bluuebunny/crossref_metadata_2025_split huggingface dataset:
Functional studies to understand class II MHC as a gene modifier in cystic fibrosis
Authors: Lu Shiping , Song Kejing , Kolls Jay K. 
Published: January 2023

Abstract
Cystic fibrosis (CF) is an inherited life-threatening disease caused by mutated chlorine channel cystic fibrosis transmembrane conductance regulator(CFTR). Around 60% of CF patients have homozygous F508del mutation. Along with chronic bacterial infection, the integrity and function of pulmonary epithelium were compromised. Pseudomonas aeruginosa (P. a) is the most predominant pathogen, leading to decreased lung function and increased mortality in CF patients. So, prevention/eradication of airway P.a colonization is crucial to maintain lung function. Genome-wide association studies revealed human leukocyte antigen class II(HLAII) within the F508del population are associated with the age of P.a colonization and lung disease severity. However, the role of HLA class II in CF progress is not fully defined. We hypothesized that there may exist differences in antibody isotypes, titer, specificity or affinity that influence/determine lung function of CF patients. Therefore, we recruited a cohort of non-progressive F508del CF patients with confirmed P. a colonization but different lung function. Our results showed sera of CF patients have significantly higher specific IgG and IgG1 titers and stronger bacterial surface binding against mucoid P.a compared of non-CF controls. To assess antigen specificity, we performed immunoprecipitation followed by proteomics, that antibodies from CF sera have a common target, outer membrane protein OprI. Besides, CF sera inhibited bacterial biofilm formation time-dependently compared to non-CF serum. Taken together these studies may shed light on the role of HLA class II as a gene modifier in CF.
A Type I interferon response is associated with increased mTOR activation in idiopathic multicentric Castleman disease
Authors: Pai Ruth-Anne Langan , Japp Alberto Sada , Gonzalez Michael , Rasheed Rozena F , Okumura Mariko , Arenas Daniel , Pierson Sheila K , Layman Awo Akosua Kesewa , Kao Charlly , Hakonarson Hakon , van Rhee Frits , Betts Michael R , Kambayashi Taku , Fajgenbaum David C 
Published: January 2023

Abstract
Idiopathic multicentric Castleman disease (iMCD) is a deadly hematologic illness of unknown etiology involving episodic disease flares characterized by systemic inflammation and multiple organ system dysfunction. We previously showed that the mTOR signaling pathway is elevated in lymph nodes of iMCD patients and that an mTOR inhibitor is effective in preventing disease flares in a small cohort of patients. However, the upstream mechanisms and the cell types and mediators involved in disease pathogenesis remain unknown. Here, we developed a targeted approach to identify candidate cellular drivers and mechanisms in iMCD through flow cytometric and single-cell transcriptomic analysis. Using paired PBMC samples collected from ten iMCD patients during flare and later following resolution of flare (remission), we identified increased T cell activation and alterations in NK cell and monocyte subset frequencies during iMCD flare. These changes were associated with increased Type I Interferon (IFN-I) response gene signatures across CD8+ T cells, NK cells, and monocytes as well as mTOR signaling gene signatures within monocytes. Finally, we demonstrated that increased mTOR activation in iMCD may occur downstream of IFN-I signaling as we observed significantly greater induction of pS6, a readout of mTOR activation, in monocytes and T cells from iMCD remission samples compared to healthy donors. Importantly, this IFN-I-mediated mTOR activation can be abrogated through treatment with the JAKi, ruxolitinib. The data presented here corroborate the notion of widespread systemic inflammation during iMCD disease flare and suggest a role for hyperresponsiveness to IFN-I as a mechanistic driver of increased mTOR signaling in iMCD.
Epigenetic Regulation of the COX-2 Pathway Modulates Macrophage Inflammation in Diabetic Wound Repair
Authors: Davis Frank M , Dendekker Aaron , Joshi Amrita , Wilke Carol , Deng Hongping , Smith Andrew , Obi Andrea , Huang Steve , Robinson Scott , Melvin William J , Fuentes Jaime , Kunkel Steven L , Moore Bethany B , Gallagher Katherine 
Published: January 2023

