bluuebunny/crossref_metadata_2025_split huggingface dataset:
rhl deficient-Pseudomonas aeruginosa induces enhanced host necroptosis through upregulation pqs within quorum sensing
Authors: Liu Zihao , Wen Haitao 
Published: November 2024

Abstract
As the leading cause of nosocomial infections, the relationship between Pseudomoans aeruginosa (P. aeruginosa) and host innate immune responses still arouses the interest in innate immunity research. Quorum sensing (QS), a communication system evolved by P. aeruginosa to mediates its density, is involved in various activities during bacterial infection. Recent study has revealed the link between QS and host innate inflammatory responses, extending the role of QS in interaction with host defense. Although previous evidence suggests PCD exists during anti-P. aeruginosa responses, it remains unclear that what role of quorum sensing plays in connection with PCD during infection. In this study, we exhibited that the deficiency of QS subsystems, rhl, dramatically increased the cell death induced by P. aeruginosa in mouse bone marrow-derived macrophages (BMMs). However, the cell death was completely blocked by using the Casp1/11−/−Casp8−/−Ripk3−/− BMMs, indicating the association between QS and host PANoptosis. Intriguingly, we discovered the rhl deficiency upregulated downstream pqs signaling in P. aeruginosa, which significantly promoted the activation of necroptosis through elevated phosphorylation of MLKL. Deletion of pqsA gene in rhl deficiency strains of P. aeruginosa successfully rescued the necroptosis in BMMs. Taken together, our data highlight the crosstalk between QS and host PCD, ae well as a novel rhl – pqs – necroptosis axis in cell death signaling pathway.
Exploring the Therapeutic Potential of Gracilaria verrucosa-Derived Polysaccharide in Metabolic Syndrome: A Comprehensive Study from Molecular Mechanisms to Microbial Correlations
Authors: Zhang Guiguo , Kim Eunyoung , Cui Jiamei , Ko Kayeon , Kang Minhyeok , Kim Hyo Jin , Yang Jiwon , Lee Yunkyoung , Unno Tatsuya , Jee Youngheun , Jeong Youjin , Li Zemin , Wang Yunpeng 
Published: November 2024

Abstract
Gracilaria verrucosa-derived polysaccharide (GVPS) is recognized for its health benefits, yet a comprehensive exploration of its effects, particularly on the gut-liver-adipose tissue axis in metabolic syndrome, is lacking. In this study, we unraveled GVPS's protective mechanism on intestinal barrier inflammation in an intestine-mimicked co-culture model through RNA-seq analysis. Additionally, we explored its impact on the pathophysiology of a diet-induced obese (DIO) model and characterized GVPS's structure. As a result, GVPS alleviated inflammation and enhanced gut permeability in the inflamed co-culture model through partial regulation of mucin synthesis. In DIO mice, GVPS reduced body weight, adipose tissue weight, blood glucose, triglyceride, and inflammatory cytokine levels, while ameliorating obesity-induced tissue dysfunction and including gut microbiome alterations, suggesting potential modulation of the gut-liver-adipose tissue axis through increased short-chain fatty acid. Further, correlation analyses revealed core microbes (Lactobacillus and Bacteroides) and core genes (Gnb4, Poc1b-galnt4, and Cxcr3) influenced by GVPS. GVPS was revealed to be a long-chain polysaccharide with highly branched and helical domains composed of more than 90% galactose and with a molecular weight of 8.1 × 104 g/mol. Taken together, our findings highlight GVPS as a promising therapeutic agent for metabolic syndrome, unraveling its molecular mechanisms and microbial associations.
Naturally occurring CD4+CD25+ T regulatory cells induced during burn injury exhibit decreased apoptosis.
Authors: Fazal Nadeem 
Published: November 2024

Abstract
The aim of this study was to characterize the molecular pathways of cell signaling of the immune system affected by burns. The adherent PP (Peyers Patches) and MLN (Mesenetric Lymph Nodes) cells were obtained from burn and burn-plus-peritonitis animals and cocultured with CD4+CD25- T cells from sham rat PP and MLN for 24-72 hours. At several time points during coculture, non-adherent T cells were separated and checked for CD25 expression and their apoptosis (Propidium iodide and Annexin V labeling followed by flow cytometry). The T cell apoptotic behavior was evaluated via measurements of mitochondrial morphology (whole cell confocal microscopy using mitochondria-specific stain), mitochondria membrane potential change (dye uptake), and mitochondrial cytochrome C release (Western blot analyses).This might imply that potential inhibitory effects of the Treg cells might be reinforced by a decrease in their apoptotic rate. We evaluated whether an apoptotic rate decrease in the induced Treg results from the actions of burn and burn-plus-peritonitis related antigens. Furthermore, we evaluated if there was difference in the extent of potential anti-apoptotic response in the induced Treg cells in the burn vs. burn-plus-peritonitis injured animals. A greater decrease in Treg cells’ apoptosis in the burn/peritonitis group might be able to contribute to a prolongation of their “suppressive” effect on the CD4+ helper T cells in the combined injury condition.
Skull bone marrow serves as a niche of adaptive immunity for CNS immunosurveillance
Authors: Park Jang Hyun , Kipnis Jonathan 
Published: November 2024

