bluuebunny/crossref_metadata_2025_split huggingface dataset:
A metabolic sensor controls pathologic ILC2 function to regulate airway inflammation
Authors: Monticelli Laurel A 
Published: January 2023

Abstract
Employing models of allergen exposure, pathogen infection, and chronic inflammation, research in the Monticelli lab is examining how the innate immune system responds to tissue-specific cues to modulate cellular metabolism in order to coordinately regulate resolution of inflammation and promotion of tissue homeostasis at the body’s barrier surfaces. Our recent findings indicate that subsets of innate lymphoid cells (ILCs) utilize distinct metabolic pathways to fuel their proliferation and activation, and that this bioenergetic re-wiring influences their proinflammatory and tissue protective functions. Ongoing studies are examining how particular cell-extrinsic signals (such as cytokines) and cell-intrinsic factors (such as enzymes and transcription factors) control this metabolic reprogramming.
In new unpublished studies, we’ve found that lung-resident ILC2s upregulate expression of the metabolic ‘sensor’ transcription factor aryl hydrocarbon receptor (Ahr) upon activation with select airway allergens. Genetic or pharmacologic manipulation of Ahr signaling in murine models directly regulated ILC2 responses during airway inflammation, suggesting that ILC2-intrinsic sensing of Ahr ligand metabolites is critical for protection versus progression of innate immune lung disease pathogenesis.
PDGFRα ablation leads to alteration of ECM and immune cell composition in the lung
Authors: Park Juwon , Lee Christina , Tallquist Michelle D. 
Published: January 2023

Abstract
Fibroblasts are the major cells responsible for tissue homeostasis, repair, and remodeling. In particular, PDGFRα is expressed by mesenchymal progenitors in the lung that constitute the myofibroblast population which transiently express α-SMA during alveologenesis. In the fibrotic lungs, PDGFRα+ lineages can differentiate into subpopulation of myofibroblasts which regulate tissue repair and remodeling. Although the contribution of PDGFRα+lineage to lung development and fibrosis are particularly well-known, their roles in the lung parenchyma at baseline are less characterized.
To explore how PDGFRα+ fibroblasts affect extracellular matrix in baseline lung, we used genetic ablation of PDGFRα+ fibroblasts using Pdgfrα-CreERT2-driven expression of diphtheria toxin A. Histologically, thin mesenchyme was observed in fibroblast-ablated adult lungs. A majority of PDGFRα+ lineages are Col1a1-GFP+ cells, but PDGFRα-ablated lungs showed a significant decrease in the number of PDGFRα lineage and Col1a1-GFP+ cells. In addition, decreased expressions of ECM genes, such as Col1a1, Col1a2, and fibronectin-1 were observed in PDGFRα-ablated lungs. These data indicated that PDGFRα+ cells are a major source of extracellular proteins and PDGFRα ablation leads to alteration of ECM homeostasis in the baseline lung. Flow cytometry analysis of the lung tissues revealed that PDGFRα ablation resulted in elevated numbers of leukocytes and neutrophils. However, fibroblast loss did not affect macrophage numbers. These data suggested that fewer PDGFRα+ cells or loss of ECM or both can affect the recruitment of immune cells in the lung. In summary, changes in ECM environment by PDGFRα ablation leads to altered immune cell composition in the lung.
Non-cell-autonomous role of myofibroblasts in pulmonary fibrosis through lactate induction of M2 macrophage polarization
Authors: Liu Gang 
Published: January 2023

Abstract

Rationale
There has been growing evidence that metabolic dysregulations play critical roles in the pathogenesis of lung fibrosis, particularly idiopathic pulmonary fibrosis (IPF). Recent studies from our group as well as others’ showed that lung myofibroblasts displayed augmented glycolysis and secreted more lactate than normal fibroblasts. In this study, we examined the effect of lactate, the end product of myofibroblast glycolysis, on the phenotypic alterations of macrophages that has been frequently implicated in lung fibrosis.

Methods
Levels of M2 macrophage markers were determined by real-time PCR and Western blotting. Lactate transportation into cells was inhibited by siRNA knockdown of lactate MCT1 or MCT1 inhibitors.

Results
First, we confirmed that alveolar macrophages (AM) from fibrotic mouse lungs exhibited a M2 macrophage phenotype, as evidenced by increased expression of M2 markers Arginase 1 (Arg1) and vascular endothelial growth factor (VEGF) in these cells. We found that lactate induced M2 polarization of bone marrow derived macrophages (BMDM) and AMs. Furthermore, conditional media from lung myofibroblasts as well as coculture with lung myofibroblasts promoted M2 differentiation of BMDMs and AMs. Lactate induced M2 polarization could be inhibited by incapacitating lactate transporter MCT1 through siRNA knockdown or specific inhibitors.

