bluuebunny/crossref_metadata_2025_split huggingface dataset:
CX3CR1 modulates SLE-associated cardiovascular disease in MRL/lpr mice
Authors: Lu Ran , Geng Shuo , Cabana-Puig1 Xavier 
Published: August 2023

Abstract
Systemic lupus erythematosus (SLE) is a chronic and complex autoimmune disease that can cause multi-organ damages. Patients with SLE often have higher risk for heart disease, with poorly defined underlying mechanisms. We generated a Cx3cr1-deficient MRL/lpr lupus-prone mouse which exhibits a distinct phenotype of exacerbated glomerulonephritis. Upon feeding with a high-fat diet, Cx3cr1−/− MRL/lpr mice developed significantly more atherosclerotic plaques that were promoted by Cx3cr1 deficiency-mediated activation of Ly6C++ monocytes. The activated monocytes expressed ICOS-L that interacted with ICOS-expressing follicular T helper cells, which in turn facilitated a germinal center reaction to produce more autoantibodies. Through a positive feedback mechanism, the increased circulatory autoantibodies further promoted the activation of Ly6C-expressing monocytes and their display of ICOS-L. Together, we uncovered a novel, Cx3cr1 deficiency-mediated pathogenic mechanism contributing to SLE-associated atherosclerosis in MRL/lpr mice. The results of these studies will lead to the identification of new therapeutic targets for SLE patients at risk of developing cardiovascular disease.
Silencing of aryl hydrocarbon receptor repressor modulates Th17-cell immunity in human autoimmune hepatitis
Authors: Longhi Maria Serena , Gao Li , Zhang Wei , Zhang Lina , Nastasio Silvia , Graham Jonathon J , Bonder Alan , Patwardhan Vilas , Robson Simon C 
Published: August 2023

Abstract
Th17-cells play a key role in the pathogenesis of autoimmune hepatitis (AIH), a severe hepatopathy characterized by hypergammaglobulinemia, seropositivity for autoantibodies and interface hepatitis on histology. Aberrant Th17-cell response in AIH is linked to alterations of aryl-hydrocarbon-receptor (AHR) signaling. These result in Th17-cell inability to respond to AHR activation. Since AHR can be regulated upon binding to aryl-hydrocarbon-receptor-repressor (AHRR), we investigated whether defective Th17-cell response to AHR derives from aberrant AHRR regulation in AIH. Th17-cells obtained from AIH patients and healthy controls (HC) were exposed to the AHR endogenous ligands unconjugated bilirubin and L-kynurenine (L-kyn), with or without AHRR siRNA.
Levels of AHRR mRNA were similar in AIH and HC Th17-cells. Silencing of AHRR by siRNA boosted Th17-cell response to L-kyn, as reflected by increased CYP1A1, this effect being noted in AIH but not in HC-derived Th17-cells. AHRR blockade did not change the levels of AHR-regulated genes like CD39, IL10, IL17, and IL22, but decreased the levels of IL1b, in the absence and presence of L-kyn in AIH Th17-cells. Silencing of AHRR limited the differentiation of naïve CD4-cells into Th17-cells and modulated Th17-cell transcriptome by downregulating SOCS2, CISH and IL2RA.
Overall, these data indicate that blockade of AHRR restores Th17-cell response to AHR activation and modulates Th17-cell differentiation by decreasing IL1b along with genes involved in cell activation and linked to JAK/STAT signaling. Silencing of AHRR might represent a novel therapeutic strategy to modulate effector Th17-cell immunity and restore immune homeostasis in AIH.
Supported by grants from NIH (R01DK124408 and R01DK108894)
Single-cell sequencing of PBMC characterizes a distinct inflammatory monocyte subset in Lyme disease patients with Post-Treatment Lyme Disease Syndrome (PTLD)
Authors: Chen Xin , Zhou Xin , Ji Xuhuai , Miranda Molly , Rebman Alison , Kathuria Karan , Robinson William H , Aucott John , Davis Mark M 
Published: August 2023

