bluuebunny/crossref_metadata_2025_split huggingface dataset:
Type II interferon signaling plays a critical role in inducing T helper type 1 immune responses and adaptive immunity after influenza vaccination
Authors: Kim Ki-Hye , Lee Young-Tae , Hwang Hye suk , Ko Eun-Ju , Lee Youri , Jung Yu-Jin , Kang Sang-Moo 
Published: January 2023

Abstract
The roles of interferons (IFN) remain poorly understood in generating long-term protective immune responses to vaccination despite their well-known anti-viral innate immunity. We investigated the roles of IFN receptor (IFNR) signaling in inducing adaptive immune responses and protective immunity to influenza virus-like particle (VLP) vaccination by using A129 and AG129 mouse models. AG129 mice showed a significant defect in raising IgG2a Th1 antibody responses despite of the induction of comparable IgG1 Th2 type and hemagglutination inhibiting antibodies compared to those in A129 mice. After lethal challenge infection, the AG129 vaccinated mice were not protected as evidenced by 20% severe weight loss, high airway hyperresponsiveness, histopathology, excessive infiltration of neutrophils, inflammatory chemokine and cytokines, and 80 folds higher lung viral titers compared to the A129 vaccinated mice that were 100% protected without displaying weight loss. AG129 mice were not able to induce rapid recall of plasma cells, germinal center B cells, and IFN-r+ CD4 and CD8 T cells. Depletion of T cells in A129 mice after vaccination resulted in lower efficacy of protection. The role of type I IFNR were determined in AB6 mice by comparing with B6 mice after vaccination. The AB6 mice did not show significant defects in developing IgG1 and IgG2c antibodies and in conferring protection after vaccination and challenge, despite of inability to recruit monocytes, compared to those in B6 mice. These results suggest that type II IFNR signaling plays a more critical role in developing adaptive immunity after vaccination than type I IFNR signaling, and that both type I and II IFNR signaling is required for effective control of influenza virus infection.
IL-1 cytokines promote ADAMTS-mediated remodeling of the lung extracellular matrix during severe influenza A infection in mice
Authors: Boyd David F. , Guo Xizhi , Thomas Paul G. 
Published: January 2023

Abstract
The lung extracellular matrix (ECM) is extensively remodeled following respiratory viral infection. This remodeling occurs during inflammation when immune cells migrate to the site of infection and during repair as the ECM is modified to regenerate damaged tissue. Matrix proteases, including the A Disintegrin and Metalloproteinase with Thrombospondin motifs (ADAMTS) gene family, play a critical role in these remodeling processes. The immune mechanisms that regulate matrix protease activity and their effect on host responses to lung infection have not been well characterized. Previously, we found that ADAMTS-4 knockout mice exhibited improved survival following lethal influenza A (IAV) challenge and signs of reduced immunopathology, including fewer numbers of inflammatory T cells. Here, by flow cytometric sorting of immune and stromal cell populations, we identified fibroblasts as the main producers of ADAMTS-4 in the lung during severe IAV infection, with ~50-fold higher levels of mRNA compared to other lung cell populations. Stimulation of primary lung fibroblasts in vitro with a wide range of inflammatory cytokines demonstrated that only IL-1β and IL-1α induced expression of ADAMTS-4. Co-stimulation of lung fibroblasts with IL-1 cytokines and TNF-α resulted in a synergistic effect and an increase of ADAMTS-4 expression to greater than 6-fold above baseline levels. IL-1 treatment of lung fibroblasts also induced expression of the lung ECM proteoglycan versican (VCAN), a major enzymatic target of ADAMTS-4. These results suggest a role for IL-1 cytokines in regulating lung ECM remodeling, and highlight the potential of modulating the IL-1/ADAMTS-4 pathway to reduce immunopathology following severe respiratory infection.
Metformin alleviates liver injury through mTOR-mediated T cell regulation in viral hepatitis in mice
Authors: Sun Jiaren , Liang Yuejin , Xu Lanman 
Published: January 2023

