bluuebunny/crossref_metadata_2025_split huggingface dataset:
Respiratory Syncytial Virus exacerbates acute lung damage during ovalbumin-induced asthmatic inflammation
Authors: Muralidharan Abenaya , Bauer Christopher D , Sun Keer 
Published: January 2023

Abstract
With more than 235 million people affected, asthma is the most common chronic disease in the world. In addition, respiratory viral infections, particularly respiratory syncytial virus (RSV) infection, has been associated with asthma development and significant exacerbation of asthmatic symptoms. While there are several theories exploring the causal role of RSV infection in asthma development, the pathogenic mechanism underlying the effect of RSV on asthma exacerbation remains to be understood. In this study, we investigated the effects of RSV infection on airway immune responses and lung damage in ovalbumin (OVA)-induced asthmatic mice. We found that RSV infection exacerbates acute lung damage in asthmatic mice, as indicated by their significantly increased protein and LDH levels in the airway. Although asthma is considered an allergic disease with increased Th2 responses, the levels of IL-4 and IL-5, as well as eosinophil recruitment, were unaffected in OVA-induced asthmatic mice with or without RSV super-infection. Moreover, pro-inflammatory responses, such as TNF-alpha, KC and MIP-2 production, and neutrophil infiltration, were also comparable between RSV-infected asthmatic mice and controls that only received RSV infection. Interestingly, the number of resident alveolar macrophages significantly decreased in RSV-infected asthmatic mice, as compared with RSV-infected non-asthmatic and uninfected asthmatic controls. Considering the crucial role of alveolar macrophages in resolution of airway inflammation, our future studies will determine whether RSV impairs alveolar macrophage self-maintenance, thereby prolonging airway inflammation and exacerbating lung damage during asthma.
Airway Microbiota-Host Interactions Regulate Secreted Leukocyte Proteinase Inhibitor Levels and Influence Allergic Airway Inflammation
Authors: Jaeger Natalia , McDonough Ryan , Hernandez-Leyva Ariel , Rosen Anne , Wilson Naomi G. , Russler-Germain Emilie V. , Chai Jiani N. , Bacharier Leonard B. , Hsieh Chyi-Song , Kau Andrew L. 
Published: January 2023

Abstract
Mucosal immune responses fine-tuned by naturally evolved interactions with native microbes influence airway inflammation but are not routinely integrated into experimental models. Here, we leverage a recently discovered murine-adapted airway microbe, Bordetella pseudohinzii (Bph), to investigate how chronic colonization impacts mucosal immunity and the development of allergic airway inflammation (AAI). Despite the persistent colonization, we did not observe significant weight loss in Bph colonized mice. Microscopic examination of the lungs demonstrated the formation of lymphoid aggregates, consistent with inducible Bronchus Associated Lymphoid Tissue (iBALT). Airway colonization of mice with Bph elicits an antigen-specific Th17 immune response that aids in controlling bacterial abundance. Remarkably, when animals undergo allergic airway challenge, mice previously colonized with Bph demonstrate protection from AAI. This phenotype corresponded to a reduction in type 2 cytokines, eosinophilic infiltration, goblet cell metaplasia, and airway hyper responsiveness. Colonization with Bph does not appear to impact the degree of allergic sensitization nor the presentation of allergen in the lung. Further, colonization and the Th17 response was associated with increased expression of Secreted Leukocyte Proteinase Inhibitor (SLPI), an antimicrobial peptide with anti-inflammatory properties. We confirmed these findings in humans by showing that higher levels of SLPI correlate both to improved asthma control and the presence of the asthma-associated bacterium, Haemophilus influenzae. We propose that SLPI could be used as a biomarker of beneficial host-commensal relationships in the airway.
A single cell approach to identify the role of IL-9 secreting tissue-resident CD4+ T cells in allergic airway recall responses
Authors: Kharwadkar Rakshin P , Ulrich Benjamin J , Fu Yongyao , Koh Byunghee , Nelson Andrew Scott , Kaplan Mark H 
Published: January 2023

