bluuebunny/crossref_metadata_2025_split huggingface dataset:
MicroRNA-29 Stabilizes IFN-γ mRNA by inhibiting GW182 (174.5)
Authors: Savan Ram , Legiewicz Michal , McFarland Adelle , Schwerk Johannes , Bindewald Eckart , Lin Fan-ching , Orr Selinda , Yoshikawa Noriko , Hegamyer Glenn , Yalamanchili Rajesh , Ramakrishnan Karthika , Kronfli Anthony , Saleh Bahara , McVicar Daniel , Carrington Mary , Colburn Nancy , Anderson Stephen , Shapiro Bruce , Le Grice Stuart , Young Howard 
Published: January 2023

Abstract
Tight regulation of interferon-gamma (IFN-γ) expression is critical for an optimal immune response. We have extensively studied the mechanisms responsible for the post-transcriptional regulation of IFN-γ expression. AU-rich element (ARE)-mediated decay (AMD) via the tristetraprolin (TTP) complex is responsible for robust degradation of the IFN-γ mRNA. We found that microRNA-29 (miR-29) targets the IFN-γ 3’UTR and, unlike the conventional inhibitory miRNAs, stabilizes the mRNA. Resolution of the secondary structure showed that the ARE and miR-29 binding site are in close proximity and a series of experiments manipulating the RNA structure revealed that this proximity enables miR-29 to antagonize TTP degradation. Interestingly, miR-29 is unable to degrade the mRNA even in the absence of TTP. Recently we have found that GW182, a major degradation protein in the miRISC, is unable to be recruited to the mRNA as a result of the location of the miR-29 binding site in the secondary structure. The ability of miR-29 to stabilize the IFN-γ mRNA demonstrates a novel molecular mechanism of miRNA regulation.
Crosstalk between STAT3 and RANK signaling pathways during osteoclastogenesis (174.7)
Authors: Zhang Huiyuan , Hu Hongbo , Jin Jin , Ohashi Erika , Greeley Nathaniel , Li Haiyan , Sun Shao-cong , Watowich Stephanie 
Published: January 2023

Abstract
Osteoclasts are a specialized cell type in the bone marrow microenvironment with a critical role in bone resorption. Osteoclasts develop from macrophage precursors in response to RANK ligand (RANKL) stimulation. Osteopenia and pathologic fractures frequently occur in patients with Hyper IgE syndrome, which is caused by loss-of-function mutations in STAT3 . How impaired STAT3 function translates to these clinical features is not understood. We found that mice with conditional Stat3 deletion in bone marrow have increased osteoclast numbers in vivo; therefore, we examined STAT3 function in RANKL-induced osteoclast differentiation from bone marrow macrophages (BMMs). We found that STAT3 negatively regulates RANK signaling by inhibiting TRAF6 ubiquitination and activation of the downstream signaling proteins NF-κB, JNK and p38 MAPK. Stat3-deficient BMMs show enhanced osteoclast gene expression and osteoclast formation in vitro. STAT3 is induced in BMMs by M-CSF, not RANKL, suggesting that M-CSF signal transduction via STAT3 conditions osteoclast precursors for appropriate RANK-RANKL signaling. We identified the deubiquitinase Uch37 as a STAT3-dependent gene regulating osteoclastogenesis. Thus, our data suggest STAT3 restrains osteoclast development and bone resorption by mediating the amplitude of RANK signaling via Uch37 regulation.
Neuroimmune semaphorin 4D is necessary for optimal lung allergic inflammatory response (175.16)
Authors: Chapoval Svetlana , Nkyimbeng-Takwi EusebuisHenry , Shanks Kathleen , Smith Elizabeth , Iyer Apoorva , Lipsky Michael , DeTolla Louis , Keegan Achsah 
Published: January 2023