Abstract
Lyme disease (LD) is the most common tick-borne disease in the United States. Most LD patients can return to healthy (RTH) status after antibiotic treatment. Still, 20% of LD patients develop Post-Treatment Lyme Disease Syndrome (PTLD), including fatigue and musculoskeletal pain that persist for a long time. Previous RNA-seq studies showed that most individuals with PTLD had an inflammatory gene expression compared to RTH, but the specific immune components that contribute to PTLD are not well understood. Here, we performed the single-cell sequencing analysis of PBMCs from 6 RTH and 4 PTLD patients collected during multiple clinic visits after antibiotic treatment over two years. We identified a CD14+ monocyte cluster significantly enriched in 4/4 PTLD patients and 2/6 RTH patients from the beginning to 6 months post-treatment. This monocyte cluster displayed distinct inflammatory gene signatures such as CCL3, CCL4, IL1B, CXCL2, CXCL8, and others. RTH patients with such inflammatory monocytes showed low expression of CXCR2 compared to PTLD, suggesting that higher CXCR2 signaling in inflammatory monocytes may contribute to the development of PTLD. In addition, pathway analysis of upregulated genes in PTLD inflammatory monocytes indicated that this subset was induced by molecules of bacterial origin and involved in the regulation of lymphocyte activation. In conclusion, our single-cell study identified a distinct inflammatory monocyte that was enriched and may contribute to PTLD. Tracking this inflammatory monocyte subset could lead to a more accurate prediction of PTLD and identify molecular biomarkers and pathways for therapeutic intervention.
Boosting NAD blunts TH17 inflammation via arginine biosynthesis and redox regulatory control in healthy control and psoriasis human subjects
Authors: Han Kim K , Singh Komudi , Meadows Allison , Sharma Rahul , Hassanzadeh Shahin , Wu Jing , Goss-Holmes Haley , Huffstutler Rebecca , Teague Heather , Mehta Nehal , Griffin Julian , Tian Rong , Traba Javier , Sack Michael N 
Published: August 2023

Abstract
Although NAD+ levels modulate metabolism, how this regulates immunometabolism/inflammation remains unclear. Employing Nicotinamide Riboside (NR) to boost NAD, we explored TH17-linked inflammatory in Psoriasis. Primary Psoriasis CD4+ T cells exposed to NR reduced IL-17 secretion and RNA-seq/pathway analysis implicated NR in modulating sequestosome 1 (SQSTM1/p62)-coupled oxidative stress. In parallel, NR reduced CD4+ T cell reactive oxygen species (ROS) levels and activated the NRF2 transcription factor. Depletion of NRF2 or SQSTM1 diminished NR effects on ROS and TH17 activation. Metabolomic analysis implicated NR in arginine biosynthesis and L-arginine replicated NR CD4+ T cell effects. Genetic disruption of the argininosuccinate lyase synthesis enzyme ameliorated NR antiinflammatory effects, supporting that NR, via arginine biosynthesis orchestrates NRF2 activation, CD4+ T cell antioxidant defenses and blunted TH17 responsiveness. A pilot in-vivo human study similarly showed that NR increased arginine, antioxidant enzyme gene expression and blunted TH17 regulation, implicating NAD metabolism in CD4+ T cell-linked inflammation.
NHLBI Division of Intramural Research (MNS – ZIA-HL005102), NIH Bench to Bedside award (MNS and RT, HL-129510-04S1) and the NIH Office of Dietary Supplementation (JT) and the UK MRC (JLG – MR/P011705/2; UKDRI-5002; MAP UK).
Enteric helminth infection confers protection against lethal respiratory influenza virus infection
Authors: Tai Chi , Xie Jia-Xun , Lin Jr-Shiuan 
Published: August 2023

Abstract
Chronic helminth infection has been considered a serious public health issue. Due to the widespread of helminthiasis, people co-infected with helminth and other pathogens, such as virus, may be common. Studies suggest that helminth infection exert immunomodulatory effects that may alter host susceptibility to subsequent unrelated pulmonary pathogens, such as Mycobacterium tuberculosis. However, the outcome of helminth-respiratory viral co-infection remains controversial.
Here, we established an enteric helminth Heligomosomoides polygyrus bakeri (Hpb)-influenza virus co-infection mouse model, then characterized the immune responses modulated by Hpb infection in the lungs of the helminth chronically infected mice. Our results showed that enteric helminth-infected mice exhibited increased survival and reduced weight loss after lethal influenza virus infection compared with helminth-inexperienced mice. Further analysis revealed that enteric helminth infection altered immune landscape in the lungs by increasing effector CD4+ and CD8+ T cells infiltrated into the airway, as well as upregulating type I interferons and pro-inflammatory cytokines in the lung tissues before influenza virus infection. After influenza virus infection, viral titers were significantly decreased, whereas the viral-specific antibody responses and cellular responses were increased in the lungs of helminth-infected mice. Moreover, histological examination of the lungs revealed that cell infiltration in lung parenchyma and airway lumen was reduced in helminth-infected mice. Taken together, these results suggested that enteric helminth infection confers “bystander” protection against pulmonary influenza virus infection.
Supported by grants from MOST (109-2320-B-002-074-MY3), NHRI (EX110/111-11033SI) and NTU (111L7829), Taiwan
Lung pathogenic, P2RX7-dependent CD4+ T cell immune responses to influenza are exacerbated by co-exposure with lung allergens
Authors: de Gois Macedo Bruna , Santiago-Carvalho Igor , Jacobsen Elizabeth A , da Silva Henrique Borges 
Published: August 2023

