspondingly, CCL24 was found to be highly expressed in liver biopsies of patients with PSC. CCL24 serum levels correlated with Enhanced Liver Fibrosis score, most notably in patients with high alkaline phosphatase levels. These results suggest that blocking CCL24 may have a therapeutic effect in patients with PSC by reducing liver inflammation, fibrosis, and cholestasis.
Authors
Raanan Greenman, Michal Segal-Salto, Neta Barashi, Ophir Hay, Avi Katav, Omer Levi, Ilan Vaknin, Revital Aricha, Sarit Aharoni, Tom Snir, Inbal Mishalian, Devorah Olam, Johnny Amer, Ahmad Salhab, Rifaat Safadi, Yaakov Maor, Palak Trivedi, Christopher J. Weston, Francesca Saffioti, Andrew Hall, Massimo Pinzani, Douglas Thorburn, Amnon Peled, Adi Mor
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