bluuebunny/crossref_metadata_2025_split huggingface dataset:
M2-polarized macrophages as a potential cell therapy to mitigate inflammation-induced preterm birth
Authors: Garcia-Flores Valeria , Romero Roberto , Xu Yi , Miller Derek , Slutsky Rebecca , Robertson Sarah A , Gomez-Lopez Nardhy 
Published: January 2023

Abstract
Preterm birth is the leading cause of neonatal morbidity and mortality worldwide. A substantial fraction of spontaneous preterm births are due to intra-amniotic inflammation; yet, to date, no anti-inflammatory strategies exist to treat this clinical condition. We propose that boosting homeostatic immune cells that are reduced at the maternal-fetal interface of women who underwent preterm birth can serve as a novel strategy to prevent this syndrome. First, using immunophenotyping, we showed that women who experience preterm birth have low proportions of M2-polarized macrophages at the maternal-fetal interface. Next, we tested whether adoptive transfer of M2-polarized macrophages could prevent intra-amniotic inflammation-induced preterm birth in mice. Bone marrow-derived myeloid cells (BMDM) from non-pregnant mice were differentiated and polarized towards M2 macrophages, as proven by flow cytometry. The adoptive transfer of M2-polarized macrophages, but not BMDM, prevented preterm birth and neonatal death. To increase the translational value, M2-polarized macrophages from mid and late pregnancy were also tested, and those from mid pregnancy were more effective in preventing preterm birth. Using GFP-positive M2-polarized macrophages, we showed that adoptively transferred cells migrate into the maternal (lung, liver, uterus) and fetal (placenta, lung) tissues as well as the maternal-fetal interface prior to preterm birth. The adoptive transfer of M2-polarized macrophages dampened pro-inflammatory responses in the maternal circulation and amniotic cavity. Collectively, these findings raise the prospect of a novel cellular anti-inflammatory approach to prevent preterm birth and adverse neonatal outcomes.
The ImmunoGenetic Theory of Cancer Survival: Insights from the analysis of 200+ unselected breast cancer patients followed for over 8 years
Authors: Williams R Michael , Yunis Edmond J. 
Published: January 2023

Abstract
The ImmunoGenetic approach to cancer survival has been out focus since we began collaborating in 1976. We both had had considerable experience studying the genetics and immunology of anti-cancer and autoimmune diseases related to thymus derived cells. RMW studied thymus derived cells with Byron Waksman and mouse MHC genetics with Baruj Benacerraf. EJY discovered the importance of T-cells in numerous mouse models, including breast cancer, with experiments he did in Robert Good’s laboratory. With Bernard Amos, EJY discovered the importance of more than one gene in the MHC of humans...HLA. Using published data we presented at AAI2019, the importance of homozygosity at the P2 site of Class I and the NG2A NK receptor. Innate and adaptive immune responses, involving NK cells and KIR IG receptors, are genetically controlled and appear substantially to involve natural killer cells. The mechanism is nonspecific (innate) in the killing process, but also specific (adaptive) through the KIR system inhibition of NK cell killing. Here we describe the facts that survival in breast cancer, regardless of stage at diagnosis is highly dependent on the number of NK cells in peripheral blood at the time of diagnosis. Survival is longer when NK cell number is high, when tested after surgical diagnosis. Treatments alter NK cells numbers in the blood. Radiation, even after an R0 surgery, results in a prompt decrease in peripheral blood NK cell number which then returns to baseline shortly after radiation stops. We conclude that NK cells are recruited to radiated sites. Baseline numbers of CD4+, CD8+, and CD19+ cells behave differently. The complex symphony of life is genetically controlled and extends cancer patients’ survival. Treatments are genetic and immunological.
8-iso prostaglandin E2 causes nasal congestion in allergic rhinitis of mice
Authors: Murata Takahisa , Tachibana Yuri , Nakamura Tatsuro 
Published: January 2023