Abstract
The central nervous system (CNS) has been considered as an ‘immune-privileged’ organ owing to limited graft- and cancer-rejection, as well as the absence of lymphocytes and lymphatics. However, recent findings unveiled that the immune system actively discerns the status of the CNS through the glymphatic system and meningeal lymphatics. There is a diverse immune repertoire in the CNS borders presenting antigen, affecting behaviors, and defending CNS tissues. Recent studies discovered the channels in the skull bone marrow (SBM), exchanging immune cells and cerebrospinal fluid (CSF). Consequently, molecular exchange and immune cell activation occur in the CNS border, including SBM, like mucosal tissues. Nevertheless, the mechanism responding to CNS antigens and the maintenance of tolerance is unclear. In this study, we noted greater activation and differentiation of T/ B cells in the SBM than dura mater and other BMs. SBM displayed premature features of lymphoid structures, encompassing Tfh, activated B cells, and antibody-secreting cells. We also observed that Tfh cells directly interacted with B cells and induced differentiation. Moreover, our observations indicated that skull T/B cells respond to CNS antigens, but not microbial/food antigen. Thus, our study suggests that the SBM is a niche for adaptive immune cells in response to CNS antigens. The SBM may sustain heightened inflammatory states to promptly counteract tumorigenesis and pathogen invasion, protecting CNS.
Preclinical studies to determine myelin peptide-specific nanoparticle tolerance mechanisms and clinical translation
Authors: Podojil Joseph , Cogswell Andrew , Chiang Ming-Yi , Xu Dan , Ifergan Igal , Kakade Sandeep , McCarthy Derrick , Elhofy Adam , Miller Stephen 
Published: November 2024

Abstract
Infiltration of autoreactive T cells, subsequent tissue destruction, and the release of additional self-epitopes resulting in epitope spreading underly pathogenesis in many autoimmune diseases. Treatment with Ag-containing biodegradable poly(lactide-co-glycolide) nanoparticles, i.e. tolerogenic immune-modifying particles (TIMP/CNPs), has been shown to be safe and efficacious for the induction of Ag-specific tolerance in murine models of autoimmunity, and in a Phase Ib/IIa clinical trial for celiac disease. The present studies identified novel pathways required for Ag-specific TIMP-induced tolerance, the ability of treatment to modulate spread epitope-specific CD4+ T cell activation, and the functionality of TIMPs containing human myelin-derived peptide epitopes (CNP-102) in a pre-clinical mouse model of multiple sclerosis (MS). Following treatment, myeloid cells phagocytose TIMPs, undergo apoptosis, and Ag-specific tolerance therapy increases both FoxP3+ regulatory T cells and IL-10+ Tr1 cells via a STING/IFNAR-dependent pathway. TIMP treatment also modulates spread epitope-specific T cells associated with disease progression, but not encapsulated within the TIMP, i.e. tissue-specific tolerance. Therefore, treatment activates various Ag-specific regulatory T cell subsets capable of inhibiting disease-associated autoantigens not encapsulated within the TIMP via release of immunoregulatory cytokines, and CNP-102 has proven efficacious in preclinical mouse models of MS.
High-Fat Diet-Induced Gut Microbiota Alterations Worsen Experimental Autoimmune Encephalomyelitis Severity
Authors: Shahi Shailesh , Rux Allison , Ghimire Sudeep , Lehman Peter , Meyerholz David , Mangalam Ashutosh 
Published: November 2024