Abstract
Neuroimmune semaphorin 4D (Sema4D) was found to be expressed and function in the nervous and immune systems. In the immune system, Sema4D is constitutively expressed on T cells and regulates T cell priming. Currently available data suggest that Sema4D has crucial stimulatory functions in a broad range of cells including macrophages, DC, NK cells, and neutrophils. We hypothesized that Sema4D plays a critical non-redundant regulatory role in allergic airway response. To test our hypothesis, we employed Sema4D-/- and WT mice in the well-defined mouse model of OVA-induced experimental asthma. We observed a decrease in eosinophilic airway infiltration in allergen-treated Sema4D-/- mice relative to WT mice. This reduced allergic inflammatory response was associated with decreased BAL IL-5, IL-13, and TGFb1 levels. In addition, T cell proliferation in OVA323-339 - restimulated Sema4D-/- cell cultures were downregulated. However, airway hyperreactivity to methacholine challenges was not affected by Sema4D deficiency. These data provide a new insight into Sema4D biology and define Sema4D as an important regulator of Th2-driven lung pathophysiology.
Allergic lung inflammation and susceptibility to Streptococcus pneumoniae (175.2)
Authors: Sanfilippo Alan , Metzger Dennis 
Published: January 2023

Abstract
Streptococcus pneumoniae is the most common cause of bacterial pneumonia which results in 175,000 hospitalizations as well as 40,000 deaths in the United States annually. With the introduction of a conjugate vaccine, overall disease burden has declined. However, a link between asthma and invasive pneumococcal disease (IPD) has been identified, prompting the Advisory Committee on Immunization Practices to recommend that all adults with asthma receive the pneumococcal conjugate vaccine. To study the mechanism responsible for an increased risk of IPD for individuals with asthma, we used a model of ovalbumin (OVA)-induced allergic lung inflammation (ALI). We hypothesized that mice with ALI would be more susceptible than naïve mice to an S. pneumoniae infection. Following OVA challenge, BALB/c mice were infected intranasally (i.n.) with a lethal dose of S. pneumoniae and morbidity and mortality were monitored. Surprisingly, mice with ALI were more resistant to infection than PBS treated controls. This increased resistance was highest 10 days following the final OVA challenge, despite reduced cytokine production after infection. Mice with ALI also had significantly increased early pneumococcal clearance from the lungs across a wide range of infectious challenges. We plan to further characterize the cellular response to pulmonary S. pneumoniae infection in mice with ALI to determine the mechanisms responsible for the observed increased resistance.
Polymorphisms of the Ig heavy chain 3’ Regulatory Region associates with humoral Ig Homeostasis. (176.13)
Authors: Frezza Domenico , Serone Eliseo , Daleno Cristina , Scala Alessia , Principi Nicola , Iacoacci Valentina , Karasiota Evangelista , Magrini Andrea , Massoud Renato , D'Addabbo Pietro , Plebani Alessandro , Giambra Vincenzo , Esposito Susanna 
Published: January 2023

Abstract
Aim. Incomplete maturation of immune system in the first years of life could affect different individual response to vaccination. To investigate the issue we studied a polymorphic genomic cis regulator of Ig heavy chain in response to vaccination with viral antigens. Method. Two cohorts of healthy subjects, one not yet 3 years and a second between 21 and 26 years old were vaccinated against H1N1, H2N3, B and HBV antigens respectively. From time zero the two cohorts were followed up for the total peripheral blood levels of Ig and for specific antibodies against the vaccine antigens. Subjects were genotyped for Ig heavy chain 3’ RR structural polymorphisms of enhancer hs1.2. Results. The serum specific antibodies in subjects Non responder, Responder and High responder to the vaccination is not associated with the levels of circulating IgM, IgG, IgA. However, the humoral concentration of Ig in the adult subjects correlates with hs1.2 allelic frequency as observed previously (p&lt;0.001). Children with low IgM concentration versus children with high IgM show a change of hs1.2 allele *1 frequency from 47% to 1.8% and for allele *2 from 43% to 82% (p&lt;10-9). The number of CD19 and CD27 cells were determined. Conclusions. The hs1.2 enhancer is associated with regulation of Ig levels. Children with allele *2 could have a possible advantage with wider repertoire of Ig. We suggest different controls for the production and mantainment of total and specific Ig amount with vaccination.
Mechanisms for regulation of the human antibody response to the influenza vaccine and changes with age (176.19)
Authors: Blomberg Bonnie , Romero Maria , Diaz Alain , Mendez Nicholas , Landin Ana Marie , Frasca Daniela 
Published: January 2023