Abstract
Allergic asthma is a chronic intermittent inflammatory lung disease where patients experience relatively few symptoms between exacerbations precipitated by allergen-challenge of allergic memory responses. Allergen-specific CD4+ T cells are believed to be a major mediator of allergic memory responses through the production of type 2 cytokines including IL-4, IL-5, IL-13 and IL-9. Recently, tissue-resident memory (Trm) cells have been identified in peripheral tissues that mediate mucosal barrier immunity. However, the precise role of Trm CD4+ T cells in allergic exacerbations is not clearly defined. In studies to examine the role of IL-9 in allergen-specific Trm responses to Aspergillus fumigatus we observed that all IL-9-secreting T cells had a resident memory phenotype. Inhibition of circulating T cells by administering FTY720 in the last month of rest, diminished the total CD4 T cells population in the lung, while the Th9 cells remained stable. Blockade of IL-9 prior to recall challenge phase reduced overall allergic lung inflammation as assessed both by flow cytometry and single cell RNA-seq. Within eight hours after challenge, IL-9 is one of the top genes identified by scRNA-seq that distinguishes ST2+ and ST2− CD4+ T cell populations in the lung. Using IL-9-reporter mice we also compared gene expression in isolated IL-9+ T cells and other type 2 T cells. These findings demonstrate that IL-9-producing Trms play an important role in mediating allergic memory responses. IL-9 could be a promising therapeutic target specifically in patients showing symptoms of intermittent allergic response.
IL-6 deficiency exacerbates allergic asthma and promotes Streptococcus pneumoniae pathogenesis
Authors: Schmit Taylor , Ambigapathy Ganesh , Ghosh Sumit , Mathur Ramkumar , Wu Min , Combs Colin , Khan Nadeem 
Published: January 2023

Abstract
Allergic asthma consists of diverse immune phenotypes exhibiting differential lung pathology, remodeling of the respiratory tract and mucociliary bronchial clearance. These diverse inflammatory immune mechanisms may promote or resist microbial infections in allergic human and mouse models. IL-6 governs optimal T-cell and inflammatory response leading to the resolution of bacterial and viral infections in respiratory airways. Additionally, IL-6 plays an important role in maintaining the integrity of airway barrier response during microbial infections. We hypothesized that lung IL-6 responses alleviate Streptococcus pneumoniae (Spn) pathogenesis during fungal allergic asthma caused by Aspergillus fumigatus.
Using a murine Aspergillus fumigatus asthma model, we show that IL-6 deficiency exacerbates lung inflammation and promotes Spn disease pathogenesis in allergic host. IL-6 deficiency was associated with increased lung damage, which correlated with higher levels of lung eosinophilia, inflammatory cytokines and chemokines. Additionally, IL-6 deficiency correlated with increased TGF-β1 cytokine levels, increased epithelial-mesenchymal transition and dysregulated epithelial barrier proteins in asthmatic mice.
We conclude that IL-6 offers a significant protective role in the control of Spn pathogenesis during allergic asthma by regulation of immune cell recruitment and maintenance of lung epithelial barrier integrity.
The pseudo-allergy receptor, MrgprB2/X2 is controlled by neurokinin A and the neurokinin 2 receptor in human and mouse skin
Authors: Li Yuting , Zhang Jiying , Falo Louis D , Larregina Adriana T , Sumpter Tina L 
Published: January 2023

Abstract
Within the skin, mast cells (MCs) and sensory neurons form a cohesive unit that plays an important role in initiating immune responses. Neuropeptides such as neurokinin A and substance P direct MC function by initiating signaling through neurokinin (NK) receptors, and Mas related G-protein receptors (Mrgpr)s. Neurokinin A, in particular, is thought to signal through the NK2R. Recent studies highlight the importance of the MrgprB2 (mouse) and MrgprX2 (human) in the MC response to pseudo-allergens, secretagogues and substance P. To date, a relationship between neurokinin receptors and the MrgprB2/X2 has not been investigated. In this study, we hypothesize that MrgprB2/X2 expression is controlled by the NK2R and its high affinity ligand, neurokinin A. In mice, we show that administration of neurokinin A diminishes MrgprB2 expression. Surprisingly, antagonism of the NK2R also downregulates MrgprB2 expression and in NK2R-deficient mice, MrgprB2 expression is markedly diminished. In contrast, co-administration of neurokinin A and a NK2R antagonist markedly increases MrgprB2 expression. In human skin explants, NK2R antagonism has minimal effect on MrgprX2 expression, but co-administration of neurokinin A and a NK2R antagonist upregulates MrgprX2 expression, as seen in murine skin. These data demonstrate that NK2R-signaling influences MrgprB2/X2 expression and, in absence of the NK2R, neurokinin A interacts with an unknown receptor to increase MrpgrB2/X2 expression. Collectively, these data uncover a novel role for NK2R signaling in the regulation of MrgprB2/X2. These important findings have implications for patients with dysregulated mast cell function initiated through the MrgprX2.
Decoding the role of CBLB for innate immune responses regulating systemic dissemination during Non-Tuberculous Mycobacteria infection
Authors: Nanjappa Som G. , Mudalagiriyappa Srinivasu , Sharma Jaishree , Vieson Miranda 
Published: January 2023