Abstract
Allergic rhinitis (AR) is a complex nasal disease accompanied with mast cell and eosinophils infiltration into nasal cavity. Nasal congestion is a typical symptom of allergic rhinitis that is difficult to treat. Thromboxane A2 (TXA2)-TP receptor axis is reported to be involved in nasal congestion; however, its detailed mechanism is unknown. Here, we assessed the involvement of TP-mediated signaling in nasal congestion of mice. Intraperitoneal sensitization and intranasal administration of ovalbumin induced rhinitis with nasal congestion in mice. Pharmacological TP blockade but not TXA2 synthase inhibition abolished the nasal congestion accompanied with vascular hyper-permeability. These data suggest the presence of some other TP ligand than TXA2 in nasal cavity. LC-MS/MS based comprehensive analysis identified 15 types of lipid metabolites in nasal lavage fluid (NALF) of AR. The levels of almost all metabolites were higher in the NALF of AR than that in non-AR. Among these, we detected a possible TP ligand, 8-iso PGE2 in the AR NALF. Both in vitro and in vivo experiments showed that treatment of 8-iso PGE2 caused vascular hyper-permeability which was inhibited by pharmacological TP blockade. In addition, intranasal administration of 8-iso PGE2 induced nasal congestion which was significantly inhibited by TP blockade. We identified 8-iso PGE2 as a novel TP ligand which exacerbate nasal congestion in rhinitis mice.
Cul5 E3 ubiquitin ligase limits Th2 and Th9 differentiation by regulating IL4 receptor level in CD4 T cells
Authors: KUMAR BINOD , Field Natania , Herbert De’broski R , Oliver Paula 
Published: January 2023

Abstract
Allergic asthma is a chronic airway disease characterized by increased airway resistance and airway remodeling. It is well established that increased Th2 and Th9 cells is responsible for this phenotype, the mechanisms restricting these cell numbers are poorly understood. Here we show that the E3 ubiquitin ligase, Cul5, restricts Th2 and Th9 differentiation and prevents allergic asthma. We found that Cul5 activity measured by neddylation is increased following CD4 T cell stimulation. We generated mice lacking Cul5 in T cells that showed mild Th2 inflammation in lung specifically. Upon house dust mite exposure these mice exhibited increased eosinophilia, goblet cell hyperplasia, and airways remodeling. Mechanistically, we show that in activated T cells, Cul5 associated with cytokine-induced SH2 protein (CIS), a SOCS-box protein. CIS act as a substrate receptor for Cul5 E3 ubiquitin complex and limits IL-4 receptor level on the surface, that correlated with increased Th2 and Th9 differentiation and/or persistence in vivo. These data support that Cul5 works with CIS to attenuate IL-4R signaling and reduce susceptibility to allergic asthma.
CD1d-dependent NKT cells establish Th1-polarity to promote resolution of dengue virus infection
Authors: St. John Ashley L , Choi Youngjoo , Rathore Abhay 
Published: January 2023

Abstract
NKT cells are innate-like T cells that can rapidly produce cytokines or acquire cytotoxicity upon activation, which can shape subsequent adaptive immunity towards invading pathogens. During infection by the arboviral pathogen dengue virus (DENV), NKT cells are recruited to the skin, yet their contributions to cutaneous virus clearance are unclear. Moreover, the individual contributions of various NKT subsets to DENV immunity are poorly defined. Here, we show CD1d-dependent (CD1d-dep) NKT cells promote DENV infection resolution in skin and draining lymph nodes (dLNs) through recruitment of cytotoxic lymphocytes (CTLs), including CD8+ T cells and NKT-like cells to the skin and CD4+ and γδT cells to the dLN. CD1ddep NKT cells and NKT-like T cells are major producers of chemotactic factors for CTLs and Th1 cytokines. Impaired Th1 immunity in CD1d-KO mice was also apparent as CD4+ and CD8+ T cells produced less IFN-γ and more IL-4 and Th2-associated IgG1 levels were higher than Th1-associated IgG2a levels and promoted antibody dependent enhanced disease. These results demonstrate that CD1ddep NKT cells establish Th1 polarity during the early response to DENV, which significantly affects infection resolution and memory formation.
Peripheral blood MAIT cell response to enterotoxigenic E. coli strains H10407 and B7A after controlled human infection models (CHIMs)
Authors: Eller Michael A. , Lal Kerri G , Kim Dohoon , Vasan Sandhya , Gramzinski Robert A. , Maciel Milton 
Published: January 2023