Abstract
Aging is associated with a decline in the ability of the individual to mount protective immune responses, e.g. antibodies (immunoglobulins, Ig). Understanding the molecular mechanisms of the age-related impairment in immune functions will help to prevent infectious diseases and improve the biological quality of life in the elderly. We hypothesize that the increased pro-inflammatory status of the elderly, called inflammaging, impairs the capacity of the individual to make protective antibodies and to respond to vaccination. Our data indicate that aged B lymphocytes make TNF-α before vaccine challenge, which impairs their function,including optimal AID and class switch recombination (CSR) of Ig. We previously showed that the transcription factor E47 and enzyme, AID (activation-induced cytidine deaminase), both crucial for class switch recombination, are decreased with age in both mice and humans. We here report that human unstimulated (ex vivo) B cells from elderly have significantly higher levels of TNF-α than young subjects and that the t0 TNF level negatively correlates with the in vitro t28 influenza vaccine response (as measured by AID) which in turn correlates with the in vivo serum HAI response. Thus, these results reveal new molecular mechanisms which contribute to reduced antibody responses in aging and should have immediate impact on crucial development of effective vaccines to protect elderly individuals from diseases typical of old age.
Regulation of Central B-cell Tolerance by Aicda and Myd88 (176.20)
Authors: Kuraoka Masayuki , Snowden Pilar , Holl T. , Liao Dongmei , Reynolds Alexander , Kelsoe Garnett 
Published: January 2023

Abstract
V(D)J recombination generates a highly diverse repertoire of B-cell antigen receptors crucial for effective humoral immunity. This process also frequently creates autoreactive B cells that are mostly eliminated during B-cell development. Early immature B cells that are polyreactive or bind nuclear antigens are preferentially eliminated in the bone marrow at the pre-B to immature B-cell transition. Residual autoreactive clones are further suppressed in the periphery. Despite years of study, the mechanism(s) of these tolerance checkpoints are not understood. Recently, we and others have shown that expression of activation-induced cytidine deaminase (AID), the product of Aicda gene, by immature B cells plays an unanticipated role in purging self-reactive B cells in mice and humans. We now show that co-activation of immature B cells by anti-IgM F(ab’)2 and CpG DNA synergistically increases AID expression, implying that cross-talk between BCR- and Toll-like receptor 9 (TLR9)-mediated signals may regulate AID expression in immature B cells. By extension, we hypothesized that MyD-88 would also play a crucial role in central B-cell tolerance. Consistent with this idea, mice deficient for Myd88 exhibited reduced capacity to purge autoreactive immature/transitional B cells; the clonal deletion of self-reactive 3H9 VDJ knock-in mice is significantly impaired in the absence of MyD88 expression. We are currently investigating interaction of Aicda and Myd88 in central tolerance in B cells.
Regulated release of nitric oxide by nonhematopoietic stroma controls expansion of the activated T cell pool in lymph nodes (176.23)
Authors: Lukacs-Kornek Veronika , Malhotra Deepali , Fletcher Anne , Acton Sophie , Kutlu Elpek , Turley Shannon 
Published: January 2023