Abstract
Extracellular ATP (eATP) is a danger signal released by inflamed tissues, and can be sensed by immune cells via P2RX7. P2RX7 promotes lung pathology induced by influenza infection, by inducing exacerbated numbers of lung CD4+ T cells. In response to influenza, lung CD4+ T cells are comprised of a type 1 (Th1)-like population, and a subset resembling follicular helper (Tfh) CD4+ T cells; this subset is called tissue-resident helper (Trh). Trh cells amplify lung effector immune responses. Trh cells express high P2RX7 levels, and current research in our laboratory shows that P2RX7 is crucial for Trh cell establishment and subsequent lung damage. We have also found that the intensity of lung damage caused by influenza is positively correlated with P2RX7+ lung Trh cells. It is not clear, however, how concomitant exposure to influenza and type 2 immunity-inducing lung allergens (a common clinical occurrence in the United States) affect P2RX7+ lung Trh cells and their resultant tissue damage. We investigated this, using House Dust Mite (HDM) allergen exposure together with Influenza (PR8) infection. HDM/PR8 co-exposure induced worsening of lung inflammation, compared to single exposure to PR8. This inflammation had type 1 characteristics (i.e. parenchymal immune cell accumulation and absence of mucus). The increased lung damage generated by HDM/PR8 exacerbated the generation of influenza-specific P2RX7+ lung Trh cells. The accumulation of lung Trh cells (and subsequent tissue damage) caused by HDM/PR8 was abolished in T cell-specific P2RX7-knockout mice. Our results suggest that local inflammation, eATP release and sensing, and lung Trh cells together dictate the intensity of lung damage, regardless of the nature of the lung disease agent.
R01AI170649
The Upper Respiratory Tract Exhibits Reduced Interferon Response that Contributes to Limited CD8+ T Cell Recruitment and Delayed Clearance of Human Metapneumovirus
Authors: Sojati Jorna , Parks Olivia Bartlett , Williams John V 
Published: August 2023

Abstract
Human metapneumovirus (HMPV) is a leading cause of acute upper and lower respiratory infections. Although nearly everyone is infected during early childhood, re-infections occur often, highlighting difficulty in building long-term immunity. We employed a mouse model of HMPV infection to elucidate differences in upper and lower tract immune responses, and address why upper airway infection does not establish durable protective immunity. We found HMPV burden was higher in nasal airways and exhibited delayed clearance compared to lung. Additionally, there was low nasal expression of antiviral interferons (IFN) and inflammatory cytokines. Key innate immune cells, including macrophages, monocytes, and dendritic cells, were present in the nose at baseline but were not upregulated by infection. We previously showed HMPV-specific lung CD8+T cells (TCD8) are impaired, exhibiting sustained high PD-1 levels and reduced functionality. Despite higher HMPV viral load, there were few HMPV-specific nasal TCD8 and they did not exhibit impairment. To test whether low nasal IFN led to this phenotype, we administered type I IFN in an upper airway-restricted fashion early post-infection. This led to lower HMPV nose titers, increased cell number, higher PD-1 expression, and reduced functionality in HMPV-specific nasal TCD8. Despite the subdued nasal immune response, intranasal vaccination with a small-volume HMPV dose elicited modest reduction of lung and nose titers on challenge but no improvement in clinical disease. Our findings reveal a quiescent nasal immune landscape despite high HMPV burden that contributed to slow clearance and was modulated, in part, by low IFN expression.
Supported by NIH R01 AI085062-06 (JVW), T32 AI138954-4 (JS), and UPMC Children’s Hospital of Pittsburgh Research Advisory Council Graduate Fellowship (JS).
The Immunomodulatory Effects of E. coli Heat-Labile Enterotoxins on the Respiratory Immune
Authors: Ryan Madison , Stroud Margaret , Buchanan Zachary , Rojas Andrea , Knapp Mary-Peyton , Okinaga Adam , Connell Terry , Fiester Steven , Arce Sergio , Grier Jennifer Theresa 
Published: August 2023