Abstract
Metformin is not only the first-line medication for the treatment of type 2 diabetes, but also has other effects, such as anti-inflammatory, anti-oxidative, and anti-tumor activities, in animal models. However, the therapeutic potential of metformin during viral hepatitis is uncertain. In this study, C57BL/6 mice were treated with oral administration of metformin (250 mg/kg) for 7 days daily, infected with different doses of adenovirus (i.v. inoculation), and then received metformin for another 7 days. All mice were sacrificed at 7 days post-infection. We found that metformin treatment ameliorated the liver injury induced by different doses of adenovirus infection, as judged by the significant decrease in liver alanine transferase levels, liver histopathology scores, as well as intrahepatic lymphocyte (IHL) and splenocyte counts. Compared to the PBS-treated groups, metformin-treated mice had significantly decreased numbers of activated T cells in the liver, as well as expression of IL-2, IFN-γ, and TNF-α in CD4+ and CD8+ T cells, especially among CD8+ T cells. Metformin treatment also significantly reduced phosphorylated S6 kinase beta 1 (S6K1)-positive CD4+ and CD8+ T cells in the liver, indicative of decreased mTORC1 activity in these cells. These data indicate that metformin can alleviate adenovirus-induced acute liver injury in mice, and that the beneficial effects of metformin may be mediated in part through mTORC1 pathway in T lymphocytes.
Bacterial amyloids from biofilms induce type I interferon response in plasmacytoid dendritic cells
Authors: Qiu Connie Claire , Gallucci Stefania 
Published: January 2023

Abstract
An increased expression of type I interferon (IFN) regulated genes is a hallmark of systemic lupus erythematosus, a complex autoimmune inflammatory disease. Although the exact etiology of lupus is unknown, infections can be an important environmental trigger for flares, and are a major cause of morbidity and mortality. Medically, bacterial biofilms are important for the establishment of chronic, persistent infections. Bacteria within these aggregates are embedded into their biofilms, allowing them to dramatically increase their ability to withstand physical insults and tolerate host defenses. To strengthen the extracellular matrix of their biofilms, bacteria produce amyloids, complex proteins with a conserved beta sheet structure. We have reported that Salmonella and E. coli biofilms contain the functional amyloid protein curli, which complexes with eukaryotic and bacterial DNA. Systemic administration of curli-DNA complexes accelerated autoimmunity in lupus-prone mice. Infections with curli-expressing Salmonella or E. coli gave the same results, implicating curli as a pathogenic factor in how biofilm-producing infections may contribute to lupus pathogenesis. We present here for the first time that bacterial amyloid curli activates plasmacytoid dendritic cells (pDCs), the primary producer of type I IFNs, in vitro. Additionally, we show that curli induces a robust production of IFNα and expression of interferon-stimulated genes, including CXCL10. Furthermore, curli induces in vivo activation of DCs in lupus-prone and wild-type mice. Our results identify bacterial amyloid curli as a novel activator of pDCs, and suggest that curli may accelerate lupus by directly activating pDCs and their powerful type I IFN activity.
A protective MHC class II molecule prevents autoimmune diabetes by selecting for specific intestinal microbes early in ontogeny
Authors: Silverman michael A. , Denu Lidiya , Lubin Jean-Bernard 
Published: January 2023

Abstract
Type 1 diabetes (T1D) affects millions of people worldwide. The incidence has risen significantly over the past few decades. Both genetic and environmental factors contribute to T1D. Certain HLA haplotypes such as DRB1*1501-DQB1*0602 dominantly protect against T1D yet the mechanism of this remarkably protection remains unknown. We recently demonstrated that the protective major histocompatibility complex (MHC) E molecule prevents autoimmune diabetes in NOD mice by shaping the intestinal microbiome early in ontogeny. This finding presents a novel paradigm in which genetic protection from immune system dysregulation is mediated via commensal microbiota. An important gap in knowledge is which intestinal microbes prevent autoimmunity by modulating the immune system. We hypothesize that those microbes that differentially stimulate humoral immune responses in the previously reported MHCII E-expressing NOD (Eα16/NOD) mice may also modulate the immune system to prevent autoimmunity. We address this question by leveraging the exquisite sensitivity and specificity of the humoral immune system to identify a subset of microbes via flow cytometry that stimulate mucosal and/or systemic immune responses to prevent autoimmunity.
Bacterial amyloids from biofilms break tolerance in lupus by simultaneous BCR/TLR signaling
Authors: Lee Michael Hweemoon , Tursi Sarah A. , Nicastro Lauren K. , Caricchio Roberto , Tükel Çagla , Gallucci Stefania 
Published: January 2023

