bluuebunny/crossref_metadata_2025_split huggingface dataset:
RAGE antagonist decreases β-amyloid, HMGB-1, RAGE expression in the brain, and prevented long-term cognitive impairment in experimental bacterial meningitis
Authors: Barichello Tatiana , Moreira Ana Paula , Steckert Amanda V , Michels Monique , Generoso Jaqueline S , Simoes Lutiana R , Dominguini Diogo , Rafael Cassia P , Barata Joana , Petronilho Fabricia , Dal-Pizzol Felipe 
Published: January 2023

Abstract
Bacterial meningitis is a serious infection of the central nervous system that causes learning and memory impairment. Our central hypothesis is that during meningitis, the inflammation increases the synthesis of amyloid-beta (Aβ1-42) and up regulates receptor for advanced glycation end products (RAGE). Then the Aβ-RAGE-axis triggers long-term cognitive impairment in meningitis survivors. To test this, we evaluated Aβ1-42 deposition, RAGE, and high mobility group box-1 (HMGB-1) expression in the rat brain. We evaluated the behavioural response by treating the rats with RAGE-antagonist, N-benzyl-4-chloro-N-cyclohexylbenzamide (FPS-ZM1). The animals were separated into four groups: control/saline, control/FPS-ZM1, meningitis/saline, and meningitis/FPS-ZM1 (n=10). Experimental design: male 60-day-old Wistar rats received an intracisternal injection of 10 μL of artificial cerebrospinal fluid as a placebo or an equivalent volume of Streptococcus pneumoniae suspension at concentration of 5×109 CFU/mL. Eighteen hours after meningitis induction, all animals received ceftriaxone. Ten days after inoculation all blood cultures performed were negative showing that the animals were free from infection. At 10 day after meningitis induction the results from western-blot showed increased expression of Aβ, RAGE, and HMGB-1 in the hippocampus and prefrontal cortex of meningitis group. The FPS-ZM1 adjuvant treatment prevented the Aβ1-42, RAGE, and HMGB-1 expression in both brain structures and prevented long-term memory impairment in the meningitis group. The bacterial meningitis may trigger cognitive impairment through up-regulating Aβ-RAGE axis and RAGE-antagonist prevented cognitive impairment.
Hematopoietic MyD88 mediates protection against virulent Francisella tularensis infection via IFN-γ, but does not require myeloid or dendritic cell MyD88 signaling
Authors: Skyberg Jerod A , Lacey Carolyn A 
Published: January 2023

Abstract
Francisella tularensis is a highly infectious intracellular bacterium that causes the potentially fatal disease tularemia. MyD88 has previously been shown to confer protection against both attenuated and virulent strains of F. tularensis, however the underlying mechanisms of protection are largely unexplored. Here we investigated cell-specific mechanisms of protection against virulent F. tularensis infection using mice with conditional MyD88 deficiencies. MyD88 deficiency in myeloid or dendritic cells did not enhance susceptibility to F. tularensis, regardless of the route of infection. In addition, myeloid or dendritic cell MyD88 deficiency did not markedly hinder the production of inflammatory cytokines. In contrast, MyD88−/− mice, or mice with hematopoietic MyD88 deficiency display elevated bacterial burdens, and markedly reduced cytokine levels. While IL-12 levels were not diminished in MyD88−/− or hematopoietic MyD88-deficient mice infected with F. tularensis, IFN-γ production was abolished in these animals. In particular, IFN-γ production by splenic NK cells was abated in mice lacking hematopoietic MyD88. Neutralization of IFN-γ from wild-type, but not hematopoietic MyD88-deficient mice, resulted in elevated tissue F. tularensis burdens. Caspase-1/11−/− mice also displayed enhanced bacterial burdens, diminished serum IL-18 levels, and reduced IFN-γ production. Collectively, our data shows that hematopoietic MyD88 is required for IFN-γ production that is protective against F. tularensis infection. As IL-18 requires MyD88 for signaling to induce IFN-γ production, MyD88 signaling in hematopoietic cells, such as NK cells, may result in the production of protective IFN-γ via caspase1/11 dependent IL-18.
A novel role for Connexin 43 in IFN beta expression during Chlamydia trachomatis infection and cytosolic DNA-sensing
Authors: Tripathy Manoj Kumar , Zhang Yugen , Bodnar Wanda , Nagarajan Uma M 
Published: January 2023