Abstract
Heat-Labile Enterotoxins (HLTs) are bacterial secreted proteins with unique immunomodulatory properties. Type II HLTs are produced by E. coli and have been found to possess mucosal and systemic adjuvant properties, but they have never been investigated in respiratory-specific responses. The goal of this study was to determine the impact of three Type II HLTs (LT-IIa, LT-IIb, LT-IIc) on the respiratory-specific immune response. Cell cultures of the human lung epithelial cell line, A549, were stimulated with LT-IIa, LT-IIb, or LT-IIc, in the presence or absence of lipopolysaccharide (LPS), a known immunostimulant. Cell viability was measured by flow cytometry, with cell morphology observations via light microscopy. Immune responses were evaluated via quantitative polymerase chain reaction (qPCR) to quantify RNA expression or enzyme-linked immunosorbent assay (ELISA) for cytokine secretion at 6 and 18 hours post treatment. HLT treatment resulted in no significant changes to cell viability, although cytoplasmic inclusions were consistently visible in LT-IIc-treated cells. IL-6, a marker of inflammation, showed reduced RNA expression in HLT-treated cells at 6 hrs with a return to baseline by 18 hrs. IL-6 cytokine secretion in HLT-treated cells was also decreased, with the greatest reduction at 18 hrs of treatment. Thus, immune responses triggered by HLTs are potentially less inflammatory than those induced by LPS, although a more in-depth characterization of the expression of other cytokines is needed. These results demonstrate that Type II HLTs drive a modified, and potentially less inflammatory, respiratory immune response compared to LPS, which could have significant impacts in the treatment of inflammatory lung conditions.
Acknowledgement: This work was funded in part by a Transformative Seed Grant from the Health Sciences Center at Prisma Health and a University of South Carolina School of Medicine Greenville Summer Research Scholars Fellowship awarded to MR.
Naïve T cell activation in the draining lymph nodes is accelerated by airway resident CD4 T cell activation
Authors: Finn Caroline M , Prokop Emily , McKinstry Kai 
Published: August 2023

Abstract
Tissue-resident memory CD4 T cells (TRM) protect against pathogens through the early shaping of inflammation at sites of infection. The extent to which their activation can impact subsequent systemic T cell responses is not clear. To ask if lung CD4 TRM recognizing antigen can impact systemic T cell responses against the same antigen presented in secondary lymphoid organs, we generated OVA-specific lung TRM primed by infection with an influenza virus expressing OVA peptide. We isolated the OVA-specific TRM 30 days after infection and transferred one million to naive mice intranasally resulting in an airway-resident TRM cohort similar in magnitude to TRM generated in virus-primed mice. We then recalled the transferred TRM by intranasal administration of FITC-labelled OVA protein to focus on TRM recall in the absence of virus-induced inflammation. One day after OVA challenge more FITC+ APC were present in the draining lymph nodes (dLN) of mice with TRM, suggesting antigen presentation to systemic T cells may be accelerated in the presence of airway TRM. We confirmed this by tracking naive OVA-specific CD4 T cells (OT-II) and CD8 T cell (OT-I) cohorts transferred i.v. to mice harboring OVA-specific TRM or not: more responding naive cells, expressing higher levels of activation markers, were detected 3 days after OVA challenge in mice with TRM. By 4 days, more responding cells were present in the lungs of TRM recipients, indicating that TRM and systemic T cell responses form a circuit via enhanced antigen presentation in the lymph nodes. Our results suggest that enhanced kinetics of systemic T cell activation induced by TRM activation in the airways may represent a novel mechanism of their protection against influenza and other respiratory viruses.
EFFECT OF ARTIFICIAL MITOCHONDRIAL TRANSFER FROM LINE CELLULAR HSC-3 TO LYMPHOCYTE TCD4+, AS A MECHANISM INDUCTOR OF EXHAUSTED PHENOTYPE
Authors: Cáceres Bárbara Evelyn Antilef , Cisterna Solange Estefania , Quiroga Romina Andrea , Novoa Sergio Andrés Sanhueza , Cabrera-Garcia Camilo Daniel , Grez Camila Paz Muñoz , Zuñiga Felipe , Ferrada Luciano , Gonzáles Wilfredo , Luz Patricia , Caicedo Andrés , Labarca Gonzalo , Perez Andy , Nova-Lamperti Estefania 
Published: August 2023

Abstract

Background
Oral squamous cell carcinoma (OSCC) is the most frequent type of oral cancer. The tumor microenvironment of OSCC induces an alteration of the T lymphocyte, promoting an exhausted phenotype. The main organelle of metabolism is the mitochondrion and in recent years it has been indicated that several cells have the capacity to transfer mitochondria, including cancer cells. However, it has not been evaluated whether mitochondria transfer from cancer cells to T lymphocytes induces an exhausted phenotype in T lymphocyte. The aim of this work was to analyze the exhausted phenotype in TCD4+ lymphocytes after artificial transfer of mitochondria (MitoCeption) obtained from the oral cancer cell line HSC-3.

