bluuebunny/crossref_metadata_2025_split huggingface dataset:
Invariant NKT cells functionally link microbiota-induced butyrate production and joint inflammation
Authors: Lee Sangsin , Kim Hye Young , Chung Doohyun 
Published: January 2023

Abstract
Emerging evidence indicates that the gut microbiota contributes to the regulation of joint inflammation by modulating the function of immune cells. However, the mechanism by which the microbiota regulates joint inflammation is unclear. To address this, we investigated the effect of the gut microbiota on antibody-induced arthritis (AIA). Feeding mice a high-fiber diet attenuated AIA in a microbiota-dependent manner. Among the short-chain fatty acids produced by the microbiota, butyrate suppressed cytokine production by invariant (i)NKT cells by inhibiting class I histone deacetylases. Furthermore, butyrate ameliorated AIA in wild-type, but not iNKT cell-deficient Jα18-knockout (KO), mice. Adoptive transfer of butyrate-pretreated iNKT cells had no effect on AIA in Jα18 KO mice, whereas transfer of untreated iNKT cells into Jα18 KO mice restored AIA. In conclusion, our data indicate that gut microbiota-induced butyrate production attenuates AIA by inhibiting cytokine production by iNKT cells. Thus, the microbiota–butyrate–iNKT cell axis may be a therapeutic target for joint inflammation.
Intrinsic function of STAT3 in B cells is to promote B cell proliferation and maturation
Authors: Oladipupo Favour , Egwuagu Charles E , Yu Cheng-Rong , Choi Jin Kyeong 
Published: January 2023

Abstract
We previously showed that STAT3 promotes T cell survival by restraining unbridled activation and proliferation of T cells (J Biol Chem. 286:30888–97). We also showed that STAT3 regulates Th17 differentiation and the loss of STAT3 in CD4+ T cells prevents development of experimental autoimmune diseases (J Immunol. 180:6070–6). However, the intrinsic and extrinsic functions of STAT3 in B cells are not well understood. In this study, we have generated mice lacking STAT3 in CD19+ B cells and investigated the functions of STAT3 in B cells. Targeted deletion of stat3 in the conditional STAT3KO mouse strain (CD19-CRE-STAT3KO) was verified by Western blot analysis by showing loss of STAT3 expression in CD19+ B cells. We further show by lymphocyte proliferation assays and cell cycle analysis that the CD19-STAT3KO mice proliferated less compared to WT counterparts. Moreover, compared to the development of WT B cells, the STAT3KO mice contained a significantly higher percentage of immature B cells. These results suggest that STAT3 might exhibit diametrically opposite effects in B and T cells; Whereas STAT3 promotes B cell proliferation, STAT3 promotes T-cell survival and inhibits T cell activation/proliferation through up-regulation of Class O Forkhead Transcription Factors. In summary, our study reveals for the first time that STAT3 is required for B cell maturation.
Innate signaling pathways contribute towards formation of the extra-follicular B cell response
Authors: Lam Jonathan , Baumgarth Nicole 
Published: January 2023

Abstract
B cell responses are often assessed by the strength of the induced germinal center response. Yet proliferation and differentiation of antigen-specific B cells into antibody-secreting cells (ASCs) in extrafollicular (EF) responses, not germinal centers, are correlated in time with clearance from influenza virus infection. The signals responsible for initiation of the EF response, and subsequent differentiation into plasmablasts and plasma cells, have yet to be elucidated. Here we demonstrate that components of major innate signaling pathways are necessary for robust formation of ASCs during primary influenza infection. Of many different knockout mouse strains that lacked signaling in inflammatory pathways, only MyD88/TRIF double knockouts (DKOs) showed drastically reduced plasmablast/plasma cell formation as defined by expression of IRF4, a necessary transcription factor for ASC differentiation, and CD138, a marker of plasma cells. This was also demonstrated in DKO B cell chimeric mice, along with reduced influenza-specific antibody secretion. MyD88 and TRIF are downstream signaling components of Toll-like receptors (TLRs). However, mice lacking Unc93, TLR2 and TLR4 and thus all TLR signaling, but with MyD88 and TRIF intact, generated normal EF responses. We conclude that MyD88 and TRIF play a TLR-independent and B cell intrinsic role in early ASC generation. Current work is aimed at elucidating the role of MyD88/TRIF in the regulation of IRF4-induction.
Linking Endoplasmic Reticular Stress, ELL2, and Alternative Splicing
Authors: Milcarek Christine 
Published: January 2023