Abstract
Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease, in which infections are considered to play a pathogenic role, but the cellular and molecular culprits remain unknown. Bacterial biofilms are multicellular bacterial communities important in the establishment of chronic infection by pathogens. We have previously shown that curli fibers, functional bacterial amyloids present in Salmonella and E. coli biofilms, can complex with DNA. Systemic administration of these curli/DNA complexes accelerated autoimmunity in lupus-prone mice and induced autoantibody production in wild-type mice, suggesting curli/DNA complexes as novel players in SLE pathogenesis. This affect was diminished in TLR2 or TLR9 deficient mice. We present here evidence that curli/DNA complexes polyclonally activate B cells in vivo in wildtype mice, lupus-prone mice and 3H9 mice, the latter expressing an anti-DNA Ig heavy chain and whose B cells are normally tolerized. Interestingly, curli/DNA complexes can activate B cells in the absence of T cell help. Indeed, curli/DNA complexes induce polyclonal proliferation and activation in B cells purified from wild-type and lupus prone mice in vitro. Interestingly, curli/DNA complexes also induce isotype switching and aicda, the master regulator of class switch recombination, in the absence of T cells help in vitro. The induction of non-canonical NFkB in the absence of T cells suggests that the fibrillar structure of curli/DNA complexes can cross-link BCR, some recognizing DNA. Our results suggest that curli/DNA complexes may induce anti-DNA antibody production by simultaneous BCR/TLR signaling, which leads to B cell antibody production in the absence of T cell help.
Systemic recognition of immunogenic insulin peptides promotes T cell diabetic autoimmunity in multiple lymphoid tissues
Authors: Wan Xiaoxiao , Zinselmeyer Bernd , Zakharov Pavel , Vomund Anthony , Hu Hao , Lichti Cheryl , Unanue Emil R. 
Published: January 2023

Abstract
Recognition of insulin is essential for initiating autoimmune diabetes in the non-obese diabetic (NOD) mice; however, how this autoantigen is presented to pathogenic T cells remains unclear. In patients with type 1 diabetes, insulin autoantibodies (IAAs) are the earliest sign of disease. In NOD mice IAAs are detected before immune infiltration in islets, suggesting that insulin autoreactivity originates from peripheral lymphoid sites. This is confirmed by our previous studies showing formation of insulin-specific germinal centers in multiple lymph nodes accompanied by differentiation of cognate T follicular helper cells, indicating widespread insulin recognition. In this study, we used a two-photon imaging system that robustly and accurately detected presentation of the limited amounts of insulin peptide-MHC complexes. We demonstrate that insulin recognition by CD4 T cells takes place concomitantly in various lymph nodes, a process precisely guided by the specific epitope but not the autoimmune environment. Importantly, a unique set of insulin-reactive T cells specifically recognized free insulin peptides but not the conformational protein. During chronic antigen recognition, these T cells exhibited an effector but not exhaustion phenotype, manifested by transcriptional activation, metabolic reprogramming and enhanced pathogenicity. These findings reveal a unique pattern of insulin recognition that may account for its prime role in triggering autoimmune diabetes.
CX43 is essential for optimal cGAS function during cytosolic DNA-sensing
Authors: Nagarajan Uma , Zhang Yugen , Bodnar Wanda , Kiatthanapaiboon Amy , Hagan Robert , O’Connell Catherine , Tripathy Manoj Kumar 
Published: January 2023

Abstract
During intracellular Chlamydia infection, cytosolic DNA is sensed by cyclic GMP-AMP synthase (cGAS) that catalyzes the synthesis of cGAMP from ATP and GTP. cGAMP is a key mediator of IFN beta expression during DNA sensing and can also transfer to adjacent uninfected cells through intercellular connexin gap-junctions to induce intrinsic immunity. In this study, we investigated the role of gap junction protein connexin 43 (CX43) during Chlamydia infection. Using RNA-in situ hybridization, we discovered a distinct intracellular contribution of CX43 in IFN beta expression in the infected cells and cells transfected with DNA, a function distinct from its intercellular gap-junction role affecting IFN beta expression in adjacent uninfected cell. CX43 is essential for IFN beta expression during DNA-sensing upstream of STING activation, but not required during RNA-sensing. CX43 co-localized with transfected DNA and on the chlamydial inclusion membrane with cGAS. CX43-depleted cells showed significantly reduced cGAMP production during DNA-sensing. CX43 forms hemichannels on intracellular membrane, which open and close to allow nucleotide transfer. Blocking this transport across CX43 hemichannel reduced IFN beta expression during infection and DNA-sensing, without altering CX43 localization. These results uncover a novel role of CX43 in cGAMP synthesis by cGAS during cytosolic DNA-sensing.
The scaffolding protein IQGAP1 interacts with Nucleotide Binding Domain Leucine Rich Repeat CARD containing protein (NLRC3) and inhibits type I interferon production
Authors: Davis Beckley K. , Tocker Aaron M. , Durocher Emily , Talento Suzanna M. , Trieschman Kate , Rechnitzer Alma A. , Jacob Kimberly , Roberts David M. 
Published: January 2023