Abstract
Multiple sclerosis (MS) is a complex neuroinflammatory disease caused by both genetic and environmental factors. Genetically, HLA class II alleles such as HLA-DR2 and –DR3 are strongly linked with MS. Among environmental factors, obesity and gut microbiota has emerged as an important risk factor in MS pathogenesis and severity. This study investigated the impact of High-Fat-Diet (HFD)-induced gut microbiota alterations on experimental autoimmune encephalomyelitis (EAE), utilizing HLA-DR3 (0301) and HLA-DR2(1501).DQ6(0602) transgenic (Tg) mice, crucial for investigating genetic-environment interactions. HFD induces obesity in HLA-DR3, HLA-DR2.DQ6 Tg, and C57BL/6 (B6) mice, exacerbated EAE severity and induced CNS inflammation, and demyelination. Fecal microbiota analysis revealed microbiome dysbiosis with a significant increase in hydrogen sulfide (H2S)-producing bacteria such as Desulfovibrio piger and Bilophila wadsworthia. Mono-colonization of D. piger and B. wadsworthia in gut microbiota-depleted B6 mice mirrored the heightened EAE severity observed in HFD-fed mice. Further, antibiotic depletion study in HFD-fed mice reduced EAE severity and fecal H2S levels, highlighting importance of H2S-producing gut bacteria in obesity-induced EAE modulation. This study identified a disease-promoting role of H2S-producing gut bacteria and underscored the possibility of targeting bacterial H2S as a potential therapeutic intervention to alleviate disease severity in obese MS patients.
IDO2 mediates inflammatory responses through both enzymatic and non-enzymatic mechanisms
Authors: Peng Weidan , Merlo Lauren , Mandik-Nayak Laura 
Published: November 2024

Abstract
The tryptophan catabolizing enzymes indoleamine-2,3-dioxygenase (IDO)1 and IDO2 play important immune modulatory roles in development of inflammation and tolerance. In contrast to the immune regulatory function described for IDO1, IDO2 is a proinflammatory modifier of disease in models of autoimmune arthritis and contact hypersensitivity. Using catalytically inactive IDO2 knock-in mice, we found that the enzymatic function of IDO2 was required to mediate inflammation in contact hypersensitivity but was not required for the development of autoimmunity, suggesting IDO2 acts through both enzymatic and non-enzymatic mechanisms depending on the immune context. Mechanistic studies identified the transcription factor Runx1 as a protein that directly binds to IDO2. The IDO2-Runx1 interaction is blocked by a therapeutic IDO2 monoclonal antibody, implicating Runx1 as a potential downstream mediator of IDO2 function. Runx1 has been shown to directly activate/repress genes involved in B cell activation and differentiation and indirectly affect transcription by inhibition of the NFκB pathway. Preliminary studies using luciferase reporter assays show that IDO2 does not affect Runx1’s direct transcriptional activity, suggesting that the downstream non-enzymatic IDO2 pathway is mediated by Runx1 indirect transcriptional regulation. Taken together, these data demonstrate IDO2 modulates inflammatory immune responses using both its enzymatic function and a non-enzymatic Runx1-mediated pathway.
IRF5 is required for iHPC differentiation and Inhibiting IRF5 activity rescues TLR7-Driven MAS
Authors: Lu Ailing , Thulin Natalie , Huang Amanda , Hamerman Jessica 
Published: November 2024

Abstract
Abstract: Macrophage Activation Syndrome (MAS) is a severe complication in rheumatic diseases, notably systemic juvenile idiopathic arthritis (sJIA), marked by uncontrolled macrophage and T cell activation causing systemic inflammation and multiorgan dysfunction. In a TLR7 overexpressing mouse model (TLR7.1), we observed spontaneous MAS-like disease with thrombocytopenia and anemia, due to a unique population of hemophagocytes called inflammatory hemophagocytes (iHPCs). We demonstrated the critical role of IRF5 signaling in iHPC development using IRF5-deficient mice. However, whether IRF5 is required for iHPC differentiation in TLR7-driven MAS and whether loss or inhibition of IRF5 function in vivo protects from disease onset and/or severity remains unknown.
Methods: We used IRF5-/- mice and IRF5 inhibitor (N5-1) in the TLR7.1 MAS model to examine the requirement of IRF5 for the differentiation and function of iHPCs. IRF5 activation was determined by imaging flow cytometry over the course of disease onset and in response to either preclinical or therapeutic dosing of N5-1.
Results: Results show decreased iHPCs in TLR7.1/IRF5+/- and TLR7.1/IRF5-/- mice. N5-1 inhibits iHPC generation, prevents hemophagocytosis, and rescues TLR7.1 mice from MAS.
Conclusions: These findings underscore the critical role of IRF5 in iHPC development, suggest exploring IRF5 inhibitors in preclinical models and understanding their safety and efficacy could pave the way for treating or preventing MAS.
YTHDF2 promotes tumor immune evasion by inhibiting CD8+ T cell-mediated anti-tumor immunity
Authors: Ma Shoubao , Xiao Sai , Caligiuri Michael , Yu Jianhua 
Published: November 2024