Abstract
Macrophage plasticity is critical for normal tissue repair to ensure transition from the inflammatory to proliferative phase of healing. In pathologic conditions, such as type 2 diabetes (T2D), wounds fail to heal due to impaired resolution of inflammation. There is increasing evidence that epigenetic-based mechanisms control macrophage function. The cyclooxygenase (COX)-2/Prostaglandin E2 (PGE2) axis, as well as upstream pathways including cytosolic phospholipase A2 (c(PL)A2), have been associated with chronic inflammation, however the underlying mechanisms of COX-2/PGE2 regulation in wound repair have not been examined. Here, we find in human and murine diabetic wounds, that PGE2 production is elevated in wound macrophages and regulates inflammation. Further, epigenetic modification of the COX-2/PGE2 pathway was regulated by MLL1, a methyltransferase, that increased H3K4 trimethylation on the cPLA2 promoter in diabetic wound macrophages and human T2D monocytes resulting in increased cPLA2 expression. Myeloid-specific deletion of MLL1 restored basal cPLA2 levels. Separately, increased TGFβ1 in diabetic wounds augmented miR-29b and DNMT 3a/3b in wound macrophages, resulting in hypomethylation of the Cox-2 gene promoter and overexpression of COX-2/PGE2. Inhibition of the PGE2 pathway, with a macrophage-specific nanocarrier containing a COX-2 inhibitor improved diabetic healing. Taken together, our results indicate the COX-2/PGE2 pathway is a critical regulator of macrophage-mediated inflammation in diabetic wounds and therapeutic manipulation of this pathway improves pathologic wound repair.
Wildfire smoke exposure is associated with decreased methylation of the PDL2 gene
Authors: Prunicki Mary , Miller Sarah , Hopkins Austin , Poulin Matthew , Movassagh Hesam , Yan Liying , Nadeau Kari Christine 
Published: January 2023

Abstract

Objective
To investigate the association between wildfire smoke exposure and DNA methylation of Foxp3-related genes using targeted bisulfite specific methylation sequencing assays recently developed by EpigenDx.

Methods
Subjects (n=16) from the San Francisco Bay area were recruited and gave blood samples during wildfire smoke exposure from the Paradise, CA wildfire 165 miles away. Subjects had their blood re-drawn 3 months later when there was no smoke exposure. An immunology/Foxp3 methylation panel was developed for 20 genes covering 150 CpG sites, targeting genes known to exhibit distinctive methylation profiles in regulatory T cells. Multiplex PCR amplified the regions of interest, using minimal sample DNA and generates inserts ready for NGS adaptor ligation. By initially amplifying specific regions of bisulfite treated DNA, library preparation is enriched with a population of molecules that have potential as indicators or affecters of gene regulation. Using our EpigenDx Ion Torrent library preparation kit, we can ligate these amplified regions to barcoded adaptors in one step.

Results
Paired t-tests revealed less methylation of the PDL2 gene during wildfire exposure at sites immediately upstream of the transcriptional start sites (CpG #-85: p=.002; χ̄ wildfire= 26.3 +14.0; χ̄ no wildfire= 30.8+15.9 and CpG #-86:p=.004; χ̄ wildfire = 22.2+13.4; χ̄ no wildfire= 25.7+15.6), but not in the 5′UTR region (CpG #-84; p=.53). No significant differences were found for the other genes.

Conclusion
Wildfire smoke is associated with decreased PDL2 gene methylation. PDL2, a programmed death ligand, downregulates T cell responses and has previously been associated with airway inflammation and cancer, but not pollution exposure.
Chronic Colitis Impairs Heart Function by Inducing Epigenetic Remodeling in the Adult Heart
Authors: Li Qingjie , Kline Kevin T , Zhong Xiaoying S , Lian Haifeng , Peng Jun , Powell Don W 
Published: January 2023

Abstract

Background and Aims
Inflammatory bowel disease (IBD) represents a spectrum of chronic inflammatory mediated conditions with known extraintestinal manifestations. The interplay between heart and gut in IBD has previously been noted, but the mechanisms remain elusive. The aim of this study was to identify epigenetic mechanisms by which chronic colitis impairs cardiac function.

Methods
To induce chronic colitis, dextran sodium sulfate (DSS, 5% in drinking water) was given to adult rats for 5 days followed by 9 days with normal drinking water for 4 cycles over 8 weeks. Transthoracic echocardiography (TTE) was performed to evaluate heart function.

Results
DSS-induced chronic colitis led to a significant decrease in left ventricular ejection fraction on TTE (68% vs 49%, P&lt;0.05), increased left ventricular mass (107 vs 148, P&lt;0.05), and increased B-type natriuretic protein (222 vs 487, P&lt;0.05). Cardiac and circulating BDNF, as well as GSK-3β, BCL2 and pAKT(S133), was markedly decreased. BDNF was also decreased in colitis induced by trinitrobenzene sulfonic acid. MiRNA profiling showed a total of 52 miRNAs significantly increased in DSS colitis, 7 of which are predicted to target BDNF. RT-qPCR subsequently validated the increase of miR-1b, Let-7d, and miR-155-5p in the adult heart by colitis. Transient transfection demonstrated that miR-1b, Let-7d, and miR-155-5p suppress BDNF in H9c2 rat myoblasts. BDNF overexpression mitigated H2O2-induced oxidative damage n H9c2 cells. Cardiac-specific conditional knockout of BDNF enlarged the heart size and impaired cardiac function.