Abstract
Mucosal associated invariant T (MAIT) cells are an unconventional T cell subset with a semi-invariant TCR that recognizes microbially-derived riboflavin metabolites and elicit broad antimicrobial activity. MAIT cells are implicated in the control of bacterial infections, however, their role in enterotoxigenic E. coli (ETEC) infection, a common cause of traveler’s diarrhea, is unknown. Using multi-color polychromatic flow cytometry and RNA-seq on sorted peripheral MAIT cells of volunteers orally challenged with ETEC strains H10407 (CFA/I+LT+ST+; median time to first loose stool, mtFLS=47h; n=8) or B7A (CS6+ LT+ST+; mtFLS=13h; n=12), we observed that MAIT cells express higher levels of gut-homing molecules a4b7 and CCR9 7-days post-challenge. Moreover, MAIT cells also have an increase in expression of markers of activation CD38 (p=0.003) and cell proliferation Ki-67 (p=0.01) 7-days post-challenge, despite no change in overall frequency. RNA-seq revealed distinct transcriptional signatures 7-days post challenge in both challenge models. Gene set enrichment analysis (GSEA) showed that challenge with both ETEC strains elicit an upregulation of pathways involved in MAIT cell proliferation and division. Several pathways involving IL-1 secretion and the inflammasome were also upregulated after H10406 challenge. Meanwhile, B7A challenge upregulated innate-like pathways such as Natural Killer Cell Activation. These data suggest that MAIT cells are responding during ETEC challenge with upregulation markers of gut homing, activation and proliferation, but undergo differential means of activation after CHIMs with H10407 compared to the more fact-acting B7A ETEC strain.
Nox2 deficiency in neutrophils promotes excessive and sustained inflammatory responses at local and distal sites of inflammation
Authors: Haist Kelsey Cornell , Henson Peter M , Bratton Donna L 
Published: January 2023

Abstract
NADPH oxidase 2 (Nox2) plays important roles both in protection from pathogens and in responses to inflammatory stimuli, and its functional loss is the cause of Chronic Granulomatous Disease. While earlier reports implicated macrophage Nox2 as the major contributor to inflammatory responses, we sought to determine the respective contributions of Nox2 in resident macrophages or neutrophils to early inflammatory responses induced by two different stimuli and routes of induction. We hypothesized that absence of Nox2 function in resident macrophages would drive excessive, prolonged inflammation. Intraperitoneal (i.p.) zymosan or intratracheal (i.t.) killed A. fumigatus in Nox2-deficient mice both drive a severe, sustained inflammatory response locally with continually elevated levels of neutrophils, monocytes, and macrophages and granulomata formation, whereas WT mice exhibit rapidly resolving responses. We employed a novel mixed bone marrow chimera approach in which neutrophils are predominantly Nox2-sufficient yet resident macrophages are largely Nox2-deficient. We treated these mice and WT control mixed chimeras with both i.p. zymosan and i.t. killed A. fumigatus and characterized the inflammatory response in both the lung and peritoneal cavity after either stimulus. Notably, the Nox2-deficient mixed chimeras responded similarly to WT control chimeras, including reduced neutrophil and monocyte recruitment and absence of granulomata, demonstrating that Nox2 deficiency specifically in neutrophils drives excessive inflammation in response to both i.p. zymosan and i.t. A. fumigatus. These data highlight the importance of neutrophil Nox2 in normal progression and resolution of these inflammatory responses.
Accumulation and activation of group 2 innate lymphoid cells in the aged brain alleviate aging associated cognitive decline
Authors: Fung Ivan Ting Hin , Sankar Poornima , Zhang Yuanyue , Robison Lisa S. , Zhao Xiuli , D’Souza Shanti , Salinero Abigail E. , Wang Yue , Qian Jiang , Kuentzel Marcy , Chittur Sridar V. , Temple Sally , Zuloaga Kristen L. , Yang Qi 
Published: January 2023

Abstract
Increasing evidence has challenged the traditional view about the immune privilege of the brain, but the precise roles of immune cells in regulating brain physiology and function remain poorly understood. Here we report that tissue-resident group 2 innate lymphoid cells (ILC2) accumulate in the choroid plexus of aged brains. ILC2 in the aged brain are long-lived, relatively resistant to cellular senescence and exhaustion, and are capable of switching between cell cycle dormancy and proliferation. They are functionally quiescent at homeostasis but can be activated by IL-33 to produce large amounts of type-2 cytokines and other effector molecules in vitro and in vivo. Intracerebroventricular transfer of activated ILC2 revitalized the aged brain and enhanced the cognitive function of aged mice. Administration of IL-5, a major ILC2 product, was sufficient to repress aging-associated neuroinflammation and alleviate aging-associated cognitive decline. Targeting ILC2 in the aged brain may provide new avenues to combat aging-associated neurodegenerative disorders.
C-Type Lectin Receptor Dectin-1 Suppresses the Development of Experimental Autoimmune Encephalomyelitis
Authors: Yan Chengkai , Tang Na , Guo Hui , Zhang Jian 
Published: January 2023