Abstract

Background
The DNA sensor cGAS is essential for IFNβ expression in cells infected with Chlamydia. cGAMP generated during DNA sensing can also transfer via intercellular gap-junction proteins, connexins CX43/45 leading to IFNβ expression in adjacent uninfected cells. Present study highlights a novel role for CX43 in IFNβ expression during DNA-sensing and during Chlamydia infection, independent of its gap junction function.

Methods
Total IFNβ transcripts were measured by qRT-PCR following CX43 or CX45 siRNA mediated knockdown (KD). Single cell RNA-ISH method view RNA™ was used to visualize IFNβ mRNA in infected HeLa cells. CX43 localization was studied using IF and confocal microscopy.

Results
CX43-KD in HeLa cells reduced IFNβ expression by &gt;90% (p&lt;0.001) compared to control or CX45 KD, as measured by qRT-PCR. CX43-KD also reduced IFNβ mRNA in dsDNA transfected cells (p&lt;0.001) but not with poly IC RNA. RNA-ISH showed IFNβ mRNA transcripts in infected cells (&gt;90%) and in adjacent uninfected (~10%) cells, but not in distal uninfected cells, suggesting cell contact is required for adjacent-cell effect. Surprisingly, RNA-ISH of CX43-KD cells showed &gt;85% reduction in IFNβ transcripts (p&lt;0.0001) in infected cells, in addition to the loss of transcripts in cells adjacent to infected cells. CX43 localized proximal to the chlamydial inclusion membrane. Co-localization of CX43 was also observed with transfected dsDNA, but not dsRNA.

Conclusion
CX43 depletion has been shown to increase autophagy in cells. Here we show that CX43 depletion decreases IFNβ induction during DNA sensing. Our results suggest that like STING, CX43 could be a key player in both DNA sensing and autophagy, but with opposing roles. (Funded by NIAID R01-AI067678 to UN).
Ontogeny of tissue autoantigen expression influences the mechanism of tolerance by Foxp3+ regulatory T cells
Authors: Tung Kenneth S K , Lenart Dominik , Litwinowicz Agata , Harakal Jessica , Qiao Hui 
Published: January 2023

Abstract
We studied the ontogeny of organ-specific antigen expression and its effects on inducing tolerogenic regulatory T cells (Treg). Autoimmune ovarian disease (AOD) occurred in B6AF1-AIRE null mice, associated with antibody responses to the oocyte antigen NALP5 (syn. MATER) but not zona pellucida 3 (ZP3). Between postnatal days 1 and 2, numerous ovarian ZP3- primary oocytes undergo apoptosis, providing antigens to maintain tolerance to NALP5. Although ZP3 tolerance is AIRE-independent, transient Treg-depleted adult B6AF1-DEREG mice developed AOD and autoantibody responses to both ZP3 and NALP5. To investigate the origin of ZP3-specific Tregs, we examined the ontogeny of autoantibody responses after Treg depletion. Unlike adult mice, juvenile mice with Treg depletion from postnatal days 5 to 13 developed AOD and produced autoantibodies to NALP5 but not ZP3. In addition, juvenile AOD was Th1-dominant and adult AOD was Th2-dominant. The conversion from Th1 to Th2 was evidenced by the emergence of an IgG1+ ZP3 autoantibody response after Treg depletion on postnatal day 23, nine days after the onset of physiological follicular atresia occurring on postnatal day 14. Follicular atresia accompanies normal estrus in ~80% of growing oocytes, involving granulosa cell apoptosis and removal of dead ZP3+NALP5+ oocytes by antigen presenting cells. We conclude that ZP3-specific Treg development is a late event occurring beyond the neonatal period; and it likely occurs outside the thymus in response to ovarian ZP3 derived from the estrus cycle. Therefore, the ontogeny of tissue autoantigen exposure in an internal organ can regulate the induction of Treg-dependent tolerance to organ-specific antigens.
The transcription factor Ets1 cooperates with IL17 signaling to promote autoimmunity and immunodeficiency.
Authors: Sunshine Alex C , Luo Wei , Sinha Satrajit , Garrett-Sinha Lee Ann 
Published: January 2023