Abstract
RNA splicing patterns in antibody-secreting cells are shaped by endoplasmic reticulum stress, ELL2 transcription elongation factor induction, and changes in the levels of snRNAs. Endoplasmic reticulum stress induces the unfolded protein response; among these stress proteins is Ire1, whose auto-phosphorylation drives it to acquire a regulated mRNA decay activity. The mRNA-modifying function of phosphorylated Ire1 non-canonically splices Xbp1 and yet degrades other cellular mRNAs with related motifs, in a cell-specific manner. Naïve splenic B cells will activate Ire1 phosphorylation early on after lipopolysaccharide (LPS) stimulation, within 18 h; large-scale changes in mRNA content and splicing patterns result. Inhibition of the mRNA-degradation function of Ire1 is correlated with further differences in the splicing patterns and a reduction in the mRNA factors for snRNA transcription. Some of the &gt;4000 splicing changes seen at 18 h after LPS stimulation persist into the late stages of antibody secretion, up to 72 h. Meanwhile some early splicing changes are supplanted by new splicing changes introduced by the up-regulation of ELL2 which is necessary for immunoglobulin secretion; it does this by changing mRNA processing patterns of immunoglobulin heavy chain and &gt;5000 other genes. unexpectedly, ubiquitination of c-myc by the ELL family members also plays a role in plasma-blast survival.
Reciprocal regulation of Th2 and Th17 cells by PAD2-mediated citrullination
Authors: Sun Bo , Chang Hui-Hsin , Salinger Ari , Tomita Beverly , Bawadekar Mandar , Shelef Miriam A. , Weerapana Eranthie , Thompson Paul T. , Ho I-Cheng 
Published: January 2023

Abstract
Dysregulated citrullination, a unique form of post-translational modification catalyzed by the peptidylarginine deiminases (PADs), is associated with several major risk factors of rheumatoid arthritis, a disease characterized by the presence of anti-citrullinated protein antibodies. While PADs have been identified decades ago, their physiological roles in the immune system are still poorly understood. Hereby we report that PAD2 is the dominant PAD in Th cells. Its expression is induced by anti-CD3 stimulation. Pharmacological inhibition or genetic ablation of PAD2 augments Th2 differentiation but attenuates Th17 differentiation of human and mouse primary Th cells. This effect is due to alterations in the activity of GATA3 and RORgt. Mechanistically, both GATA3 and RORgt interact with and are citrullinated by PAD2 in primary Th cells. Citrullination of R330 of GATA3 weakens its DNA binding ability, whereas citrullination of four arginine residues of RORgt enhances its DNA binding. Furthermore, PAD2-deficient mice are more susceptible to allergic airway inflammation. Taken together, PAD2-mediated citrullination reciprocally regulates the differentiation of Th2 and Th17 cells.
VSTM4 is a novel negative regulator of T cell activation
Authors: Wang Jinghua , Manick Brian , Renelt Mark , Suin Jing , Hansen Louis , Person Anthony , Kalabokis Vassilios , Wu Guoping 
Published: January 2023

Abstract
The B7-like proteins play critical immunomodulatory roles and constitute attractive targets for the development of novel immunotherapies. In this study, we demonstrated that a fusion protein, containing the extracellular domain of V-set and transmembrane domain containing 4 fused to Fc (VSTM4-Fc), inhibited human T-cell activation. VSTM4 markedly suppressed human T cell proliferation in the presence of T-cell receptor signaling. Furthermore, VSTM4 significantly reduced IFN-γ, IL-2, and IL-17 cytokine production by human T cells. Moreover, VSTM4 profoundly decreased T cell activation marker CD69 expression on CD3+, CD4+, and CD8+ T cells. VSTM4 also inhibited naïve CD4+ T cell differentiation into Th1 cells. Our results showed strong binding of VSTM4-Fc to human activated T cells but weak binding to resting nonactivated T cells. Thus, we identify VSTM4 as a novel immunoglobulin superfamily (IgSF) protein with robust T cell inhibitory activity. VSTM4 represents a new negative regulator of T cells and may be a unique target for developing new immunotherapy strategies for the treatment of immune-related diseases, including autoimmunity and cancer.
CTCF is necessary for CD8+ effector T cell differentiation
Authors: Quon Sara J , Yu Bingfei , He Zhaoren , Russ Brendan , Turner Stephen J , Murre Cornelius , Goldrath Ananda W 
Published: January 2023