Abstract
Non-Tuberculous Mycobacteria (NTM) are ubiquitous in nature, present in soil and water, and cause primary and disseminated infections in the immune-compromised individuals. NTM infections are surging in recent years at 8% annually, due to an increase in immune-suppressed population, medical interventions, and underlying lung diseases. The innate immune responses, frontiers for controlling infections and dissemination, are poorly defined during NTM infections. Here, we define the role of CBLB, an E3-ubiquitin ligase, for innate immune responses and disease progression in a mouse model of NTM infection in the absence of antigen-specific T-cell responses. We found that NTM was readily disseminated into the tissues in the Cblb KO mice in a time- and infection route-dependent manner, compared with the WT group. We uncovered defects in many innate immune cells in Cblb KO mice: poor responses with NK cells, inflammatory monocytes, neutrophils, and activation of conventional dendritic cell responses. Strikingly, Cblb-deficient macrophages were able to produce higher ROS in both in vivo & in vitro compared with the WT group. Histopathological studies buttressed the role of Cblb for disseminated NTM infection. Collectively, Cblb plays a dichotomous role in innate immunity, and may help prevent the dissemination of NTM in the infected host. Our studies illuminate the translational implications for controlling NTM infections by modulating the innate immune immunity.
The role of high-mobility group box 1 protein in respiratory syncytial virus-induced autophagy
Authors: Kempaiah Kempaiah Rayavara , Hosakote Yashoda Madaiah 
Published: January 2023

Abstract
Respiratory syncytial virus (RSV) is the most common cause of acute lower respiratory tract infections in infants and young children worldwide, for which no efficacious treatments or vaccines are currently available. Although the pathogenic mechanisms of RSV-induced acute airway disease are still unclear, lung immune and inflammatory responses are key. High-mobility group box 1 (HMGB1) is a redox-sensitive multifunctional protein that serves as both a DNA regulatory protein and an extracellular signaling molecule that mediates the activation of inflammatory responses to infection/injury. HMGB1 has been implicated in mitochondrial function and quality control. The objective of this study is to investigate the role of HMGB1 in autophagosome formation and mitochondrial quality control in RSV infection. Studies were conducted in lung epithelial cells including A549 and normal small alveolar epithelial cells. Our studies show that RSV induces HMGB1 secretion in lung epithelial cells via NFκB and TLR4 pathways, and activates innate immune cells to promote inflammation. We show that RSV-induces LC3B and promote autophagy whereas recombinant HMGB1 (rHMGB1) treatment inhibits RSV-induced autophagy. We also show that RSV infection inhibits the inflammasome pathway in lung epithelial cells but rHMGB1 treatment activates inflammasomes. Our results indicate that RSV-induced epithelial HMGB1 secretion triggers inflammasome activation in innate immune cells to promote inflammation. Understanding HMGB1 and associated cellular signaling in RSV-induced lung inflammation may pave the way for the development of novel therapeutic interventions to treat not only RSV, but also other respiratory infections that affect humans of all ages.
Interferon-mediated Reprogramming of Intracellular Cholesterol Metabolism in Response to Secreted Bacterial Toxins
Authors: Lee Minsub S , Zhou Quan , Chi Xun , Hsieh Wei Yuan , Fang An-Chieh , Scumpia Philip O. , Williams Kevin , Damoiseaux Robert , Bensinger Steven 
Published: January 2023

Abstract
Macrophages undergo profound metabolic reprogramming in response to activation signals. However, the purpose and the mechanism of this reprogramming remains poorly understood. Cholesterol is an essential lipid molecule that modulates biochemical and biophysical properties of cellular membranes. Microbes have evolved strategies which specifically exploit the presence of membrane cholesterol to facilitate pathogenesis. Cholesterol-dependent cytolysin (CDC) are pore-forming toxins produced by gram-positive microorganisms that results in loss of membrane integrity, cellular dysfunction, and cell death. Herein, we delineate a unappreciated immune cell strategy that relies on rapid reprogramming of cholesterol homeostasis to avoid the deleterious effects CDCs. We show that interferon signals convey resistance to CDCs in myeloid cells by altering the availability of cholesterol in the plasma membrane (PM). Mechanistic studies reveal that resistance to CDCs occurs as a result of the movement of cholesterol from the PM to the endoplasmic reticulum (ER), and ultimately into an intracellular esterified pool. We also find that IFN-mediated inhibition of cholesterol synthesis is required to ensure maximal resistance to CDC challenge. Finally, we demonstrate that the IFN-mediated inhibition of cholesterol synthesis is dependent on production of the oxysterol, 25-hydroxycholesterol, and that the loss of CH25H renders mice more susceptible to CDC-mediated tissue damage. Together, these data provide evidence for remodeling of membrane lipid composition as a host defense strategy to bacterial toxins, and suggests that metabolic reprogramming of lipid architecture has significance beyond that of supporting immune function.
Internal N6-methyladenosine modification controls the innate immune response to viral RNA
Authors: xue miaoge , Lu Mijia , Li Anzhong , Zhang Zijie , He Chuan , Li Jianrong 
Published: January 2023