Conclusions
Our data suggest that lung myofibroblast derived lactate promotes the pro-fibrotic differentiation of lung macrophages. We provide novel insight into the mechanism by which lung myofibroblasts participate in the pathogenesis of lung fibrosis. Targeting lactate secretion or intake by lung macrophages could be novel strategies to treat lung fibrosis.
Role of cardiac macrophages in controlling the infection and homeostasis of steady state heart function in aging
Authors: Saljoughian Noushin , Wu Qian , Kumar Naresh , Ganesan Latha P. , Lafuse William P , Rajaram Murugesan 
Published: January 2023

Abstract
Activation of immune system following cardiac infection is critical for mounting inflammatory and regenerative response to maintain the steady state heart function. Cardiac resident macrophages (CRMs) play a critical role in maintenance of homeostatic functions and tissue repair during infection. There are two subsets of CRMs in the heart CCR2+MHCIIhigh and CCR2−MHCIIhigh/low. We have previously demonstrated that Mycobacterium avium (M.a.) infection causes cardiac arrhythmia and dissemination of bacteria into the heart tissue of old mice. These abnormalities are due to an increased infiltration of myeloid cells and fibrosis. In order understand the role of CRMs in cardiac dysfunction in aged mice, we used the young and old mouse infection model. Cardiac single cells were prepared and analyzed with flow cytometry. The results show that the infiltration of myeloid cells into the heart was significantly increased in young mice during early stage of infection. In particularly, we observed an increased frequency of MHC-IIhigh CRMs in the heart of young mice upon M.a infection. In contrast, the aged mice shows an increase in numbers but fail to maintain the CRM frequency during the course of infection. Interestingly, we also observed the higher expression of MerTK on CRMs in the young mice than old mice. Our in vitro experiments demonstrated that activation of LXR enhances the expression of MerTK in macrophages and efferocytosis function. In conclusion achieved data indicates that the accumulation of MHC-II high CRMs and MerTK positive macrophages in the hearts of young mice provides the mechanism of M.a. clearance and efficient regeneration. Thus, MerTK is a promising therapeutic target in prevention of cardiac damage caused by M.a. in ageing.
Bidirectional crosstalk between neutrophils and adipocytes promotes adipose tissue inflammation
Authors: Watanabe Yasuharu , Nagai Yoshinori , Takatsu Kiyoshi 
Published: January 2023

Abstract
Obesity-associated adipose tissue inflammation contributes to the development of type 2 diabetes. Chronic activation of IL-1β system in adipose tissue on metabolic disorders is well demonstrated. However, a mechanism for its expression and activation in the tissue has remained unexplored.
Here we demonstrate that IL-1β transcript was enriched in neutrophils of white adipose tissue (WAT), and the expression of IL-1β was up-regulated by a high-fat diet in the WAT but not in other tissues, including bone marrow, peripheral blood, and spleen. The co-culture of neutrophils with 3T3-L1 adipocytes indicate that contact interaction with adipocytes is critical for the expression of IL-1β via NF-κB activation in adipose tissue neutrophils. Lipolysis of adipocytes accumulated neutrophils prior to macrophages in the WAT, and produced high levels of IL-1β via an ASC-caspase-1-mediated inflammasome pathway. Leukotriene B4 production in the WAT also contributed to neutrophil accumulation. Furthermore, neutrophils and IL-1β contributed to the expression of chemotactic molecules involved in high-fat diet-induced macrophage infiltration into the WAT. We have identified previously unappreciated roles for neutrophils in the development of adipose tissue inflammation: robust IL-1β production and infiltration of macrophages to initiate chronic inflammation.
Slc11a1 gene variants influence over host response patterns and periodontal diseases resistance and susceptibility phenotypes
Authors: Melchiades Jéssica Lima , Cavalla Ian Franco , Colavite Priscila Maria , de Campos Soriani Azevedo Michelle , Fonseca Angelica Cristina , Trombone Ana Paula Favaro , Silva Renato Menezes da , de Faveri Marcelo , Figueiredo Magda Ferez , Garlet Gustavo P 
Published: January 2023