Abstract
Naive T cell differentiation into effector and memory subsets in response to infection requires the coordination of numerous factors that regulate changes in gene expression to support proliferation and cell function. Chromatin accessibility and DNA looping influence transcription factor binding, facilitate enhancer-promoter interactions, and insulate genes. CCCTC-Binding Factor (CTCF) is a highly conserved protein important for organizing the genome and partnering with transcription factors, but its role in CD8+ T cell differentiation has yet to be determined. We show that loss of CTCF in CD8+ T cells alters the expression of genes important for subset differentiation and these changes are reflected during Listeria infection where the formation of memory-precursor cells is favored while the formation of terminal effector cells is impaired. At a memory timepoint, CTCF knockdown enhances intestinal Trm accumulation despite impairing circulating memory maintenance. ChIP-Seq and HiC reveals that terminal effector cells gain CTCF binding within topologically associated domains, often overlapping with H3K27ac peaks which marks active enhancers and promoters. As genes near the overlap of CTCF and H3K27ac peaks have increased expression in terminal effector cells, we propose that one role of CTCF is to promote effector function by stabilizing promoter-enhancer interactions which influences the expression of fate-determining genes. Insights into the role of CTCF in CD8+ T cell differentiation during infection will yield valuable insight into dynamic chromatin changes regulating T cell differentiation and inform the development of therapies which better utilize the T cell response.
Epithelial versus myeloid-derived IL-33 controls different aspects of pathogen-specific immunity
Authors: Herbert DeBroski R , Herbine Karl , Hung LiYin , Pastore Christopher , Singh Brenal , Tanaka Yuki , Bryce Paul J. , Kambayashi Taku 
Published: January 2023

Abstract
Sensing of tissue injury through interleukin 33 (IL-33) release from damaged epithelial and endothelial cells directs effector function(s) of T helper and cytotoxic subsets, group 2 innate lymphocytes, and various myeloid cells. However, it is unclear whether noncanonical IL-33 production from conventional dendritic cells (cDC) shapes infection outcome. This study interrogated whether IL-33 from epithelial cells functioned differently from IL-33 derived from conventional dendritic cells (cDC) during helminth driven Type 2 inflammation. Data show mice temporally deleted of intestinal epithelial cell IL-33 (VillinCre-ERIL33flox/flox)failed to induce ILC2 expansion and host immunity against the hookworm parasite Nippostrongylus brasiliensis, whereas selective loss of cDC-derived IL-33 (CD11cCreIL33flox/flox) abrogated ST2+Foxp3+Treg responses, enhanced TH2 and ILC2 responses, and accelerated worm clearance. Lack of cDC intrinsic IL-33 impaired Foxp3+Treg expansion and anti-IL-2/IL-2 complex administration restored Treg numbers and suppressed worm clearance in CD11cCreIL-33flox/floxmice compared to CD11cCrecontrols. Collectively, this work emphasizes cellular source as a key determinant in the ability of IL-33 to direct pathogen-specific immunity.
The severities of Pseudomonas aeruginosa infection are enhanced by group 2 innate lymphoid cells in severely burned mice
Authors: Ito Ichiaki , Finnerty Celeste C , Herndon David N , Kobayashi Makiko , Suzuki Fujio 
Published: January 2023

Abstract
Pseudomonas aeruginosa burn wound infection and subsequent sepsis cause high mortality of severely burned patients. In our previous studies, group 2 innate lymphoid cells (ILC2) were increasingly detected in the lamina propria of severely burned mice. In this study, a role of ILC2 on the severity of pseudomonal systemic infections was investigated in severely burned mice. Severely burned mice (3rd degree, 25% TBSA burn) were infected s.c. with 103 CFU of P. aeruginosa. These mice were, then, treated i.p. with 100 μg/mouse of SR3335, an inhibitor of ILC2 proliferation, once daily for 2 days starting 1 day after burn injury. To test a role of circulating ILC2 on the pseudomonacidal activity of normal mouse PBMCs, these 2 cell preparations were transwell-cultured. In the results, the number of ILC2 increased in the circulation of mice 3–5 days after burn injury, but not in these burn mice treated with SR3335. All of the burn mice died within 6 days of P. aeruginosa infection, while 75% of the same mice treated with SR3335 survived. The pathogen was killed effectively by normal mouse PBMCs stimulated with heat-killed bacteria. The killing activity of these PBMCs was not shown in transwell-cultures with burn mouse PBMCs or circulating ILC2 isolated from severely burned mice. In contrast, normal mouse PBMCs transwell-cultured with burn mouse ILC2-depleted PBMCs killed the pathogen. These results indicate that the severities of P. aeruginosa infections are enhanced by ILC2 detected in circulation of burned mice.
Characterization of the function of murine guanylate-binding protein 9 in the context of bacterial and parasitic infections
Authors: Lichte Jens , Degrandi Daniel , Lindenberg Valesca , Mölleken Katja , Hegemann Johannes , Pfeffer Klaus 
Published: January 2023