Conclusions
Chronic colitis suppresses cardiac BDNF by elevating miRNAs; this was accompanied by biochemical and TTE findings suggestive of heart failure.
The hematopoietic transcription factor GATA2 is a novel regulator of apoptotic cell clearance by macrophages in atherosclerosis
Authors: Yin Charles , Vrieze Angela M , Akingbasote James , Pawlak Emily N , Jacob Rajesh A , Hu Jonathan , Sharma Neha , Blackler Garth , Dikeakos Jimmy D , Barra Lillian , Nagpal Dave , Heit Bryan 
Published: January 2023

Abstract
Atherosclerosis is an inflammatory disease involving formation of lipid-rich lesions within the arteries. Macrophages clear apoptotic cells that accumulate within these lesions. Defective apoptotic cell clearance is a hallmark of advanced atherosclerotic disease, yet mechanisms that drive this defect are poorly understood. In this study, we identify the hematopoietic transcription factor GATA2 as a novel regulator of macrophage-mediated apoptotic cell clearance.
Macrophages were isolated by laser capture microdissection from atherosclerotic lesions in aortic tissue obtained from patients undergoing open heart surgery. Gene expression profiling was performed on these macrophages by microarray, with macrophages derived from peripheral blood monocytes used as a control.
We found approximately 3,000 genes to be differentially expressed in aortic punch macrophages, with enrichment in pathways involved in apoptotic cell clearance. In particular, we identified upregulation of GATA2. Mutations in GATA2 have previously been associated with increased risk of coronary artery disease and we found that overexpression of GATA2 in vitro resulted in decreased ability of macrophages to both internalize and degrade apoptotic cells. Conversely, GATA2 downregulation is sufficient to abrogate oxLDL-induced defective apoptotic cell clearance.
Atherosclerotic macrophages exhibit dysregulated expression of genes involved in apoptotic cell clearance and upregulation of GATA2. Recapitulation of GATA2 overexpression is sufficient to impair apoptotic cell clearance in vitro. To our knowledge, we are the first to identify a potential role for GATA2 in driving defective apoptotic cell clearance in atherosclerosis.
Aerosolized Toll-like Receptor Agonists Suppress Allergic Inflammation
Authors: Goldblatt David , Fouts Adrienne , Wali Shradha M , Valverde-Ha Gabriella , Moczygemba-Martinez Margarita , Huston David P , Tuvim Michael J , Dickey Burton , Evans Scott 
Published: January 2023

Abstract
Recent studies have linked exposure to microbes and a reduction of allergic diseases. We sought to determine whether activation of innate immunity by aerosolized Toll-like receptor (TLR) agonists could attenuate the development of allergic inflammation in mice.
BALB/cJ mice were sensitized and challenged with House Dust Mite (HDM). Some mice were treated by aerosol with ligands for TLR9 (ODNm362) and TLR2/6 (Pam2CSK4) in combination (Pam2-ODN). Allergic inflammation was assessed by quantification of leukocytes in bronchoalveolar lavage fluid (BALF) and epithelial mucin content with periodic acid fluorescent Schiff stain (PAFS). Pam2-ODN-treated mice exhibited a 94% reduction in eosinophils, 90% reduction in lymphocytes, and a 44% reduction in epithelial mucin content. Lymphocyte subset analysis showed a 50% reduction in TH2 cells without a detectable change in any other TH subset. Using an alternate allergic inflammation model with Ovalbumin (OVA) Pam2-ODN-treated mice showed greater than 50% reductions in total and OVA-specific IgE serum concentrations. IgG2a concentrations, which are reduced in OVA-sensitized mice, returned to baseline with Pam2-ODN treatment.
There is a stark contrast of the efficacy in mice treated before and after sensitization that suggests Pam2-ODN may modulate the tendency of sensitization when exposed to aeroallergens. Previous studies have shown that lung epithelial cells are required for Pam2-ODN lung responses, and taken together with these new data, Pam2-ODN may reprogram airway epithelial cells to be tolerogenic to aeroallergens, but additional investigation is required to understand the precise molecular mechanism of Pam2-ODN in this context.
Reduced BDCA3+ dendritic cells in nasal mucosa induce severe inflammation in patients with allergic rhinitis and chronic rhinosinusitis
Authors: Park Sang Chul , Kim Tae-Gyun , Cho Hyung-Ju , Kim Chang-Hoon , Yoon Joo-Heon 
Published: January 2023