Abstract
Dectin-1 (encoded by Clec7a) is a mainly myeloid cell-expressed natural killer (NK)-cell-receptor-like C-type lectin that functions as a fungal recognition receptor by binding to b-glucan carbohydrates. However, the role of Dectin-1 in adaptive immunity is not fully understood. In this study, we surprisingly found that mice deficient for Dectin-1 develop severe experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis (MS). The heightened EAE severity observed in Clec7a−/− mice correlates with increased Th17 response in the draining lymph nodes. Further analysis showed that Clec7a−/− mice have a reduced regulatory CD8+ T cells, a newly discovered CD8+ T cell subset defined as the surface expression of CD8, CD44, CD122, and Ly49+, which have been shown to suppress EAE development. In support of a critical role of Dectin-1 in non-CD4+ T cells in the development of EAE, Tcrb−/− mice receiving wild-type and Clec7a−/− CD4+ T cells develop a comparable degree of EAE. Therefore, our data suggest that Dectin-1 regulates EAE development possibly via controlling regulatory CD8+ T cell development.
Identification of germinal center-specific lipid species
Authors: Cho Sung Hoon , Jones Marissa , Spraggins Jeffrey , Caprioli Richard M , Boothby Mark Robin 
Published: January 2023

Abstract
Germinal centers (GCs) are microanatomic structures that B cells proliferate, are selected for affinity maturation, undergo antibody (Ab) class-switch recombination and differentiate into Ab-secreting plasma cells and memory B cells. Nutrient availability, metabolic reprogramming process, and spatial localizations of biomolecules can impact on GC response and quality of humoral immune response. By using matrix-assisted laser desorption/ionization-imaging mass spectrometry (MALDI-IMS), we identified that the ether lipid species are preferentially enriched in germinal centers, and the perturbation of ether lipid synthesis attenuatedGC response and antigen-specific Ab production. These results suggest that molecular programing of GC lymphocytes is tied to increased ether lipid synthesis and that these species are functionally important in humoral immunity.
Circulating classical monocytes share a common transcriptional signature with skin macrophages in Systemic Sclerosis
Authors: Makinde Hadijat M , Dominguez Salina T , Cuda Carla M , Gadhvi Gaurav , Aren Kathleen , Zeng Chang , Eickelberg Garrett J , Khanna Dinesh , Assassi Shervin , Frech Tracy , Winter Deborah R , Perlman Harris , Hinchcliff Monique 
Published: January 2023

Abstract
The etiology and pathogenesis of systemic sclerosis (SSc) are poorly understood. Circulating monocytes likely play a critical role in SSc progression through secretion of proinflammatory molecules and as precursors of macrophages that can reorganize the extracellular matrix, thereby leading to development of end-organ fibrosis. Here, we evaluate the transcriptional similarities between circulating classical monocytes (CMo) and skin macrophages of SSc patients. Bulk RNA-seq was performed on sorted CMo from SSc blood obtained through the Prospective Registry of Early Systemic Sclerosis (PRESS) cohort, and transcriptional profiles were analyzed along with profiles from matched control samples. Additionally, sorted CD45+ cells from skin biopsies of one SSc patient and one control patient were prepared for single-cell RNA-seq. There was a numerical expansion of skin macrophages from the control to the SSc sample, but no significant difference in the quantity of circulating CMo between control and SSc patients. Of the 152 significantly upregulated genes (DESeq2, p&lt;0.05, fold change&gt;2) observed in circulating CMo population and the 290 upregulated genes (fold change&gt;2) in the skin macrophage cluster compared to their respective controls, we found 23 genes in common (p&lt;1.23×10−8, hypergeometric distribution test). These shared genes were involved in various immune and inflammatory regulation processes. These data indicate that a common transcriptional signature may exist between circulating CMo and macrophages present in the skin of SSc patients, potentially suggesting that macrophage-specific pathways at the site of fibrosis can be detected in a circulating precursor population.
MDA-5 mediated RNA sensing signaling responds to the cellular RNAs escaped from RNA surveillance causing apoptotic cell death
Authors: Wang Qingde , Gao Wentao , Guo Xinfeng , Rodrigiguez Nathaniel , Billiar Timothy R 
Published: January 2023