Abstract
Internal N6-methyladenosine (m6A) modification is one of the most prevalent and abundant modifications of RNA. The m6A methylation is catalyzed by host methyltransferases (METTL3 and METTL14) and can be reversibly removed by host demethylases (FTO and ALKBH5). Recent studies have revealed that RNA of many DNA and RNA viruses contain m6A methylation and that viral m6A can play a pro-viral or anti-viral role. However, the biological functions of viral RNA m6A methylation remain poorly understood. In this study, we found that genome and antigenome of human respiratory syncytial virus (RSV), a non-segmented negative-sense RNA virus, are m6A methylated and that viral m6A methylation positively regulates RSV replication and gene expression. Interestingly, virion RNAs purified from RSV grown in METTL3-knockout cells induced significantly higher type I interferon responses than virion RNAs purified from RSV grown in wild type cells, demonstrating that viral RNA m6A methylation inhibits innate immunity. Similarly, inactivation of m6A methylation in RSV genome and/or antigenome by site-directed mutagenesis induced significantly higher innate immune responses than wild type RSV RNA. Mechanistically, these m6A-unmodified or m6A-deficient RSV RNAs trigger a higher expression of pattern recognition receptors (such as RIG-I and MDA5), enhance their binding affinity to the innate immune RNA sensors, and enhance the phosphorylation of downstream transcription factor IRF3, leading to an enhanced activation of type I interferon signaling pathway. Taken together, our study identified a novel biological function of viral m6A methylation, which is to serves as a molecular marker for host innate immunity to discriminate self from nonself RNAs.
NLRC3 Localizes to the Endoplasmic Reticulum via Interactions with a Novel ER-Resident Protein
Authors: Davis Beckley K , Baker Taylor , Rechnitzer Alma , Hamby Matthew , Troiani Zachary , Stenske Sarah , Davis Samuel , Bauer Anna 
Published: January 2023

Abstract
Sensing of cytosolic nucleotides is a critical initial step in the elaboration of type I interferon. One of several upstream receptor cGAS (cyclic-GMP-AMP synthase) binds to cytosolic DNA and generates di-cyclic nucleotides that act as secondary messengers. These secondary messengers bind directly to Stimulator of Interferon Genes (STING). STING recruits TANK binding kinase 1 (TBK1) which acts as a critical node that allows for efficient activation of interferon regulatory factors (IRFs) to drive the anti-viral transcriptome. NLRC3 is a recently characterized nucleotide-binding domain, leucine rich repeat containing protein (NLR) that negatively regulates the type I interferon pathway by inhibiting subcellular redistribution and effective signaling of STING, thus blunting the transcription of type I interferons. NLRC3 is predominantly expressed in lymphoid and myeloid cells. IQGAP1 was identified as a putative interacting partner of NLRC3 through yeast two hybrid screening. Here we show that a novel ER-resident protein associates with NLRC3 in human cells. This interaction occurs at the ER. This data provides a mechanism by which NLRC3 localizes to the ER to affect STING signaling in response to cytosolic nucleotides.
Olfactory receptor 2 (Olfr2) and its human ortholog OR6A2 expressed in macrophages drive NLRP3 inflammasome activation and exacerbate atherosclerosis in mice
Authors: Orecchioni Marco , Kobiyama Kouji , Winkels Holger , Ghosheh Yanal , McArdle Sara , Mikulski Zbigniew , Fan Zhichao , Wen Lai , Jung Yunmin , Roy Payel , Myamoto Yukiko , Matsunami Hiroaki , Eckmann Lars , Latz Eicke , Wang Zeneng , Hazen Stanley L , Ley Klaus 
Published: January 2023