Abstract
Genetic variants in Slc11a1 are shown to be associated with different infectious diseases in humans. This study aimed to correlate the Slc11a1 genetic polymorphisms rs2290708 and rs3731865 with periodontal diseases resistance/susceptibility profiles in humans, and to evaluate impact of Slc11a1 hypo/hyperresponsive variants on experimental periodontitis in mice. Genotypic analysis was performed in 45 patients with chronic periodontitis (CP), 476 healthy individuals (H) and 207 individuals with chronic gingivitis (CG), and subgroups were analyzed for analysis of possible correlations between expression/genotype and in vitro tests. The polymorphisms rs2290708 and rs3731865 were associated with periodontitis risk, with a higher frequency of the genotypes CT+TT and GC+CC and the alleles T and C in the CP group in the control case approach. The analysis of the putative SNPs functionality demonstrated that polymorphic T (rs2290708) and C (rs37371865) alleles were associated with increased TNF-α, IL-1β, IL-6, RANKL and RANKL/OPG ratio in periodontal lesions. In vitro results reinforced the potential hyper-reactive nature of the polymorphic alleles T and C, since macrophages bearing such alleles presented an increased the production the same cytokines cited above. The hyperreactive variants of Slc11a1, prevalent in AIRmax mice when compared with hyporeactive AIRmin strain, were associated with increased alveolar bone loss, leukocyte influx and production of proinflammatory cytokines in experimental periodontitis. Therefore, polymorphisms in the Slc11a1 influence host response patterns and periodontal diseases phenotypes in experimental and human periodontitis.
Supported by grants from FAPESP (2019/12120-7 and 2015/24637-3)
EVALUATION OF CELL MEDIATED IMMUNITY OF PROTECTIVE VZV VACCINATION IN ADULTS BY FLUORESCENT T- AND B-CELL ELISPOT ASSAY ON A SINGLE CELL LEVEL
Authors: Ettischer-Schmid Nicole , Strecker Kevin , Preyer Rosemarie 
Published: January 2023

Abstract
Since decades it is known that immunity against varicella zoster virus (VZV) is mainly mediated by cellular immune reactions, predominantly conveyed by T-cells. Vaccination against VZV is now recommended not only in children, but in adults from 50 years to reduce the risk of herpes zoster (HZ) development, which increases by age. The aim of this work was to evaluate mechanisms and differences of the T- and B-cell mediated immunity against VZV in vaccinated adults and non-vaccinated younger adults by 3-colour fluorescent Enzyme-Linked-ImmunoSpot (EliSpot) Assay.
To evaluate T-cell mediated immunity, IFNy, IL-2 and IL-5 were simultaneously detected in one well. Our underlying hypothesis says that freshly vaccinated donors should express all three cytokines, whereas younger adults with a vaccination and/or infection during childhood should express a different cytokine pattern when stimulated with VZV. Adult donors with a known history of VZV infection showed significantly more spots when stimulated with peptide mixes compared to adult donors with no history of VZV infection.
For evaluating functional B-cells, latent and lytic peptide mixes were used to stimulate B-cells and total antibody-production for IgG and IgM was detected in one well in parallel. This was done for short incubation times to detect antibody-secreting cells (ASCs) in the periphery and for longer incubation times for memory B-cell evaluation.
The range for an effective vaccination should be confirmed by further investigations with more and well characterized donors. Furthermore, these trials could facilitate the detection of significant differences between vaccinated and non-vaccinated donors and open the possibility to define effectiveness of vaccination.
Targeting shingolipids inhibits alcohol-induced liver disease
Authors: Deng Zhongbin , Chu Shenghui , Sun Rui , Gu Xuemei , Chen Liang 
Published: January 2023

Abstract
Chronic alcohol consumption is accompanied by intestinal inflammation. However, little is known about how alterations to the intestinal immune system and sphingolipids contribute to pathogenesis of alcoholic liver disease (ALD). We used WT mice, RORγt-deficient mice and sphingosine kinase-deficient mice in a chronic-binge ethanol feeding model. Targeted lipidomics assessed the sphingolipids in gut and liver samples. Ethanol-fed and control mice were treated by SK1 inhibitor. Gut immune cell populations, the amounts of sphingolipids, and the level of liver injury were examined. We found that alcohol intake induces an increase in Th17 cells in the gut. Increased Th17 cells were due to upregulation of SK1 activity and Rorc activation. The pathogenic role of S1P/S1PR1 signaling in ALD was attributable to the migration and activation of Th17 cells. Importantly, deletion of SK1 markedly attenuated alcohol-induced liver inflammation, steatosis, and damage. In conclusion, our findings suggest that S1P signaling was crucial in the pathogenesis of alcoholic liver disease in a Th17 cell dependent manner.
Nexus between CNS resident microglia and migrating peripheral T cells pave the way for host immunity against neurotropic virus infection
Authors: Sarma Jayasri Das , Chakravarty Debanjana , Saadi Fareeha , Khan Reas , Burrows Amy , Kundu Soumya , Sharma NIkhil , Bergmann Cornelia , Shindler Kenneth S , Sen Ganes C 
Published: January 2023