Abstract
Ets1 is a lineage-specific transcription factor that regulates B and T cell functions in development and disease. Mice that lack Ets1 (Ets1 KO) develop spontaneous autoimmune disease with high levels of autoantibodies. Naïve CD4+ T cells isolated from Ets1 KO mice have differentiate more readily to Th17 cells and secrete IL-17, a cytokine extensively implicated in autoimmune disease pathogenesis. To determine if increased IL-17 production contributes to the development of autoimmunity in Ets1 KO mice, we generated Ets1/IL-17 Receptor double knock out (DKO) mice. We found that the absence of IL-17 signaling did not prevent or ameliorate the phenotype of Ets1 KO mice, but rather that DKO animals exhibited worse symptoms with striking increases in the numbers of Th2 cells and Tfh cells as well as germinal center B cells, isotype-switched B cells, memory B cells and plasma cells. Furthermore, DKO mice develop spontaneous skin lesions colonized by Staphylococcus aureus (S. aureus). When DKO mice were experimentally infected with S. aureus they were unable to clear the bacteria. Curiously, the increased bacterial susceptibility was age-dependent as 2 month old DKO mice were not susceptible, whereas 4 month old mice were. Our current model is that excessive immune activation over time leads to production of autoantibodies that target immune effector mechanisms important for anti-bacterial immunity, such as anti-microbial peptides, thereby resulting in susceptibility to S. aureus. Our studies may have important implications in understanding the mechanisms that drive pathogenesis in human diseases characterized by both autoimmunity and immunodeficiency.
Naive T cells are intrinsically biased in helper T cell functions
Authors: Sood Aditi , Rogers Dakota , Mandl Judith N. , Melichar Heather J 
Published: January 2023

Abstract
CD5, a negative regulator of T cell receptor (TCR) signals, is a cell surface protein whose expression reflects the self-reactivity of the TCR for self-peptide. Recent studies have shown that CD5lo versus CD5hi T cells differentially respond to foreign antigen in primary and recall responses and may also have biased differentiation potential. Within the CD4+ T cell lineage, in particular, evidence points to the preferential recruitment of CD5hi CD4+ cells into the memory compartment and biased regulatory T cell development. However, the extent to which CD5 levels influence T cell differentiation and effector cytokine production is unknown. We have expanded upon these findings to show that ex vivo activated murine CD5lo CD4+ T cells produce relatively greater amounts of the Th1 cytokine IFNγ compared to their CD5hi counterparts. Interestingly, this difference is specific to IFNγ production and is not attributable to differential expression of the Th1 cell-specific transcription factor T-bet. Given the distinct metabolic programs associated with these T cell subsets and recent evidence that glycolysis regulates IFNγ production through an epigenetic mechanism, we propose that CD5 levels shape T cell function by direct or indirect regulation of cellular metabolism. Consistent with this, our preliminary data suggests that modulation of cellular acetate levels can restore IFNγ production in CD5hi cells similar to that of CD5lo cells. Our ongoing studies are focused on epigenetic and metabolic profiling of CD5lo and CD5hi cells in order to better understand the observed lineage bias.
Reciprocal regulation of Th17 and Treg cell differentiation by RhoA
Authors: Kalim Khalid Wasim , Yang Jun-Qi , Li Yuan , Zheng Yi , Guo Fukun 
Published: January 2023

