bluuebunny/crossref_metadata_2025_split huggingface dataset:
IL-10 promotes mast cell homeostasis and differentiation towards a mucosal mast cell phenotype
Authors: Ranjitkar Saurav , Maldonado Perez Nicole , Tedeschi Caitlin , Jordan Nathan , Mathias Clinton 
Published: November 2024

Abstract
We recently demonstrated an unexpected role for IL-10 in driving mast cell (MC) activation and proliferation. IL-10 stimulation significantly enhanced IgE-mediated MC activation, upregulated FceRI expression, and promoted MC-mediated food allergy. Surprisingly, IL-10 also amplified cytokine production in un-activated MCs and enhanced their proliferation and survival, suggesting a role for IL-10 in MC homeostasis. Herein, we demonstrate that IL-10 can significantly expand MC proliferation and activity during homeostatic conditions. Treatment with IL-10 enhanced the proliferation and survival of both IL-3 and IL-3+SCF cultured bone marrow-derived MCs (BMMCs). This corresponded with a dramatic increase in cytokine production in IL-10-treated cells, along with upregulation of FceRI expression. While SCF was dispensable for the increased FceRI, it significantly enhanced cytokine production compared to cells cultured in IL-3 alone. Further analysis revealed a distinctive mucosal MC phenotype in IL-10-treated cells, characterized by beta7-integrin expression and enhanced secretion of murine MC protease-1. Lastly, autocrine IL-10 also supported MC expansion and function, as blocking IL-10 signaling attenuated MC expansion, inducing apoptosis, and decreasing cytokine production. Taken together, these data suggest an important role for IL-10 in maintaining MC responses during physiological conditions.
Profiling autoreactive IgG, IgM, IgA and IgE antibodies in system lupus erythematosus patients using antigen microarrays
Authors: Li Quanzhen , Wei Junxia , Zhu Chengsong , Luo Hui 
Published: November 2024

Abstract
OmicsArray™ antigen microarrays bearing 120 antigens were used for profiling IgG, IgM, IgA and IgE autoantibodies in 240 well defined SLE patients and matched healthy controls (HCs). Our analysis show that the average number of positive IgG autoantibodies in SLE is 28.5 with over 95% of SLE patients harbor 5 or more autoantibodies, comparing with 3 positive IgG Autoantibodies in HCs with 25% have 5 or more autoantibodies (p&lt;0.05). A group of 19 IgG autoantibodies targeting to various nuclear antigens (dsDNA, chromatin, histone, Sm/RNP, PCNA, CENP-B, etc.) were significantly enriched in SLE by clustering analysis. The presence of IgG autoantibodies against DNA-associated antigens were most significantly associated with disease activity (SLEDAI) and lupus nephritis (r=0.56, p&lt;0.001) in SLE. The IgG autoantibodies which are positive in HCs were mostly those targeting non-nuclear antigens, such as collagens, alpha-actinin, heparin and cardiolipin. However, some ANA positive HCs exhibited higher IgM specificities targeting to both non-nuclear and nuclear antigens whereas in SLE the IgM autoAb reaction were relatively lower. IgA autoantibodies were detected in over 50% of SLE patients, preferentially targeting to DNA- and RNA-associated antigens indicating the high prevalence of IgA autoantibodies may play a role in SLE. IgE autoantibodies were not detectable for most autoantigens except about 15% of SLE patients showed positive IgE autoantibodies to a small subset of DNA antigens.
Klebsiella michiganasis as a tissue repairing commensal in gut inflammation
Authors: White Zachary , Sano Teruyuki , Kapustka Isabel 
Published: November 2024

Abstract
Commensal bacteria are recognized as contributors for both tissue inflammation and tissue homeostasis. Therefore, we tested their potential for gut inflammation and tissue repairing using Germ-Free (GF) mice using stools from healthy human donors. Although, DSS-treated WT GF mice all die within 10 days due to severe colonic epithelial damage, gnotobiotic WT mice colonized with a healthy microbiome survived and carried more IL-22 producing innate and adaptive immune cells. This suggests that healthy stools contain wound healing commensals, however, IL10 KO mice with the same stools developed colitis, indicating a colitogenic potential. To eliminate colitogenic from wound healing commensals we utilized various antibiotics in human stool inoculated mice. These treated mice showed significant reductions in their microbiomes. Importantly, IFNg/IL-17A double producing pathogenic CD4 T cells were decreased leading to no colitis in gavaged IL10 KO mice. Additionally, gnotobiotic WT mice colonized with cecum contents from treated human stool gavaged IL10 KO survived lethal DSS treatment. We isolated Klebsiella michiganasis (K. michiganasis) from their cecum and confirmed that monocolonization of K. michiganasis in GF WT mice reproduced the wound healing ability via both the IL-23 and IL1b pathways stimulating type 3 innate lymphoid cells to strongly produce IL-22. Our results suggest that non-pathogenic K. michiganasis is a promising commensal for combating gut inflammation.
Mast cell-intrinsic TGF-b signaling modulates mast cell effector function and allergic responses
Authors: Haque Tamara , Leak Lashawna , Youngblood Emily , Laky Karen , Frischmeyer-Guerrerio Pamela 
Published: November 2024