Methods
Isolated MitoTracker-labeled mitochondria from oral cancer tumor cells were Mitocepted into CD4+ T lymphocytes. Then, surface molecule expression, proliferation and cytokine secretion mediated by tumor mitochondrial transfer were analyzed by flow cytometry.

Results
The results showed that TCD4+ lymphocytes that acquired mitochondria had increased expression of 2 inhibitory proteins (TIGIT and CTLA4) and 3 proteins associated with exhausted phenotype (PD-1, PLD-1 and LAG3), compared to the control group. In addition, the mitocepted lymphocytes exhibited a significant decrease in proliferation compared to the control. For cytokine analysis, a significant decrease was observed in the mitocepted group in the secretion of IFN-gamma, TNF-alpha, IL-10 and IL-4, but not IL-17, compared to the control.

Conclusions
Therefore, we concluded that the acquisition of isolated mitochondria from HSC-3 cancer cells by CD4+ T lymphocyte induces an exhausted phenotype in the TCD4+ lymphocyte.

Regular Fondecyt Project 1211480
Role of the E3 ubiquitin ligase Peli1 in regulating antitumor T cell responses
Authors: Ko Chun-Jung , Sun Shao-Cong 
Published: August 2023

Abstract
Metabolic fitness of T cells is crucial for immune responses against infections and tumorigenesis. Both the T cell receptor signal (TCR) and environmental cues contribute to the induction of T cell metabolic reprogramming, but the underlying mechanism is incompletely understood. Here, we identified the E3 ubiquitin ligase Peli1 as an important regulator of T cell metabolism and antitumor immunity. Peli1 ablation profoundly promotes tumor rejection, associated with increased effector function and the number of tumor-infiltrating CD4 and CD8 T cells. Moreover, Peli1 deficiency inhibited the expression of PD-1 and TIM-3 and reduced the exhaustion of tumor-infiltrating CD8 T cells. The Peli1-deficient T cells display markedly stronger metabolic activities, particularly glycolysis, than wild-type T cells. Peli1 controls the activation of mTOR signaling, stimulated by both the TCR signal and growth factors, and this function of Peli1 is mediated through the regulation of the mTORC1-inhibitory proteins, TSC1 and TSC2. Peli1 mediates non-degradative ubiquitination of TSC1, thereby promoting the stabilization of the TSC complex. These results establish Peli1 as a novel regulator of mTORC1 and downstream mTORC1-mediated actions on T cell metabolism and antitumor immunity.
Pre-operative exercise therapy suppresses colorectal liver metastases by triggering anti-tumor trained immunity of Kupffer cells
Authors: Huang Hai , Zhang Hongji , Tsung Allan 
Published: August 2023

Abstract
Hepatic recurrence after surgical resection of colorectal liver metastasis is the major cause of treatment failure. Pre-operative exercise therapy (PEx) has been shown to improve outcomes from major abdominal surgeries. We demonstrate that PEx significantly attenuates liver ischemia/reperfusion (I/R) injury by inducing an anti-inflammatory phenotype in Kupffer cells (KCs). However, the mechanisms by which PEx prevents surgery-induced hepatic recurrence remain unclear.

Results
Four weeks of treadmill running significantly reduces I/R-induced hepatic metastatic tumor growth in mice compared to sedentary controls. Depletion of KCs substantially decreases I/R-induced tumor progression, indicating a pro-tumor role of KCs. Our scRNA-seq data reveal that PEx causes dramatic transcriptomic changes in KCs. A clear induction of trained immunity with noticeably higher levels of anti-tumor cytokines IFN-γ and TNF-α is observed in PEx-KCs. With scATAC-seq, we find that PEx triggers the chromatin accessibilities profile changes in KCs, which is associated with the metabolic reprogramming of itaconate/IRG1 pathway. Furthermore, PEx significantly changes the transcriptomic profile of polymorphonuclear myeloid-derived suppressive cells (PMN-MDSCs) in the tumor microenvironment (TME) and decreases them from forming neutrophil extracellular traps (NETs), which promote tumor progression. We identify the cell-cell interaction between KCs and PMN-MDSCs in the TME is significantly enriched after PEx, suggesting that PEx may facilitate KCs to modulate PMN-MDSCs. In summary, PEx ameliorates surgical stress-induced pro-tumorigenic inflammatory responses and sustains an anti-tumor immune microenvironment in the liver.

Supported by grants from NIH (R01GM137203 for Hai Huang, R01CA214865 for Allan Tsung)