Abstract
YTHDF2 is a well-known m6A reader protein that binds and destabilizes m6A-modified mRNA. We have identified YTHDF2 as a novel regulator of antitumoral polarization in tumor-associated macrophages (TAMs). However, whether YTHDF2 regulates tumor immune evasion remains unknown. Here, we found that loss of YTHDF2 inhibited tumor growth and prolonged survival in syngeneic B16-OVA melanoma and MC38 colon cancer mouse models. Mechanistically, Ythdf2 deficiency-mediated immune remolding was multifactorial, involving promoting the recruitment and polarization of TAMs via chemoattractant CX3CL1, as well as impairing the tumor glycolysis metabolism and enhancing the mitochondrial respiration of tumor-infiltrating CD8+ T cells, thereby enhancing CD8+ T cell effector functions. We screened a small compound that can target YTHDF2 and promote its degradation. YTHDF2 degrader showed a potent anti-tumor effect and better efficacy when combined with anti-PD-L1 antibody therapy. Collectively, YTHDF2 is implicated as a regulator that orchestrates immune evasion and is a promising target to enhance cancer immunotherapy.
Increased DC trafficking and T cell memory in lymphangiogenic melanoma model during immunotherapy response
Authors: Foley Colleen , Potin Lambert , Swartz Melody 
Published: November 2024

Abstract
High vascular endothelial growth factor-C (VEGFC) and lymphatic vessel density in the tumor microenvironment (TME) are associated with lymph node (LN) metastasis, immunosuppression, and poor prognosis in melanoma and other solid tumors. Paradoxically, high VEGF-C also renders immunotherapy more effective in mouse models and correlates with survival after immune checkpoint therapy in patients. Here, we asked how VEGF-C may alter the systemic anti-tumor immune response in melanoma to drive response to immunotherapy, focusing on immune cell trafficking and memory T cell development during immunotherapy response. We used a B16F10 tumor model transduced to either overexpress VEGFC (B16-VEGFC) or a control vector (B16-Control) with a model of immunotherapy using transferred antigen-specific pmel CD8+ T cells activated in vivo by gp100 peptide and CpG adjuvant vaccination.
We found that immunotherapy resulted in increased antigen-specific T cells in the B16-VEGFC vs. B16-Control tumors, and these antigen-specific T cells were more central memory. We also found more bystander activation and proliferation of endogenous CD8 T cells. In the B16-VEGFC tumor-draining LN, we observed increased CD103+ DC trafficking. Overall, VEGFC tumors promote more prolonged immunity after immunotherapy by supporting T cell memory development and enhancing ongoing immune activation and recruitment through increased DC trafficking to the LN and recruitment of newly activated and circulating T cells.
Identifying and Targeting Immunotherapeutic Resistance in Pediatric Brain Cancer
Authors: Sarkar Omar Sadi , Donninger Howard , Farge Justin , Chew Lewis , Huang Michael , Raj Ashok , Yaddanapudi Kavitha 
Published: November 2024

Abstract
Although mortality from childhood cancer is decreasing, a cure remains elusive for certain tumors. Survival rates for patients with high-grade medulloblastoma are dismal. Thus, the need for new therapeutic strategies remains an urgent unmet need. Within the tumor microenvironment (TME), suppressor cells curb the immune system, including myeloid-derived suppressor cells—a heterogeneous population of immature myeloid cells that play a role in cancer progression and metastasis. Two subsets of these cells—granulocytic MDSCs (G-MDSCs) and monocytic MDSCs (M-MDSCs)—promote this immunosuppressive milieu by inhibiting anti-tumor T cell activity. In our study, we identified M-MDSCs as a biomarker for high-grade, metastatic pediatric cancers including medulloblastoma. Our data indicated that medulloblastoma M-MDSCs are induced by high levels of the soluble factors GM-CSF and IL-6 produced by HTB-186 medulloblastoma cells. M-MDSCs from medulloblastomas are highly immunosuppressive and exert their suppressive function by inducing reactive oxygen species (ROS). Our data indicate that GM-CSF from medulloblastoma cells induces ROS production in M-MDSCs via the coordinated activation of p47phox, a critical subunit of the NOX2 NAPDH oxidase, by STAT3 and NF-κB, resulting in inhibition of T cells leading to immune suppression in the TME. These results pave the way to new therapeutic approaches for targeting immunosuppression in pediatric medulloblastoma.
Establishing an immunocompetent mouse model of CAR T anti-tumor efficacy for studies of therapeutic resistance
Authors: Rouya Christopher , Mohrs Katja , McCarthy Craig , Roselli Emiliano , Lin John , Kirshner Jessica , Dilillo David 
Published: November 2024