Abstract
Dendritic cells (DCs) are specialized antigen-presenting cells that play a crucial role in T helper (Th) cell differentiation. DCs of human airway comprise conventional DCs (cDCs) and plasmacytoid DCs (pDCs), of which the cDCs lineage consists of cDC type 1 (cDC1) and cDC type 2 (cDC2). These DCs subsets differ in ontogeny and functional properties in immune response. Thus, we aimed to evaluate the expression of different dendritic cell subsets in nasal mucosa of patients with allergic rhinitis (AR) and chronic rhinosinusitis (CRS). Nasal polyp tissues or ethmoid mucosa from patients undergoing endoscopic sinus surgery or septoplasty were collected. The expression of DCs was investigated by flow cytometry via surface markers including BDCA-1 (CD1c) for cDC1, BDCA-3 (CD141) for cDC2, and BDCA-2 (CD303) for pDC. In subjects with AR, BDCA-3+cDC levels significantly decreased in patients with accompanying CRS, more reduced in eosinophilic CRS (ECRS) than in non-eosinophilic CRS (NECRS), compared to non-CRS patients. In subjects with CRS, the expression of BDCA-3+cDC decreased in patients with accompanying AR; more reduced in multiple allergens sensitization. Consequently, the IF result showed CD4+ CD25+ Foxp3+ regulatory T cell expression was significantly decreased in CRS patients with AR compared to those without AR. Furthermore, the level of BDCA-3+cDC was also inversely related with preoperative CT scores, serum eosinophils and IgE levels. We suggest that BDCA-3+cDC may play an essential role in immunoregulation and induction of clinical tolerance. Reduced frequency of BDCA-3+cDC followed by impaired Treg expression in CRS patients with AR might reflect the mechanism of severe inflammation in patients of CRS combined with AR.
Hyperglycemia impairs tolerance and promotes allergic inflammation in mouse models of asthma
Authors: Queener Ashley , Jeong Brian M , Coden Mackenzie , Doan Ton , Walker Matthew , Nagasaka Reina , Berdnikovs Sergejs 
Published: January 2023

Abstract
Glucose is a key source of energy in systemic and cellular metabolism and has known pro-inflammatory properties. Metabolic disorders (diabetes, insulin resistance) associate with asthma and other allergic diseases. This study sought to understand the role of hyperglycemia in the allergic response. First, we injected fasted Balbc/J mice intraperitoneally (i.p.) with 2g/kg dextrose to test whether hyperglycemia promotes antigen sensitization. Within one hour of injection, we detected a rapid increase in blood glucose levels followed by an increase in expression of inflammatory markers Il1β, Tslp, and Cxcl9 in peritoneal tissue. Concurrently, MHCII+ cells infiltrated the peritoneum. Control experiments showed that inflammatory responses were not due to hyperosmotic effects. To determine whether glucose promotes allergic response, we sensitized mice to chicken egg ovalbumin (OVA) using either alum (standard adjuvant), dextrose, or a vehicle control. Both alum/OVA and dextrose/OVA treated mice mounted lung allergic inflammation in response to inhaled OVA antigen. Dextrose/OVA mice had OVA-specific IgE production similar to alum/OVA group, demonstrating glucose’s ability to promote sensitization. Total cellular infiltrates, bronchoalveolar lavage (BAL) eosinophils, and lung expression of IL-4, IL-13 and IL-33 in dextrose-sensitized mice were equal to or surpassing allergic inflammatory responses in mice given standard adjuvant. Finally, in a separate mouse tolerance model we demonstrated that hyperglycemia impairs development of tolerogenic response to innocuous OVA antigen. These results demonstrate a potentially critical role for glucose dysregulation in loss of tolerance and promotion of allergy.
E3 Ubiquitin Ligase Cbl-b Inhibits Type 2 Innate Lymphoid Cell Development by Targeting ST2 for Ubiquitination
Authors: Guo Hui , Huang Ling , Tang Na , Waldstein Kody , Varga Steven M , Zhang Jian 
Published: January 2023