Abstract
Fibroblastic reticular cells (FRCs) and lymphatic endothelial cells (LECs) are non-hematopoietic stromal cells of lymphoid organs. They influence the migration and homeostasis of naïve T cells; however, their influence on activated T cells remains undescribed. Here we report that FRCs and LECs inhibited T cell proliferation through regulated nitric oxide synthase-2(NOS2)-dependent mechanism. Moreover, in vivo NOS2 expression by FRCs and LECs controlled the size of the activated T cell pool. Mechanistically, the expression of NOS2 and production of nitric oxide (NO) paralleled the activation of T cells and required IFNGR1 signaling in FRCs and LECs, and was augmented by TNF and direct contact with activated T cells. Comparative transcriptomic analysis revealed that various adhesion molecules and multiple components of cytokine, complement and JAK-STAT signaling pathways are upregulated in FRCs in the presence of activated T cells. Based on these data, current efforts aim to identify the molecules involved in the direct stromal cell-T cell interaction influencing NO production by FRCs. This negative regulatory feedback mechanism is likely of great relevance to regulation of immune responses either to prevent excessive T cell expansion or to avoid structural damage within LNs caused by the expanding T cell pool.
The adipokines Leptin and Wnt5a have divergent effects on mast cell function and migration (177.11)
Authors: Kolawole Elizabeth , Falanga Yves , Ryan John 
Published: January 2023

Abstract
Mast cells are known for their critical role in allergy and inflammatory diseases such as asthma. Furthermore, it has been shown that mast cell numbers are increased in white adipose of the obese. Due to the epidemiological relationship between allergy and obesity, we investigated the effects of adipokines on mast cell regulation. In this work we demonstrate that the adipokine Wnt5a enhances IgE-mediated cytokine production as well as migration, with greater effect on a Th2-prone background. By contrast, the adipokine Leptin, best known for its pro-inflammatory roles, suppresses IgE-mediated cytokine production. Additionally, in vivo studies showed that Leptin receptor-deficiency magnifies IgE-mediated anaphylaxis. Interestingly, the effects of Leptin may be restricted to mast cells cultured from mice with a Th1-prone background. Characterizing the role of mast cells in obesity can increase our understanding of the links between obesity, allergy and allergic disease enabling the possibility of new therapies.
Histamine-releasing factor (HRF) in asthma and atopic dermatitis (177.16)
Authors: Ando Tomoaki , Kashiwakura Jun-ichi , Kawakami Yuko , Kawakami Toshiaki 
Published: January 2023

Abstract
Effects of monomeric IgE on mast cell biology exhibit vast heterogeneity, depending on IgE used. Highly cytokinergic (HC) IgEs can induce many activation events such as degranulation, cytokine production, etc, whereas poorly cytokinergic (PC) IgEs can induce only weak survival promotion. Because of the reminiscence to the heterogeneity in the ability of IgE molecules to prime basophils in response to HRF, this dichotomy has led us to find that a subset of IgEs bind to HRF via their Fab portions; the IgE-binding sites were mapped to two different sites of HRF, indicating that dimeric HRF can cross-link IgE-bound FcϵRI; N19 and H3 peptides blocked HRF-Ig interactions; administration of these inhibitors drastically reduced airway inflammation in asthma models, implying that blockade of HRF-Ig interactions may represent a potential prophylactic and therapeutic strategy for the treatment of asthma. Importantly, most HC, but no PC, IgEs exhibit polyreactivity to HRF and other autoantigens. Interestingly, sera from atopic dermatitis (AD) patients showed increased reactivity to autoantigens and increased levels of HRF. Some AD patients, but not healthy individuals, had high serum levels of HRF-reactive IgE. AD sera with high titers of autoreactive IgE could induce increased IL-8 secretion from human mast cells. Collectively, these results show support the autoimmune mechanism in the pathogenesis of atopic dermatitis.
Enhancement of IgE- and mast cell-dependent cutaneous inflammation by mast cell expression of C3aR and C5aR (177.5)
Authors: Piliponsky Adrian , Schafer Beatrix , Song Chang-Ho , Gerard Norma , Gerard Craig , Tsai Mindy , Kalesnikoff Janet , Galli Stephen 
Published: January 2023