Abstract
Th17 cells are important for protective immunity as well as tissue inflammation and autoimmune disorders. Treg cells, including induced Treg (iTreg) and natural Treg (nTreg), play a critical role in immune tolerance. RhoA of the Rho small GTPase family is an intracellular signal transducer that cycles between an inactive GDP-bound form and an active GTP-bound form. We have previously reported that RhoA plays an important role in Th2 cell differentiation by regulating glycolysis. In this study, we further examined the role of RhoA in Th17 and Treg cell differentiation. Genetic deletion of RhoA in T cells or pharmacologic inhibition of RhoA by a RhoA-specific inhibitor Y16 led to reduced Th17 differentiation in vitro as evidenced by reduction of Th17 effector cytokines, transcriptional downregulation of RORγT and reduced phosphorylation of Stat3. Accordingly, RhoA deficiency ameliorated house dust mites (HDM)-induced allergic airway inflammation and dextran sodium sulphate (DSS)-induced colitis in vivo where Th17 cells plays an important role. Inhibition of ROCK, an immediate downstream effector of RhoA, recapitulated the effect of RhoA deficiency or inhibition on Th17 differentiation, suggesting that RhoA regulates Th17 cell differentiation through ROCK. On the other hand, ablation of RhoA had no effect on iTreg cell differentiation. However, inhibition of ROCK enhanced iTreg differentiation, suggesting that ROCK has RhoA-independent role in iTreg differentiation. In contrast to its in-effect on iTreg differentiation, RhoA deficiency increased nTreg differentiation. Thus, our data have provided new insights into Th17 and Treg differentiation and identified RhoA as a potential therapeutic target for tissue inflammation.
Cooperative activities between STAT3 and Ikaros Zinc Finger transcription factors regulate Bcl-6 expression in CD4+ T helper cells
Authors: Powell Michael Duane , Read Kaitlin A. , Baker Chandra E. , Sreekumar Bharath , Martin R. Emily , Cooley Ian D. , Ringel-Scaia Veronica M. , Allen Irving C. , Oestreich Kenneth J 
Published: January 2023

Abstract
CD4+ T cell subtype specialization depends upon unique lineage-defining transcription factors that direct T helper cell development by both activating cell-specific gene expression programs and repressing alternative T helper cell fates. One such example is the transcriptional repressor Bcl-6, required for the development of T follicular helper (TFH) cell populations. Here, we identify the Ikaros zinc finger (IkZF) transcription factors Ikaros and Aiolos as novel regulators of Bcl-6 expression. We find that increased expression of Bcl-6 in T helper cells is associated with enhanced enrichment of Aiolos and Ikaros at the Bcl6 promoter. Additionally, we demonstrate that signal transducer and activator of transcription 3 (STAT3) physically interacts with Aiolos, suggesting a cooperative role for these factors in the activation of Bcl-6 expression. Mechanistically, the association of Ikaros, Aiolos, and STAT3 with the Bcl6 promoter was accompanied by chromatin remodeling events consistent with gene activation including increased histone acetylation. Importantly, expression of Aiolos and Ikaros was elevated in in vivo generated TFH cell populations compared to other IkZF family members. Collectively, these data describe a novel regulatory mechanism wherein STAT3 and the IkZF transcription factors Ikaros and Aiolos cooperate to regulate Bcl-6 expression. Elucidating the complex network of signals and factors that regulate Bcl-6 expression may enhance the potential to design more efficacious vaccines and develop novel immunotherapeutic approaches due to the wide-ranging importance of this transcriptional regulator.
Analysis of autophagy in activated primary human CD4+T cells under hypoxic conditions
Authors: Haug Markus , Ibrahim Hany , Kumahie Kingsley G. , Flo Trude H. 
Published: January 2023