Abstract
Interferon-γ (IFNγ) signaling induces high expression of immunomodulatory molecules in most cell types. Among these molecules, the members of the murine guanylate-binding protein (mGBP) family comprise a group of eleven proteins (mGBP1-mGBP11) shown to have important functions in cell-autonomous immunity. Upon IFNγ stimulation, mGBPs localize in vesicle-like structures distributed within the cytoplasm. Previous studies have shown that after infection with several intracellularly replicating pathogens, mGBPs rapidly relocate towards the pathogen-containing vacuoles (PCV), such as the parasitophorous vacuole (PV) of Toxoplasma gondii or the inclusions of Chlamydia trachomatis. Accumulation of mGBP2 at the PV membrane leads to loss of membrane integrity and subsequent restriction of parasite replication. Although mGBP proteins share a high sequence identity, differences in localization frequencies could be detected. For instance, mGBP1 and mGBP2 show the highest frequencies of recruitment to both Toxoplasma and Chlamydia PCVs. However, mGBP9 recruitment was more frequent to chlamydial inclusions than to T. gondii PVs. Thus, the importance of individual mGBPs might vary depending on the type of the pathogen. To analyze these findings in more detail, we started with the generation of mgbp9−/− cell- and mouse lines. Therefore, the CRISPR/Cas9 gene editing system with homologous directed integration of a single-stranded oligodesoxynucleotide is used to generate mGBP9 deficient ES cells for mouse and cell line development. In-depth analyzes of mgbp9−/− cells and mice in T. gondii and C. trachomatis infection will lead to a better understanding of immunity against intracellular pathogens.
Female mice express increased complement regulators and decreased intestinal ischemia-reperfusion injury
Authors: Fleming Sherry D , Ferm Jonathan , Amrein Jennifer 
Published: January 2023

Abstract
Intestinal ischemia reperfusion (IR) in male mice results in local and systemic tissue damage due to excessive complement activation and neutrophil infiltration. Complement components differ by sex in animal models of kidney and heart ischemia. In addition, estrogen alters blood vessel diameter during reperfusion and testosterone blockade attenuates nitric oxide production. Clinical studies associated oral contraceptive use with intestinal ischemia. Together, these data suggest that hormonal differences in females may change the mechanisms of intestinal IR injury compared to males. We hypothesized that increased intestinal complement regulator expression in females delays IR-induced C3 deposition compared to males. Male and female C57Bl/6 mice were subjected to Sham treatment or 30 mins intestinal ischemia followed by two hours reperfusion prior to collecting the mid-jejunum and serum. Intestinal sections were analyzed by RT-PCR for complement regulator expression. Additional analyses examined markers of cell death, complement deposition, and LTB4 production. Compared to male mice, female mice sustained delayed intestinal injury and decreased complement C3 deposition. In response to IR, female mice significantly increased autophagy markers and intestinal LTB4 secretion. Sham treatment increased mRNA of complement regulators, CRRY and CD55 in female mice while Factor H increased in response to IR in both sexes. Together these data suggest that local control of complement activation, neutrophil infiltration and autophagy in response to intestinal ischemia/reperfusion varies between sexes and may dictate distinct therapeutic intervention.
Dysregulation of G-CSF and neutrophil production is associated with chronic inflammation in elderly rhesus macaques
Authors: He Ziyuan , Takahashi Naofumi , Fahlberg Marissa , Slisarenko Nadia , Didier Elizabeth , Kuroda Marcelo 
Published: January 2023