Abstract
Mast cell (MC) activation via the high affinity IgE receptor, FcεRI, causes the release of mediators that are directly involved in the allergy diathesis. TGFβ has been shown to regulate MC development and function in vitro however it’s role in allergic diseases is unclear. Patients with Loeys Dietz Syndrome (LDS), a disorder caused by loss-of-function variants in genes encoding the TGFβ receptors are highly predisposed to develop atopy, thus provide an opportunity to study the role of MC TGFβ signaling in allergic diseases. Unexpectedly, IgE mediated degranulation of LDS MC were reduced compared to healthy controls in vitro. We examined active and passive IgE responses in a mouse model of LDS and mice with conditional deletion of Tgfbr1 in MCs. Both models exhibited less IgE mediated anaphylaxis and degranulation. This could not be attributed to alterations in IgE or stem cell factor receptor expression on MCs, or to the distribution of MCs in tissues. In contrast, LDS MCs exhibited enhanced responses to the type 2 alarmin, IL-33, in vitro and in vivo. Mechanistically, altered responses to IgE, IL-33, and TGFβ were linked, as the reduction of anaphylaxis in LDS mice was partially restored in IL-33RKO LDS mice. Moreover, this was tied to both transcriptional and proximal signaling mechanisms. Taken together, TGFβ signaling upregulates MC function by disrupting an IL-33/ST2 mediated regulatory pathway, which likely plays a major role in controlling IgE mediated MC functions.
Borrelia Burgdorferi mediated mitochondrial DNA release into the cytosol induces host inflammatory response via the activation of cGAS-STING signaling pathway
Authors: Priya Raj , Raghunandanan Sajith , YANG FRANK 
Published: November 2024

Abstract
Background: Mitochondrial DNA (mtDNA) is a potent ligand of inflammation when it leaks from stressed mt into the host cytosol during bacterial infections. In this study, we uncover mtDNA as one of the ligands involved in inflammatory response against B. burgdorferi (Bb) infection via the activation of cGAS-STING signaling pathway in Raw264.7 cells. Methods: Raw264.7 cells were infected with Bb & the mt stress was studied by measuring mt reactive oxygen species (mtROS) using MitoSOX dye & mt membrane potential (MMP) by JC-1 dye staining. The release of mtDNA was assessed by Immunofluorescence assay & q-RT-PCR. The co-localization of mtDNA & cGAS was determined by IP assay. To explore the requirement of mtDNA for Bb-induced inflammation, both WT & cGAS-KO cells were treated with Ethidium bromide (EtBr) to deplete the mtDNA & ELISA was done to detect the level of inflammatory cytokines. Results:Bb infection to Raw264.7 cells caused mt stress, that results in decrease of MMP, enhanced mtROS & promoted mtDNA leakage into the cytosol. Leaked mtDNA activates cGAS-STING signaling pathway & results in inflammation. Both stable knockdown of cGAS & depletion of mtDNA reduced Bb induced inflammation. Conclusions: We uncover a novel mechanism of Bb induced inflammation, which involved mtDNA leakage from stressed mt into the cytosol stimulating the cGAS-STING signaling pathway. The mtDNA-cGAS-STING pathway could be a therapeutic target to prevent Bb induced inflammatory disease.
Suppression of the Immune System in Borrelia burgdorferi Infection Shilpa Sachan, Heather Kulaga, and Nicole Baumgarth
Authors: Sachan Shilpa 
Published: November 2024