Abstract
Neurotropic virus induced neuroinflammation initiates with the activation of brain resident immune cells which causes a heightened release of chemokines/cytokines leading to a compromise in the blood brain barrier integrity. This accentuates the upregulation of regulatory molecules like antiviral Interferon stimulating gene induced tetratricopeptide repeats protein, Ifit2, and augments infiltration of peripheral immune cells. Among the early infiltrating immune cells, a large population is composed of neutrophils and monocyte/macrophages which, along with brain resident microglia, orchestrate the full panoply of innate immune responses. Ifit2 has been shown to be beneficial in protecting mice from lethal neurotropic virus infection by restricting viral replication and amplifying antiviral responses. Using a murine neurotropic coronavirus infection in Ifit2−/− mice, we report that in the absence of Ifit2, viral replication is significantly increased and mice develop severe neuropathy. Despite the enormous viral load, Ifit2-deficient mice are impaired in microglial activation and recruitment of peripheral T cells into the CNS. To further confirm the role of migratory T cells in viral-induced neuroinflammation and neurodegeneration, studies were conducted in CD4−/− mice. Results showed no significant change in acute stage pathogenesis, whereas CD4−/− mice showed accelerated loss of axon-myelin coherence during the chronic stage. Together, studies in Ifit2 and CD4 knockout mice reveal that the interplay between brain resident microglia and migratory helper T cells is important for strengthening host immunity against neurotropic virus infection.
A novel and human-specific CD46-KLF/SP interaction mediates gene expression required for successful Th1 induction
Authors: Singh Parul , Kunz Natalia , Le Friec Gaelle , Wang Luopin , Lavender Paul , Kazemian Majid , Kemper Claudia 
Published: January 2023

Abstract
Signals mediated by autocrine activation of the human-specific complement receptor CD46 during T cell receptor (TCR) stimulation are vital to Th1 induction in human CD4+ T cells, but how exactly CD46 in a molecular level mediates this role is currently undefined. CD46 is expressed in different isoforms that can bear either one of two distinct cytoplasmic tails: CYT-1 or CYT-2. Nuclear translocation of CYT-1 is a critical requirement for the expression of genes coding for nutrient-influx-channels and mTORC1 activity that mediate metabolic adaptations needed for Th1 responses. The lack of a DNA binding domain in CD46-CYT-1 precludes it from acting directly as a transcription factor (TF) and we hence hypothesized that CYT-1 regulates gene expression via direct interaction with specific TF activator and/or repressor complexes. Indeed, CUT&RUN experiments performed using our novel antibody raised against cleaved CYT-1 identified key members of the KLF/SP TFs gene family as potential interacting partners of CD46-CYT-1. Subsequent ELISA and MST experiment confirmed strong, dose-dependent CYT-1/KLF/SP TFs interactions and also demonstrated that CYT-1 fostered KLF/SP TFs binding to appropriate DNA motifs. Genome-wide comparison of the KLF/SP TFs and CYT1 bound genes in T cells revealed their enrichment in crucial basic cell-physiological pathways. Moreover, the CUT&RUN data in conjunction with ATAC-seq analyses indicated that this novel CYT-1/KLF/SP axis may control general chromatin remodeling – a notion we are currently exploring. These data define a novel and critical human-specific pathway of gene regulation and further underpin the vital role of intracellular/autocrine complement in the regulation of normal cellular activity.
Identification of MLL1 as a novel regulator of Tfh cell differentiation
Authors: Belanger Simon , Getzler Adam J , Fung Kai , Greenbaum Jason , Pipkin Matthew E. , Crotty Shane 
Published: January 2023