Abstract
Chimeric antigen receptor (CAR) T cell therapies redirect a patient's T-cells to recognize tumor antigens, and are an effective clinical strategy in the treatment of several hematological malignancies. However, targeting of solid tumors remains challenging, in part due to features of the solid tumor microenvironment that impair the expansion, persistence, and function of CAR T cells. To date, most studies employ xenograft models, thus limiting a mechanistic understanding of CAR T biology in the context of an intact immune system. To model the resistance of solid tumors to CAR T therapy and dissect how endogenous immune populations impact this process, we have generated an immunocompetent mouse model of CAR T therapy. Murine CARs recognizing human CD20 have been engineered with an extracellular scFv domain and intracellular CD3z signaling and 4-1BB costimulatory domains. Using flow cytometry and live-cell imaging assays, we demonstrate potent, antigen-dependent in vitro cytotoxicity and cytokine release by huCD20-targeting CAR T cells against solid (MC38) or heme (EL4) tumor cells engineered to express cell-surface huCD20. Moreover, huCD20 CAR T cells exhibit in vivo efficacy against both EL4-huCD20 and MC38-huCD20 tumor models, while CAR T that recognize an irrelevant antigen do not affect tumor growth. These results highlight a platform to explore resistance mechanisms and potential immune cell interactions that may impair CAR T therapy directed against solid tumors.
Identifying cancer-specific T cells for TCR T-cell immunotherapy through engineered proteins
Authors: Zhang Rongyu , Ng Rachel , McKasson Michaela , Chour William , Webster Andrew , Choi Jongchan , Xie Jingyi , Trimble Cornelia , Ribas Antoni , Heath James 
Published: November 2024

Abstract
The identification of cancer-specific T cell receptor (TCR) sequences is crucial for advancing cancer immunotherapies. Recent studies and clinical trials have revealed a vulnerability in monoclonal T cell therapy, where cancer cells can evade the immune response through the loss of HLA heterozygosity and low antigen heterogeneity. To address this challenge, cocktail T cell therapy using TCRs that target multiple HLAs and antigens has been proposed to enhance the efficacy of adoptive T cell transfer therapy.
In pursuit of this goal, we have developed peptide-bound major histocompatibility complex (pMHC) proteins in the form of single-chain-trimers (SCTs). This innovative platform allows for the rapid and high-throughput identification and isolation of cancer-targeting CD4+ and CD8+ T cells targeting a wide array of HLAs and cancer antigens. The identified antigen-specific TCRs are subsequently sequenced, validated for functionality, and assessed for potential therapeutic applications.
We applied this technology to PBMCs extracted from patients with HPV-16-related precancerous conditions in a clinical trial. We successfully identified cancer-specific TCRs, which are currently undergoing pre-clinical validations for their safety and efficacy in CRISPR-mediated TCR T cell therapy.
In summary, the application of the SCT technology holds significant value for fundamental immune-oncology studies and contributes to the advancement of immunotherapy for cancer.
Sirt2 inhibitors protect chronic inflammatory disease by improving gut epithelial barrier integrity
Authors: Hou Dan 
Published: November 2024

Abstract
Inflammatory Bowel Disease (IBD), as a chronic inflammatory disease, triggers a global health threat with poorly understood mechanisms driving its progression. Unraveling these mechanisms and identifying new therapeutic targets are crucial for improved treatments. Prior studies revealed conflicting roles of Sirtuin 2 (Sirt2) in IBD: genetic knockout of Sirt2 exacerbates IBD, while pharmacological inhibition diminishes its severity. This contradiction hinders Sirt2 inhibitor development for IBD treatment. Our investigation using distinct Sirt2 inhibitors (TM and AGK2), a PROTAC Sirt2 degrader, and genetic knockout mice addressed this puzzle. Both TM and AGK2 showed protective effects in an IBD model induced by DSS, excluding off-target effects. Mechanistically, these inhibitors suppressed ARF6-mediated E-cadherin endocytosis, fortifying intestinal epithelial integrity and the gut barrier, protecting against IBD. Interestingly, the PROTAC Sirt2 degrader, similar to Sirt2 genetic knockout, didn’t offer protection in IBD. This discrepancy suggests that Sirt2 small molecular inhibitors only partially but not all hinder Sirt2's activities, stressing the need for substrate-dependent inhibitors in IBD treatment. Overall, our study provided an interesting example that genetic knockout and pharmacological inhibition were not consistent, and this mechanistic understanding further support Sirt2 as a promising target for treating IBD.