Abstract
It is well established that invaded viral RNA triggers cell death through cytosolic RNA sensing and IFN signaling pathways. Cellular RNA, however, is tolerated, mainly due to the dynamic RNA surveillance which leads to rapid degradation of the immature and abnormally processed or potentially disease-causing RNA transcripts. Here we demonstrated that inappropriately processed cellular RNA escaped from RNA surveillance causes apoptotic cell dearth through MDA-5 mediated RNA sensing signaling. We generated a unique mouse model in which aberrant cellular RNA causes massive cell death and lethality of the mice. Through characterization of this model, we found that cell type specific deletion of the RNA editing enzyme ADAR1 led to accumulation of the cellular RNAs at insufficiently edited status which escaped from RNA surveillance. The unedited RNAs transported from nucleus to cytosol activated the RNA sensing signaling and resulted in robust type I IFN and ISG expression, concurrently occurred a massive apoptotic cell death. We found that activation of innate immune signaling was almost exclusively through the MDA-5 RNA receptor, since deletion of only MDA-5 prevented type I IFN production and the downstream ISGs. Deletion of MDA-5 not only rebalanced innate immune homeostasis, but also extinguished the apoptotic pathway, and completely rescued the lethality of the ADAR1 KO mice. In addition, we defined that it was the intrinsic apoptotic pathways activated by MDA-5 RNA sensing was responsible for the cell death. This finding indicated that cellular RNA sensing signaling initiated by RNA receptor MDA-5 could be a critical mechanism responding to the RNAs escaped from the nucleic RNA surveillance in diseased conditions.
Immunoglobulin gene rearrangement and BAFF responsive maturation defines a novel B cell population undergoing extra-BM development
Authors: Khan Wasif N , Bazile Cassandra A , Clark Emily S , Magee Jennifer , Boucher Justin C , Carlesso Gianluca , Morehouse Christopher , Shrestha Akritee , Umland Oliver , Salyakina Daria , Wesemann Duane R , Kleiman Eden 
Published: January 2023

Abstract
Transitional type-1 (T1) cells are peripheral immature B cells known to populate the spleen (spl) after completing their BCR assembly in the bone marrow (BM). To advance the understanding of splenic T1 (CD19posCD24hiCD21neg) B cells, we addressed the heterogeneity and biology of these cells using flow cytometry combined with genetically modified mice. Most recent emigrant T1 cells were selected by excluding CD23pos and including CD93high (AA4.1) B cells termed T12123DN. Transcriptomic analysis identified RAG1 and 2 as signature genes for this B cell population. Further separation of T12123DN cells based on surface IgM expression revealed a previously undescribed cell subset with undetectable cell surface IgM (-IgMneg). The spl-IgMneg subsets expresses RAG1/2 and actively undergoes Igk gene rearrangement at levels comparable to BM pre-B cells. Upon in vitro exposure to BAFF or transplantation into immunodeficient hosts, spl-IgMneg cells can give rise to fully mature IgMposIgDpos B cells. Furthermore, BAFF-R and NF-kB pathways are required for their efficient maturation. Our findings suggest that the spl-T1 population encompasses a subset of B cells that resemble but are distinct from the developing B cells in the BM. These spl-IgMneg B cells may represent receptor editing B cells, and/or precursor B cells undergoing BCR assembly and selection in the periphery, possibly providing an opportunity for tolerance induction to tissue restricted self-antigens and microbiota-derived antigens.
T-bet regulates T cell-independent plasmablast responses during intracellular bacterial infection
Authors: Newell Krista L , Levack Russell , Cabrera-Martinez Berenice , Winslow Gary M 
Published: January 2023

Abstract
T-bet+ B cells have emerged as a major B cell subset associated with both protective immunity and autoimmunity. T-bet is considered to be a master transcription factor in type I adaptive immune responses to intracellular pathogens, a response characterized by the production of interferon gamma. Our studies have shown that infection with the intracellular bacterium, E. muris, generates both extrafollicular T cell-independent T-bet+ CD11c+ IgM-secreting plasmablasts (PB), as well as T-bet+ CD11c+ IgM memory cells. Both of these B cell populations play key roles in antigen-specific humoral immunity, although the role of T-bet in their development had not been resolved. Although T-bet is often considered to define lineage in Type I B cells, we found that T-bet was dispensable for memory B cell development. Memory B cells from mice with B cell-specific T-bet deficiency exhibited nearly identical surface marker expression as those of wild-type mice, including CD11c, CD73, PD-L2, CD80, CD38, CD95, and CXCR3. In contrast, T-bet-deficient early CD11c+ splenic PB were significantly reduced in frequency, suggesting that T-bet regulates PB, but not memory cell development or differentiation. As has been reported, antigen-specific IgG2c was no longer the dominant serum antibody isotype in mice lacking B cell T-bet expression. Our data suggest that a critical function of T-bet in B cells is to promote the differentiation of short-lived antibody-secreting PB, and to restrict class switching to protective IgG2c antibodies. Our findings are relevant to how T-bet+ B cells function not only in pathogen-specific immunity, but also in autoimmune diseases, wherein the quality of the humoral response is of critical importance.