Abstract
Lyme Disease, caused by tick-transmitted infection with Borrelia burgdorferi (Bb), is an emerging vector-borne disease. Bb establishes persistence in their natural reservoir hosts and in laboratory mice. Our previous work established Bb-infection induced immune suppression, manifested in lymph tissue remodelling, rapid collapse of germinal centres, and inability to generate B cell memory. The objective of this study was to further explore the T-dependent humoral responses to Bb infection and to identify mechanisms of immune dysregulation. For this, we infected or sham-infected C57BL/6 mice with Bb, bled mice over time and measured total and influenza-specific serum IgG serum antibody levels following subsequent immunization with influenza A/PR8 virus in alum. Serum analysis revealed strong and continued hypergammaglobulinemia, contrasting the significantly reduced influenza-specific serum IgG responses in Bb-infected mice compared to sham-infected controls. Reductions in influenza-IgG levels was explained by reduced bone marrow IgG ELISPOT and were seen only when mice were infected with Bb. Flow cytometric analysis of CD4 T cells revealed the presence of CD4 Tfh cells, as well as effector CD4 T cells that showed an exhausted phenotype, even at early timepoints after in Bb infection. Together, our data reveal a profound defect in effective T and B cell responses to Bb, explaining the inability of the immune system to clear this infection.
Label-free imaging of microbial-infected cells and tissues using 2p-FLIM and MALDI-MSI identify altered NADH metabolism.
Authors: Snyder Greg , Omomo Ayotunde , White Erica , Snyder Michelle , Yang Hyojik , Scott Alison , Ray Krishanu 
Published: November 2024

Abstract
We have developed label-free imaging methods to identify and characterize microbial infection of live cells and tissues using a novel application of Fluorescence lifetime (FLT) imaging with 2-photon excitation (2p-FLIM) coupled with matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI). 2p-FLIM is often used in cancer biology to image metabolically altered cells of affected tissues and tumors. Whereas MALDI-MSI is one of the growing number of spatial ‘omic methods, that is also label-free and allows mapping of individual metabolites at cellular and tissue scales. We have previously reported the application of 2p-FLIM to characterize HIV-1-infected cells and tissues. We now report the novel application and integration of 2p-FLIM with MALDI-MSI for characterizing pathogenic bacteria patient isolates and infected tissue. We observe increases in NAD(P)H intensity and unique distributions of fluorescence lifetimes (FLTs) for select pathogenic bacteria patient isolates, which may reflect differences in OxPhos metabolism. We have further characterized Pseudomonas-infected mouse lung tissues which exhibit unique NAD(P)H fluorescence, average FLTs and spatial mapping of individual NAD+-associated metabolites. A highly integrative, cross-platform, label-free, multi-omics approach involving 2p-FLIM and MALDI-MSI may provide a better understanding of microbial infection for developing and assessing novel antimicrobial and immune-modulatory interventions.
Generation of a lethal mouse model expressing human ACE2 and TMPRSS2 for SARS-CoV-2 infection and pathogenesis
Authors: Choi Ji Hyun , Jeong Gi Uk , Hwang Insu , Lee Wooseong , Yoon Gun Young , Kim Hae Soo , Yang Jeong-Sun , Kim Kyung-Chang , Lee Joo-Yeon , Kim Seong-Jun , Kwon Young-Chan , Kim Kyun-Do 
Published: November 2024

Abstract
Mouse models expressing human ACE2 for coronavirus disease 2019 have been frequently used to understand its pathogenesis and develop therapeutic strategies against SARS-CoV-2. Given that human TMPRSS2 supports viral entry, replication, and pathogenesis, we established a double-transgenic mouse model expressing both human ACE2 and TMPRSS2 for SARS-CoV-2 infection. Co-overexpression of both genes increased viral infectivity in vitro and in vivo. Notably, double-transgenic mice showed significant body weight loss, clinical disease symptoms, acute lung injury, lung inflammation, and lethality in response to viral infection, indicating that they were highly susceptible to SARS-CoV-2. Pretreatment with the TMPRSS2 inhibitor, nafamostat, effectively reduced virus-induced weight loss, viral replication, and mortality in the double-transgenic mice. Moreover, the susceptibility and differential pathogenesis of SARS-CoV-2 variants were demonstrated in this animal model. Together, our results demonstrate that double-transgenic mice could provide a highly susceptible mouse model for viral infection to understand SARS-CoV-2 pathogenesis and evaluate antiviral therapeutics against coronavirus disease 2019.
SARS-Cov-2 antigen exposure history shapes post-infection antibody epitope and immune pressure distribution
Authors: Yisimayi Ayijiang , Jian Fanchong , Wang Jing , Song Weiliang , Cao Yunlong 
Published: November 2024