Abstract
Mast cells express receptors for complement anaphylatoxins C3a and C5a (i.e., C3aR and C5aR) and can be activated by C3a or C5a in vitro, and C3a and C5a are generated during IgE-dependent immediate hypersensitivity reactions in vivo. However, it is not clear to what extent expression of C3aR or C5aR by mast cells influences either C3a- or C5a-induced cutaneous responses, or IgE-dependent passive cutaneous anaphylaxis (PCA), in vivo. In this study we assessed whether the expression of C3aR or C5aR by mouse skin mast cells influences: 1) the cells’ responsiveness to i.d. injections of exogenous C3a or C5a, or 2) the extent of IgE-dependent mast cell degranulation and IgE-dependent PCA, in vivo. We measured the magnitude of cutaneous responses to i.d. injections of C3a or C5a, and the extent of IgE-dependent mast cell degranulation and IgE-dependent PCA responses, in mice containing mast cells that did or did not express C3aR or C5aR. We found that the majority of the skin swelling induced by C3a or C5a required that mast cells expressed C3aR or C5aR, respectively, and the extent of IgE-dependent degranulation of skin mast cells and of IgE-dependent PCA were significantly reduced when mast cells lacked either C3aR or C5aR. We conclude that the expression of C3aR and C5aR by skin mast cells contributes to the ability of C3a and C5a to induce skin swelling and can enhance the extent of mast cell degranulation and inflammation during IgE-dependent PCA in vivo.
Visualization of Helios-expressing T cells in the skin (179.12)
Authors: Nomura Takashi , Kabashima Kenji , Miyachi Yoshiki 
Published: January 2023

Abstract
The majority of Foxp3(+)CD4(+) T cells develops in thymus as thymus-derived Tregs. On the other hand, naive T cells can express Foxp3 to become "induced" Tregs under certain conditions where TGF-b plays a key role. Helios is potentially a specific marker for thymus-derived Tregs. However characteristics of Helios(+) and Helios(-) Tregs remain elusive because it is still difficult to sort these cells alive. To solve the above problem and to delineate difference between Helios(+) and Helios(-) Tregs in the skin, we established a gene-targeted mouse in which Helios-expression can be monitored by Venus, a derivative of green fluorescent protein. Venus was expressed in a subset of double negative thymocytes, intra-thymic Tregs, and 80% of peripheral Tregs in accordance with endogenous Helios expression. Characteristics of the cutaneous Tregs are currently under investigation. Our Helios/Venus mouse is a versatile tool for studying Treg-subsets in various tissues including the skin not only with flow cytometer but also under real-time two-photon microscopy. Additionally, this system would provide a novel scope for screening factors that control Helios expression and alter epigenetic state of Tregs.
The Glucocorticoid-Induced Tumor necrosis-factor related Receptor (GITR) is a redundant costimulatory molecule for conventional T (Tconv) cells and plays a dual role on Regulatory T cells (Treg). (179.17)
Authors: Ephrem Amal , Epstein Alan , Shevach Ethan 
Published: January 2023

Abstract
Treg control immune homeostasis, but are also responsible for the suppression of tumor immunity; thus, reversing Treg function is a promising strategy for cancer therapy. The GITR is highly expressed on Treg, and upregulated on Tconv after activation. The GITR-L is primarily expressed on APC. Manipulation of GITR/GITR-L interactions in vivo has resulted in enhancement of immune responses, but whether the enhancement is secondary to co-stimulation of Tconv or reversal of Treg-mediated suppression remains unclear. To resolve this controversy, we used GITR-/- and GITR-L-/- mice and Fc-GITR-L in several experimental models. Treatment of mice with Fc-GITR-L induced the expansion of Treg. Polyclonal GITR-/- Treg survived less well than WT Treg following transfer to normal mice suggesting that GITR/GITR-L interactions are important for the survival of Tconv. In contrast, the expansion of both antigen-specific WT Tconv and Treg was not impaired following transfer to GITR-L-/- recipients. Although the capacity of GITR-/- Treg to suppress IBD was similar to WT, injection of GITR-L exacerbated IBD in mice that received CD45RBhigh T cells and in mice that received and CD45RBhigh cells and Treg. GITR-L treatment in this latter group resulted in a loss of Foxp3 expression. Thus, the GITR is a redundant molecule for costimulation of Tconv, but engagement of the GITR on Treg can result in different outcomes (expansion or loss of Foxp3) depending on the nature of the immune stimulus.
Hyperthermia regulates FOXP3 expression in human FOXP3+ regulatory T cells (179.8)
Authors: Tran Dat 
Published: January 2023