Abstract
Type 2 innate lymphoid cells (ILC2) play a crucial role in driving allergic airway inflammation, but the regulation of ILC2 development is not fully understood. Previously we have shown that E3 ubiquitin ligase Cbl-b negatively regulates Th2 response, but whether Cbl-b also regulates ILC2-mediated type 2 immunity remains to be defined. In this study, we found that Rag1−/−Cblb−/− mice are hypersensitive to inhalation of A. Fumigatus, a fungus that causes allergic asthma, as revealed by heightened airway hyperresponsiveness (AHR), increased airway inflammation, and mucus production. This hypersensitivity is associated with increased frequencies of ILC2 and eosinophils, but reduced frequency of alveolar macrophages in the lungs. Consistent with this, type 2 cytokines are also increased in the lung homogenates of Rag1−/−Cblb−/− mice. At the molecular levels, ST2 undergoes ubiquitination and proteasome-mediated degradation upon IL-33 stimulation, which is abrogated in cells expressing Cbl-b C373A mutant. Therefore, our data indicate that Cbl-b inhibits the development of ILC2 and ILC2-mediated airway inflammation by targeting ST2 for ubiquitination.
Autophagy is critical for group 2 innate lymphoid cell metabolic homeostasis and effector function
Authors: Galle Lauriane , Hurrell Benjamin P , Lewis Gavin , Howard Emily , Jahani Pedram Shafiei , Banie Homayon , Razani Babak , Soroosh Pejman , Akbari Omid 
Published: January 2023

Abstract
Allergic asthma is a chronic inflammatory disorder that is characterized with airway hyperreactivity (AHR) and driven by Th2 cytokine production. Group 2 innate lymphoid cells (ILC2s) secrete high amount of Th2 cytokines and contribute to the development of AHR. Autophagy is a cellular degradation pathway that recycles cytoplasmic content. However, the role of autophagy in ILC2s remains to be fully elucidated. We characterized the effects of autophagy deficiency on ILC2 effector functions and metabolic balance. ILC2s from autophagy deficient mice were isolated to evaluate homeostasis, cytokine secretion, gene expression and cell metabolism. Also, autophagy deficient ILC2s were adoptively transferred into Rag−/−GC−/− mice, which were them challenged with IL-33 and assessed for AHR and lung inflammation. We demonstrate that autophagy is extensively used by activated ILC2s to maintain their homeostasis and effector functions. Deletion of the critical autophagy gene Atg5 resulted in decreased cytokine secretion and increased apoptosis. Moreover, lack of autophagy among ILC2s impaired their ability to utilize fatty acid oxidation and promoted glycolysis as evidenced by our transcriptomic and metabolite analyses. This shift of fuel dependency led to impaired homeostasis and Th2 cytokine production, thus inhibiting the development of ILC2-mediated AHR. Notably, this metabolic reprogramming was also associated with an accumulation of dysfunctional mitochondria producing excessive reactive oxygen species. These findings provide new insights into the metabolic profile of ILC2s and suggest that modulation of fuel dependency by autophagy is a potentially new therapeutic approach to target ILC2 dependent inflammation.
o-Coumaric acid attenuates atopic dermatitis-like skin inflammation
Authors: Kim Hyemi , Kim Sang-Hyun 
Published: January 2023

Abstract

Background
Hydroxycinnamic acids (coumaric acid; CA) and their derivatives display anti-oxidant and anti-inflammatory effects. CA has three isomers including o-CA, m-CA, and p-CA. Among them, recent report showed the effectiveness of p-CA on skin inflammation.

Objective
In this study, we investigated the role of o-CA on atopic dermatitis (AD) comparing with p-CA.

Methods
For the induction of atopic dermatitis (AD)-like skin inflammation, 1,4-dinitrochlorobenzene (DNCB) and house dust mite extract (Dermatophagoides farinae extract, DFE) were applicated repeatedly, and o-CA were orally administered. For mechanism study, tumor necrosis factor (TNF)-α and interferon (IFN)-γ stimulated human keratinocyte cell line (HaCaT) was used.

Results
In AD-like skin inflammation, the clinical symptoms including the redness, dermal/epidermal thickness, and infiltration of mast cells were significantly reduced by the oral treatment of o-CA. Local inflammatory cytokines expression and systemic production of IgE and IgG2a were also suppressed by the o-CA. In addition, o-CA inhibited the expression of interleukin (IL)-1β, IL-6 and CC-chemokine ligand 17 in TNF-α/IFN-γ stimulated HaCaT cells by the reduction of nuclear translocation of nuclear factor-κB. In all cases, o-CA showed more effectiveness than p-CA.

Conclusions
These results showed that o-CA could be a potential candidate for AD treatment.