Abstract
T cell mediated immunity is essential in the response to mycobacterial infection. Type 1 CD4+ T helper cells produce effector cytokines such as IFN-γ that contributes to the maintenance of granuloma integrity and reduction of bacterial load by activating macrophages. Activation of CD4+ T cells induces metabolic remodelling in which autophagy in addition to aerobic glycolysis is utilised to generate the energy required for cytokine production. The regulation of autophagy in activated CD4+ T cells present in the hypoxic environment of granuloma is not well understood.
Studying autophagy is most commonly carried out by western blotting and confocal microscopy. We attempted to quantify autophagy using flow-cytometry due to its ability to simultaneously report several cellular parameters combined with high analysis speed and statistical power. By combining a flow-cytometric assay for the detection of autophagosomes with multi-parameter phenotyping of CD4+ T cell subsets we found that autophagy is strongly induced in IFN-γ producing primary human CD4+T cells and correlates with CD25 expression at 48 and 72 h post activation. In addition, surface activation markers, effector cytokine production and autophagy were found to be altered in activated CD4+ T cells under hypoxic conditions. Our findings suggest that autophagy as well as cytokine-production are regulated in activated CD4+ T helper cells under similar hypoxic conditions as found in granuloma structures.
CD160 plays a protective role during chronic infection by enhancing CD8+ T cell functions through T-bet pathway
Authors: zhang linxia , zhang anli , ye lilin , zhang xiaoyan , fu yangxin , xu jianqing 
Published: January 2023

Abstract
It remains controversial on the role of glycosylphosphatidylinositol-anchored molecule CD160 during chronic infection. Here we revealed that CD160 plays a protective role during Clone 13 chronic infection by enhancing CD8+ T functionalities through T-bet pathway. In Clone 13 chronic infection, CD160 knock out mice were remarkably impaired in the capacity of containing viral infection in plasma, spleen, liver as well as in kidney. Upon LCMV specific peptides recall stimulation, CD160+CD8+ T cells were highly poly-functional and proliferative in LCMV chronic infection model. Co-transfer model demonstrated an intrinsic role of CD160 in regulating T cell functionality by sustaining T-bet expression in activated T cells. These data suggest that CD160 represents a potential target for immune intervention during chronic infection.
Differential role of CD28 and CD27 in human CD4 T cells primary and secondary responses to bacterial antigens.
Authors: Garcia Luis F , Valencia Alexis , García Ana M , Santa Luisa F , Zuluaga Carolina , Rojas Mauricio , Marín Nancy D 
Published: January 2023

Abstract
Although CD28 is considered the main T cell costimulatory molecule, CD27 has also costimulatory activity; nevertheless, it is not well established whether they play overlapping or complementary roles during CD4 T cell activation. Both molecules are co-expressed on a large percentage of CD4 T cells, mainly in naive and central memory T cells; but their ligands, CD80/CD86 and CD70 respectively, are differentially expressed on antigen presenting cells.
To further differentiate the costimulatory role of CD28 and CD27 in the human CD4 T cell responses, circulating T cells from healthy donors were stimulated with Mycobacterium tuberculosis Purified Protein Derivative (PPD) under conditions of selective blockade of CD80 and CD86 or CD70 binding. The costimulatory activities of CD28 and CD27 in CD4 T cells memory responses were compared by stimulating PBMC, from tuberculin positive (TST+) donors, with PPD in the presence of either anti-CD80 plus anti-CD86 or anti-CD70 and then measuring CD4 T cells proliferation, IFN-gamma production and CD30 expression by flow cytometry. Treatment with anti-CD80 plus anti-86 inhibited all CD4+ T cell responses, but anti-CD70 had no effect. To study their role in the CD4+ T cell primary responses, myeloid dendritic cells, from TST negative donors, were pulsed with PPD and cocultured with autologous T cells under the blockade conditions described above. Anti-CD80 plus anti-CD86 as well as anti-CD70 inhibited CD4+ T cell proliferation and CD30 expression. These results support that CD28-CD80/CD86 signals are needed for both primary and memory CD4 T cell responses, whereas CD27-CD70 signals are required mainly for the primary anti-PPD responses. (Supported by Colciencias, Colombia, contract 0275-2014).
BAMBI is a negative regulator of humoral immune responses.
Authors: Augustín Juan Jesús , Alvarez Pilar , Tamayo Esther , Iglesias Marcos , Merino Jesús , Merino Ramón 
Published: January 2023