Abstract
The COVID-19 pandemic has led to a complex immunological landscape shaped by various vaccination regimens and SARS-CoV-2 variant infections. The effect of diverse exposure history on antibody response and virus evolution is a critical, unsolved issue.
Using high-throughput single-cell V(D)J sequencing, high-throughput deep mutational scanning, and neutralization assays, we characterized epitope distributions and immune pressure of more than 6000 Receptor Binding Domain (RBD)-antibodies from various SARS-CoV-2 exposure histories, including ancestral strain vaccinated or unvaccinated individuals with single or dual infections with different variants.
We found that single variant breakthrough infections post-vaccination induce a high proportion of non-neutralizing antibodies due to immune imprinting. In contrast, dual breakthrough infections exhibit fewer non-neutralizing antibodies, akin to those in unvaccinated individuals. Furthermore, the initial infection variant influences the antibody repertoire to second infections, indicating that variant infections also induce immune imprinting. Antibody profiles shaped by diverse exposure histories exert distinct pressures on RBD, promoting the virus to evolve at convergent immune pressure sites. This is evidenced by frequent RBD mutations at positions 420, 455, 456, and 475 across different variants.
These findings highlight the potential of diversifying the antibody pressure across populations to reduce the pace of viral evolution.
Generation of a novel agonist of the human CD137 costimulatory pathway for cancer immunotherapy
Authors: Jackson Christa , Nur Arguc Feyza , Ulker Vahap , Powell Noah , Yolcu Esma , Shirwan Haval 
Published: November 2024

Abstract
The use of immune checkpoint stimulators is an increasingly attractive therapeutic approach against cancer, and costimulatory pathway agonists are being developed for clinical use. Our laboratory has focused on the 4-1BB (CD137) pathway because of its critical role in CD8+ T cell expansion, survival, acquisition of effector function, and establishment of long-term memory. We previously reported the generation of a recombinant oligomeric form of the mouse ligand, muSA-4-1BBL, which, unlike the natural 4-1BB ligand, demonstrated robust costimulatory activity in soluble form. muSA-4-1BBL showed therapeutic efficacy as the immune adjuvant component of subunit vaccines in various mouse transplantable tumor models. In this study, we generated a human version of this ligand, huSA-4-1BBL, and characterized its structure and function. The molecule binds to 4-1BB on LPS-activated human THP-1 monocytes, but not ConA-stimulated mouse T cells expressing the 4-1BB receptor. Conversely, muSA-4-1BBL binds to ConA-stimulated mouse T cells, but not LPS-activated human THP-1 cells, demonstrating species-specific binding for both molecules. To assess the cancer immunotherapeutic efficacy of huSA-4-1BBL, we generated a transgenic mouse model where mouse 4-1BB was replaced with the human ortholog. The assessment of huSA-4-1BBL anti-tumor efficacy in this model will serve as a prelude for further development and translation of this novel agonist to the clinic for cancer immunotherapy.
Characterizing functions of endogenous bile acid pools altered by Asbt-deficiency in the ileal transcriptional regulation.
Authors: Sudo Koichi , Dionne Henry , Sundrud Mark 
Published: November 2024

Abstract
Bile acids (BAs) are a diverse and abundant class of metabolites synthesized in the liver, absorbed in the ileum, and metabolized by the colonic microbiota. Besides the classical functions of BAs for lipid and vitamin absorptions in the small intestine (SI), BAs have emerged as potent immunoregulatory metabolites via interactions with G protein-coupled and nuclear receptors (NRs; e.g., FXR/NR1H4). Alterations of BA metabolism have been reported in human diseases, e.g., inflammatory bowel diseases. However, it remains unclear whether or how altered BA pools may influence the intestinal homeostasis and pathology. As in vivo studies cannot uncouple the regulatory functions of BAs from their impact on microbiota, I have developed a novel intestinal explant culture system, in which the ileal fragments can be treated with the endogenous BA pools from normal or diseased mice. The ileal, not colonic, fragments induced mRNA expressions of BA-targeted genes in the presence of (t)CDCA which is a representative and FXR-agonistic BA. Then, the fragments were cultured with the endogenous SI BA pools from healthy or Asbt-/- mice – which have altered BA pools. RNA-seq showed that some genes were similarly induced, but others were differentially regulated by each BA pools. In NR reporter assays, the BA pools from Asbt-/- mice potently activated RXRa, PXR, and ERb. Together, this study suggests abnormal BA pools differentially modulate the ileal environment via distinct NR pathways.
Antioxidant and anti-Inflammatory effects of maltol on inflammasome activation in macrophages and mice
Authors: Ahn Huijeong , Lee Geun-Shik 
Published: November 2024