Abstract
Atherosclerosis is an inflammatory disease of the arterial wall driven by macrophages and other immune cells. Olfactory receptors (Olfrs) are G-protein coupled receptors expressed in olfactory epithelium and are responsible for the sense of smell. We found that macrophages in the wall of atherosclerotic mouse aortas express some olfactory receptors including Olfr2, a specific receptor for an 8 carbon fatty-aldehyde called octanal. Octanal is detectable in food, mouse and human blood plasma, elevated by western diet, and partially derived from gut microbiota. Ligation of Olfr2 or its human orthologue OR6A2, expressed in human atherosclerotic plaque and in human monocyte-derived macrophages, is strongly pro-inflammatory, activates the NLRP3 inflammasome and, in synergy with LPS, induces secretion of IL-1β. Knockdown of Olfr2/OR6A2 in macrophages significantly reduced inflammatory cytokine secretion. To test the role of Olfr2 in atherosclerosis, we treated Apoe−/− mice with octanal or the Olfr2 antagonist citral. Octanal significantly exacerbated while citral significantly inhibited atherosclerosis. We generated Olfr2−/− mice by Crispr-Cas9. Ldlr−/− mice reconstituted with Olfr2−/− bone marrow developed ~50% smaller lesions on high cholesterol diet than littermate controls reconstituted with Olfr2+/+ bone marrow. Our findings suggest that small molecule inhibitors of Olfrs like OR6A2 are promising targets for drug development to prevent and treat atherosclerosis-based cardiovascular diseases.
NLRP3 inflammasome in immune cells regulates metastatic potential of cancer
Authors: Lee Joo Y , Lee Hye E , Yang Gabsik , Kang Han C , Cho Yong-Yeon , Lee Hye S 
Published: January 2023

Abstract
One of the main features of tumor microenvironment is inflammation accompanied with the activation of immune cells and the production of pro-inflammatory cytokines. IL-1b, one of the critical cytokines released by immune cells to promote tumor growth and metastasis by acting on its receptor, IL-1R, and to culminate in the secondary activation of immune cells and the expression of immune cytokines. Inflammasome plays a critical role in production of mature IL-1b through activation of capspase-1. Therefore, we investigated whether regulation of NLRP3 inflammasome in macrophages affected the metastatic potential of tumor cells. Activation of NLRP3 inflammasome was induced by ATP in bone marrow-derived primary mouse macrophages. The metastatic potential of tumor cells was determined by transwell migration and invasion assays. Wild-type macrophages stimulated with ATP increased the migration and invasion of melanoma cells (B16F10). However, NLRP3- or caspase-1-knockout macrophages showed greatly decreased ability to promote the migration and invasion of melanoma cells. Treatment with celastrol, an inhibitor of NLRP3 inflammasome, blocked the ability of macrophages to stimulate migration and invasion of melanoma cells. The results show that inhibition of the NLRP3 inflammasome in macrophages by genetic deficiency or a pharmacological inhibitor leads to decrease of the metastatic potential of tumor cells. The results would provide a novel anti-cancer immuntherapy to regulate the activity of NLRP3 inflammasome in tumor microenvironment. [Supported by grants from BK21 PLUS program, NRF-2019R1A2C2085739, and NRF-2017R1A4A1015036].
Nur77 controls tolerance induction, terminal differentiation, and effector functions in NKT cells
Authors: Kumar Amrendra , Hill Timothy M , Gordy Laura E. , Suryadevara Naveenchandra , Wu Lan , Flyak Andrew I. , Bezbradica Jelena S. , Van Kaer Luc , Joyce Sebastian 
Published: January 2023

Abstract
Natural killer T (NKT) cells are self-reactive lymphocytes, yet how this lineage attains self-tolerance remains unknown. NKT cells constitutively express high levels of Nr4a1-encoded Nur77, a transcription factor that integrates signal strength downstream of the T cell receptor (TCR) within activated thymocytes and peripheral T cells. Nur77 is associated with tolerance induction in conventional T cells but is of hitherto unknown function in NKT cells. Here we report that sustained Nur77 overexpression (Nur77tg) in mouse thymocytes abrogates NKT cell development. Introgression of a rearranged Vα14-Jα18 a-chain gene into the Nur77tg (Nur77tg;Vα14tg) mouse rescued development up to an early precursor stage 0. NKT cells in bone marrow chimeras that reconstituted thymic cellularity developed beyond stage 0 precursors, yielding interleukin-4-producing NKT2 but not interferon-g-producing NKT1 cell subsets. Nonetheless, NKT cells that emerged in these chimeras expressed the exhaustion marker PD1 and responded poorly to glycolipid agonists. Hence, Nur77 integrates signals emanating from the TCR to control NKT cell tolerance, terminal differentiation, and effector functions.