Abstract
BAMBI (Bone Morphogenetic Protein and Activin Membrane Bound Inhibitor) is a plasma membrane-associated negative regulator of TGFβ signaling. Using mice deficient in BAMBI and anti-BAMBI monoclonal antibodies, we have recently demonstrated the contribution of this TGFβ inhibitor to the regulation of CD4 T-cell differentiation into pathogenic TH17 cells and tolerogenic regulatory T cells. In the present study, we explored the possible involvement of BAMBI in the control of humoral immune responses. We demonstrated that BAMBI-KO mice developed increased antibody responses against T-independent antigens. In addition, these mutant mice also exhibited enhanced antibody responses against several T-dependent antigens administered by different routes and even in the absence of adjuvants. Using adoptive CD4 T-cell transfer experiments and double WT/BAMBI-KO bone marrow chimeric mice we showed that in the mutant mice, B cells exhibited intrinsic defects that improved their interaction with antigen-specific activated CD4 T cells and their subsequent activation and differentiation into germinal center B cells and antibody secreting cells. In fact, B cells from BAMBI-KO mice exhibited enhanced proliferative responses in vitro and expressed higher levels of surface molecules involved in CD4:B cell interactions. Finally, we demonstrated here that the enhanced T-dependent antibody responses observed in BAMBI-KO mice were reverted after long-term treatment with an anti-TGFβ monoclonal antibody. In conclusion, our present study described for the first time a negative role of BAMBI in the control of T-independent and Tdependent antibody responses through the regulation of TGFβ signaling.
Increased Th1 cells and enhanced pulmonary fibrosis in macrophage-specific PPARγ KO mice instilled with multiwall carbon nanotubes and ESAT-6 mycobacterial antigen.
Authors: Barrington Robert A , Malur Anagha , Mohan Arjun , Leffler Nancy , Dobbs Larry , Wingard Christopher J , Barna Barbara P , Thomassen Mary Jane 
Published: January 2023

Abstract
In sarcoidosis, a chronic granulomatous disease of unknown etiology, alveolar macrophages are deficient in the nuclear transcription factor peroxisome proliferator-activated receptor gamma (PPARγ). Pulmonary fibrosis may accompany sarcoidosis and increase morbidity and mortality. We developed a murine model of granulomatous disease elicited by instillation of multiwall carbon nanotubes (MWCNT) and reported increased granulomas in macrophage-specific PPARγ KO mice compared to wild type mice. Because mycobacterial antigens can associate with sarcoidosis, we hypothesized that both T effector cells and pulmonary fibrosis may be exacerbated by PPARγ deficiency and exposure to Mycobacterial Early Secreted Antigenic Target Protein 6 (ESAT-6). Modified Ashcroft scoring of Trichrome staining indicated increased pulmonary fibrosis in mice receiving MWCNT + ESAT-6 compared to MWCNT alone. No changes occurred with PBS or ESAT-6. Analysis of mediastinal lymph nodes revealed increased frequency and number of Th1 cells with corresponding reductions in Th2 cells in PPARγ KO mice after MWCNT, compared to wild-type controls. Notably, the number of Th1, Th2 and Th17 cells were each increased in PPARγ KO after MWCNT + ESAT-6 compared to after administration of MWCNT alone. Our findings suggest that: (1) PPARγ deficiency exacerbates Th1 activation and pulmonary fibrogenic pathways; and (2) the murine MWCNT model may offer novel insights into fibrotic transformation and possible therapeutic options.