Abstract
Aging is characterized with a loss of hematopoietic tissue in bone marrow, systemic chronic inflammation, and higher susceptibility to infectious diseases. We previously showed the tightly regulated kinetics and massive daily production of neutrophils during homeostasis in rhesus macaques aged 3 to 19 years old. Here we extended that study to further investigate the effect of aging on kinetics and production of neutrophils in more elderly rhesus macaques. We observed a neutrophil kinetics shift and higher in-group variability in rhesus macaques above 20 years old (equivalent to 70 years or more in humans) by in vivo BrdU pulse-chase labeling. In a cross-sectional study, we also measured complete blood cell counts and plasma cytokine levels from a group of 126 outdoor-housed captive Indian-ancestry rhesus macaques between 2 to 23 years old and found that aging negatively correlated with neutrophil counts and positively correlated with plasma G-CSF levels. Hierarchical clustering analysis suggested that G-CSF was strongly associated with pro-inflammatory cytokines IL-1b and MIP-1a. In elderly rhesus macaques, neutrophils expressed less myeloperoxidase and there was a higher frequency of PMN-MDSCs compared to the young adult macaques. In summary, there appears to be a dysregulated feedback mechanism wherein increased levels of G-CSF failed to restore neutrophil production in elderly rhesus macaques that was associated with induced production of pro-inflammatory cytokines and earlier release of less mature neutrophils and PMN-MDSCs. Together, these findings may contribute to the understanding of the chronic inflammation and greater susceptibility to infectious diseases in the elderly.
Baby’s First Macrophage: How do placental macrophages (Hofbauer Cells, HCs) contribute to immune tolerance and infection response during pregnancy?
Authors: Swieboda Dominika , Johnson Erica , Skountzou Ioanna , Chakraborty Rana 
Published: January 2023

Abstract
Placental immunity is dichotomous: tolerance of the semiallogenic fetus is balanced with limiting transmission of maternal pathogens. HCs are the major fetal immune cell at the placenta, but mechanisms responsible for maintaining immune homeostasis while preventing infection require elucidation. We determined the phenotype of human HCs throughout gestation and analyzed stimulation response.
Activated HCs were present in early pregnancy and reduced in number by term while maintaining similar phenotypes. Tolerant HC numbers were highest in midgestation, after a relatively intolerant phenotype early in gestation. We saw a significant shift in macrophage polarization as gestation progressed. Transcription of ARG2 exceeded iNOS at all points, reaching 10-fold higher at term.
Following treatment with IL4+IL13 or IFNγ+LPS midgestation HCs underwent significant phenotype change and activation. Basal expression of antiviral IFN stimulated genes (ISGs) was lowest at midgestation and was enhanced by IFN-α and IFN-λ1 with a 10-fold stronger response to IFN-α. RIG-I agonism induced HC activation, 10-fold iNOS upregulation and enhanced transcription of IFNs, MDA5, RIG-I, and ISGs.
Response to stimulation by IFNγ+LPS, IL4+IL13, IL1β+HAGG was limited to loss of tolerance at term. IL-10 treatment increased numbers of CD163+ HCs, and IFNγ+LPS caused loss of discernible polarization patterns. Basal expression of RIG-I, MDA5 and ISGs was highest in term HCs, but IFN-α did not activate them. RIG-I agonism reduced markers of tolerance.
HCs are variable macrophages, with phenotype and immune capacity strongly dependent on gestational age. Understanding placental immunobiology is fundamental to addressing key pregnancy morbidities.
Distribution and phenotypes of SLAMF9+ myeloid cells in mouse tissues
Authors: Mikulin Joseph A , Wilson Timothy J 
Published: January 2023

Abstract
SLAM family receptors are critical mediators of immune function, whose expression varies across tissue and cell type. However, the expression of SLAM Family Member 9 (SLAMF9), the most recently discovered protein in the family, has yet to be investigated in mouse or human tissues. In this study, we sought to discover in what tissues and the degree to which SLAMF9 is expressed in the mouse model, as well as determine whether the cells expressing SLAMF9 belong to either a known or a novel subset. We discovered that, within the non-classical monocyte subset (CD45+CD11b+Ly6c-), two broad groups emerged based on SLAMF9 expression. The SLAMF9+ cells in this subset appear to constitute a homogenous group in both the kidney and liver. Renal SLAMF9+ cells also demonstrate higher expression of MHC-II, CX3CR1, and CD11c than their SLAMF9-counterparts, as well as low F4/80 expression and no CD103 expression. However, a cell type with largely similar marker expression and lower frequency appears in the hepatic non-classical monocyte gate, indicating that the cell type may be conserved across tissues. Therefore, SLAMF9 marks a subset of CD103−, CD172a+ classical dendritic cells and may designate a specialized subset of these cells with similar functions in both the liver and kidneys.