Abstract
RATIONALE: Fever is a primordial response to infection and inflammation. FOXP3+ regulatory T cells (Tregs) are central in orchestrating immune responses and preventing autoimmunity. This study hypothesizes that fever or hyperthermia regulates immunity by downregulating FOXP3 to abrogate thymic derived nTregs. METHODS: FACS analysis of FOXP3 in Tregs from peripheral blood of 5 adult cancer patients treated for 6h with thermal therapy (TT, 40 celcius). For in vitro studies, Tregs (CD4+CD127-CD25hi) were FACS-sorted from PBMC of healthy donors and stimulated with anti-CD3/CD28/IL2 for 6h at 37 (normothermia) or 40 (hyperthermia) celcius to assess their FOXP3 expression. Treg suppressive function was measured in a 4d CFSE based assay with daily 4h hyperthermia. RESULTS: Patients treated with TT had a significant (p&lt;0.0001) decreased in geometric mean fluorescent intensity (gMFI) of FOXP3 concentration between 15-40% after 6h treatment that persisted after 18h later. There was a rise in the percentage of Tregs after 6h that fell below preheat after 18h postheat (p&lt;0.001). In vitro studies demonstrated a decreased in the gMFI of FOXP3 in Tregs after 6h hyperthermia and an abrogation of suppressive function as compared to normothermia. CONCLUSIONS: Hyperthermia can regulate immune responses by transiently abrogating Treg suppressive function through the downregulation of FOXP3 expression. Hyperthermia has the therapeutic potential to augment vaccine response and cancer treatment.
IDO modifies TLR-ligand driven macrophage cytokine production by activation of GCN2 kinase arm of the integrated stress response and subsequent CHOP/GADD153 induction (180.3)
Authors: Liu Haiyun , Bradley Jill , Huang Lei , McGaha Tracy 
Published: January 2023

Abstract
Microbial sepsis is characterized by an initial cytokine storm followed by immune suppression, vascular collapse, and multiple organ failure. Indoleamine 2,3 dioxygenase (IDO) is an intracellular tryptophan-catabolizing enzyme that is induced after exposure to LPS in vivo. While generally considered to have immunosuppressive function, IDO blockade was recently demonstrated to protect mice against systemic lipopolysaccharide (LPS)-challenge, however, nothing is known about the underlying molecular mechanisms. In this study, we report that IDO was induced in the spleen of mice 6 hours after exposure to a lethal dose of endotoxin, and IDO deficiency in hematopoietic cells significantly improved survival. Moreover, we found IDO mediated tryptophan depletion in macrophages increased pro-inflammatory cytokine production in response to LPS exposure. This was due to the activation of the GCN2 kinase arm of the integrated stress response and subsequent expression of CHOP (GADD153) resulting in enhanced constitutive NF-κB activity. Lack of either GCN2 or CHOP completely abrogated macrophage production of IL-6 under stress conditions. Further, disruption of GCN2 reduced production of TNF-α and IL-12 in response to LPS stimulation under any condition. Thus, taken together our findings demonstrate that IDO functions to modulate macrophage pro-inflammatory response via a novel amino acid deprivation mechanism dependent on the integrated stress response.