Abstract
Transcription factors controlling T follicular helper (Tfh) cell differentiation have been extensively studied in recent years. However, there is limited knowledge of the different chromatin regulators involved in the control of Tfh differentiation. Most transcription factors control gene expression with the help of chromatin regulators, which modify chromatin structure to regulate gene expression. We hypothesize that chromatin modifying enzymes are involved in the control of Tfh differentiation. To uncover novel chromatin modifying enzymes essential for Tfh differentiation, we screened a shRNA library targeting all known chromatin regulators using our in vivo RNAi screen. Utilizing this screen, we identified the histone methyltransferase MLL1 as a positive regulator of Tfh differentiation after viral infection.
We found MLL1 to be functionally important for Tfh differentiation. Knockdown of MLL1 utilizing multiple shRNAs impaired Tfh differentiation during LCMV infection. The requirement for MLL1 for proper Tfh differentiation after LCMV infection was further confirmed using a CRISPR/Cas9 approach. Additionally, ablation of MLL1 expression selectively impaired production of IL-21 by Tfh cells. To further understand the role of MLL1 in regulating the Tfh differentiation network, we performed RNA-Seq of MLL1-deficient Tfh as well as MLL1-sufficient Tfh. Analysis revealed that the expression of several genes critical for the regulation of Tfh differentiation is dysregulated in the absence of MLL1. Specific examples will be discussed.
The transcriptional coactivator OCA-B re-wires metabolism and promotes CD4 T cell memory
Authors: Tantin Dean R , Williams Matthew A , Hale J Scott , Kim Heejoo 
Published: January 2023

Abstract
OCA-B (Pou2af1/OBF-1/Bob.1) is a transcriptional coregulatory protein that is not expressed in naïve CD4+ T cells, but becomes stably induced following antigen exposure and T cell activation. We have previously shown that the transcription factor OCA-B interacts with, Oct1 (Pou2f1) is a potent regulator of metabolism. Oct1 dampens oxidative metabolism of amino acids in mitochondria and counteracts reactive oxygen species production. Possible roles of OCA-B in metabolism have not been tested. Our prior work also indicates that both OCA-B and Oct1 are critical for the generation of functional CD4 memory T cells in response to pathogen infection. By co-transferring SMARTA TCR transgenic T cells ectopically expressing OCA-B and empty vector controls into recipient mice, and infecting the recipients with LCMV, we show that OCA-B does not affect primary effector responses, but is sufficient to promote formation of long-lived memory T cells. Although there are no differences in T cell numbers or function at peak response, changes in the expression of proteins such as CD62L and ICOS are consistent with preferential entry into the memory pool and stronger response upon rechallenge. Transcriptomic profiling of cells at the same peak pathogen response timepoint identifies ~80 genes significantly differentially expressed by ectopic OCA-B expression. These genes encode metabolic regulators and transcription master regulators indicative of metabolic rewiring of these cells. This prediction was confirmed by profiling glycolytic and oxidative metabolism in OCA-B conditional knockout and control naïve CD4 T cells stimulated and rested in vitro. These results indicate that expressing OCA-B may be useful as a method of enhancing CD4 memory.
Single cell sequence analysis reveals mouse MAIT cell diversity at steady state and after infection
Authors: Chandra Shilpi , Ramirez Ciro , Ascui-Gac Gabriel , Seumois Gregory , Seo Goo-Young , Simon Hayley , Hartmann Nadine , Murray Mallory Paynich , Vijayanand Pandurangan , Kronenberg Mitchell 
Published: January 2023

Abstract
Mucosal-associated invariant T (MAIT) cells are innate-like T lymphocytes that recognize vitamin B metabolites. We have performed single-cell RNA (sc-RNA) sequencing of MAIT cells from thymus, liver, spleen and lung using 10× single-cell genomics, where we sequenced more than 7,000 cells and identified 10 clusters by unbiased clustering. MAIT cells from the different organs are distributed in most of the clusters; except two clusters were lung MAIT cell specific and another consisted of cells exclusively from thymus. The lung specific cluster reveals a tissue residency gene signature. We compared the gene expression profile of MAIT cells with iNKT (invariant natural killer T) cells. Our data reveal that most mouse MAIT cells have a Th17/NKT17–like gene signature (MAIT17), although there are some with Th1/ NKT1-like transcriptomes (MAIT1), particularly in liver and spleen. A Th2/NKT2 gene expression profile was not observed. The thymus specific cluster showed a gene expression profile similar to the most immature or progenitor iNKT cells (NKT0), consistent with other data suggesting a unique thymus differentiation pathway for mouse MAIT that is similar to iNKT cells. We also performed scRNA sequencing of MAIT cells after bacterial infection in the lung. Our results indicate that after infection the transcriptome of lung MAIT cells changes significantly at day 6 and remains altered at day 40. Therefore, our study reveals that although mouse MAIT cells are predominantly Th17 cells and to a lesser extent Th1 cells, there is some heterogeneity and there are profound and relatively long-term changes in transcriptional signatures after infection.