Abstract
Maltol (3-hydroxy-2-methyl-4-pyrone) is used widely as a food and cosmetic supplement, and it has antioxidant and anti-inflammatory activities. Inflammasome causes the maturation and secretion of interleukin (IL)-1β and -18 through activation of caspase-1 (Casp1), which contributes to various inflammatory diseases. This study examined the effects of maltol on inflammasome activation in macrophages and mice. Lipopolysaccharide (LPS)-primed macrophages were treated with a trigger of NLRP3, NLRC4, AIM2, or non-canonical (NC) inflammasomes in the presence of maltol. The secretion of IL-1β and IL-18, and cleavage of Casp1 were analyzed as indices of inflammasome activation. Mice were injected with LPS and an NLRP3 trigger with or without maltol, and the peritoneal IL-1β secretions were observed. The effects of maltol on reactive oxygen species (ROS) production and Casp1 activity were analyzed to determine the mechanism. Maltol inhibited the activation of NLRP3 and NC inflammasomes, but it did not alter the other inflammasomes. Maltol also attenuated IL-1β secretion resulting from the inflammasome activation in mice. The anti-inflammatory mechanism of maltol was revealed by the inhibition of ROS production and Casp1 activity. Maltol is suggested as a candidate of anti-inflammasome molecules.
Tpl2-/- macrophages exhibit impaired mitochondrial respiration due to type I interferon signaling in response to LPS stimulation.
Authors: Fahey Denise , Heo Junwon , Call Jarrod , Watford Wendy 
Published: November 2024

Abstract
Macrophages are essential to the innate immune system and their dysfunction has been implicated in many diseases, including autoimmunity, obesity, and cancer. Activated macrophages can alter their oxidative phosphorylation, metabolite production, and reactive oxygen species generation to elicit their diverse functions. Tumor progression locus 2 (Tpl2, MAP3K8, or COT) is a serine-threonine kinase involved in macrophage activation and function. In TLR-stimulated macrophages, TPL2 ablation induces high type I interferon (IFN) production. Previous research implicates type I IFNs in metabolic regulation, but their exact mechanism remains unclear. We hypothesize that TPL2 promotes oxidative phosphorylation in LPS-stimulated macrophages by suppressing type I IFN signaling. LPS-stimulated Tpl2-/- bone marrow-derived macrophages had decreased oxygen consumption, ATP production, and maximal respiration compared to LPS-stimulated wild type and Tpl2-/-IFNAR-/- macrophages. LPS-stimulated Tpl2-/- macrophages had reduced antioxidant gene expression compared to wild type macrophages, including SOD2, HMOX-1, and PRDX5. Disrupted IFN signaling in IFNAR-/- and Tpl2-/-IFNAR-/- macrophages significantly increased antioxidant gene expression, suggesting the absence of IFN signaling mitigates macrophage oxidative stress. These data indicate that Tpl2-/- macrophages are metabolically defective and type I IFNs contribute to the underlying dysfunction.
Ku70 senses cytosolic DNA and assembles a tumor-suppressive signalosome
Authors: Pandey Abhimanu , Shen Cheng , Man Si Ming , Ngo Chinh 
Published: November 2024

Abstract
Pattern-recognition receptors are critical in the host defence against infectious diseases and cancer. DNA is the genetic code of life but also represents a form of microbial or damage-associated signal which can induce an immune response. Central to immune surveillance are the cytoplasmic DNA sensors that respond to microbial or endogenous DNA liberated from microbes or damaged and/or dying host cells. Here, we show that mice and humans lacking a single allele of the DNA repair protein Ku70 had increased susceptibility to the development of intestinal cancer. The effect of Ku70 on attenuating intestinal cancer was independent of the role of Ku70 in DNA repair, and the production of inflammatory markers and interferons. Instead, Ku70 translocates from the nucleus into the cytoplasm where it binds to cytosolic DNA and interacts with the GTPase Ras and the kinase Raf, forming a tripartite protein complex that docks at Rab5+Rab7+ early- late endosomes. We identified that the ⍺/β domain and the C-terminal domain of Ku70 interact with the GTPase domain of Ras, whereas the C-terminal domain of Ku70 interacts with the conserved region 2 of Raf. The Ku70-Ras-Raf signalosome activates the MEK-ERK signalling pathway, leading to impaired activation of cell cycle proteins, Chk2, Cdc25A and CDK1, reducing cell proliferation and tumorigenesis. These findings suggest that therapeutics targeting components of the Ku70 signalosome could improve the treatment outcomes in cancer.