Abstract
Sensing of cytosolic nucleotides is a critical initial step in the elaboration of type I interferon. One of several upstream receptor cGAS (cyclic-GMP-AMP synthase) binds to cytosolic DNA and generates di-cyclic nucleotides that act as secondary messengers. These secondary messengers bind directly to Stimulator of Interferon Genes (STING). STING recruits TANK binding kinase 1 (TBK1) which acts as a critical node that allows for efficient activation of interferon regulatory factors (IRFs) to drive the anti-viral transcriptome. NLRC3 is a recently characterized nucleotide-binding domain, leucine rich repeat containing protein (NLR) that negatively regulates the type I interferon pathway by inhibiting subcellular redistribution and effective signaling of STING, thus blunting the transcription of type I interferons. NLRC3 is predominantly expressed in lymphoid and myeloid cells. IQGAP1 was identified as a putative interacting partner of NLRC3 through yeast two hybrid screening. Here we show that IQGAP1 associates with NLRC3 and can disrupt the NLRC3:STING interaction in the cytosol of human epithelial cells. Furthermore, knock down of IQGAP1 in THP1 and HeLa cells causes significantly more interferon-b production in response to cytosolic nucleic acids. This result phenocopies NLRC3 deficient macrophages and fibroblasts and shRNA knock down of NLRC3 in THP1 cells. Our findings suggest IQGAP1 is a novel regulator of type I interferon production possibly via interacting with NLRC3 in human monocytic and epithelial cells.
Myeloperoxidase Deficiency Attenuates Dietary and Systemic Iron-induced Toxicity
Authors: Xiao Xia , Saha Piu , Yeoh Beng San , Kumar Matam Vijay 
Published: January 2023

Abstract

Background
Iron is highly reactive and could induce oxidative stress via augmenting the activity of heme enzymes, i.e., NADPH oxidase and myeloperoxidase (MPO). Unlike the membrane-restricted NADPH oxidase, MPO remains active upon its release into circulation and thus may potentially exacerbate iron-induced oxidative damage.

Objective
To investigate the extent to which MPO is involved in iron-induced toxicity.

Methods
Acute toxicity was induced by intraperitoneal injection of FeSO4 to MPO deficient (MPOKO) mice and their WT littermates. In some studies, WT mice were pretreated with 4-aminobenzoic acid hydrazide (a MPO inhibitor). Chronic toxicity was induced by feeding 2% carbonyl iron-diet to WT and MPOKO mice. Iron status, MPO levels, inflammatory (SAA, lipocalin 2, KC, IL-6 and IL-1β), organ damage (AST, ALT) and oxidative stress (MDA) markers were assessed.

Results
Acute iron administration upregulated circulating MPO in WT mice, which may be due to increased neutrophil degranulation or oxidative burst. However, the loss of MPO activity in mice, either via inhibition or genetic deficiency, markedly reduced iron-induced organ damage and systemic inflammation. In contrast, long-term iron feeding to WT mice reduced circulating MPO, but promoted its accumulation in liver. While both MPOKO and WT mice showed similar levels of diet-induced hyperferremia, MPOKO mice displayed significantly reduced inflammatory response and oxidative stress.

Conclusion
Genetic deficiency or pharmacologic inhibition of MPO substantially attenuated acute and chronic iron-induced toxicity. Our results suggest that targeting MPO during iron overload may be a promising approach to reduce iron-induced toxicity/side effects.
An IL-2/STAT5/Eos regulatory axis promotes Th1 differentiation.
Authors: Sreekumar Bharath Krishnan Nair , Read Kaitlin A. , Powell Michael Duane , Baker Chandra E. , Zafar Jawad , Martin Emily , Allen Irving C. , Oestreich Kenneth J. 
Published: January 2023

Abstract
Members of the Ikaros Zinc Finger Transcription Factor (IkZF) family are known regulators of hematopoiesis, including the development of CD4+ T helper cell populations. Our recent work established that the IkZF family member Aiolos cooperates with STAT3 to positively regulate Bcl-6 expression in T follicular helper (Tfh) cells. Given the conservation between members of the STAT and IkZF families, and their roles in T helper cell development, we hypothesized that additional IkZF/STAT interactions may regulate the differentiation of other T helper cell subsets. Here, we find that IL-2 signaling induces expression of the IkZF factor Eos in Th1 cells. Knockdown of Eos results in a significant reduction in the expression of signature Th1 genes including Prdm1, Il2ra, and Ifng. Mechanistically, we find that Eos and STAT5 physically interact and form a transcriptional complex that is capable of inducing Prdm1 expression. In support of these data, we also find that Eos and STAT5 are co-enriched at the regulatory regions of Th1 genes including Prdm1 and Il2ra. Taken together, these findings are suggestive of a novel, cooperative role for the IkZF family member Eos and STAT5 in regulating the Th1 differentiation program.
Differing effects of TGFβ family members in the generation of IL-9-secreting T cells
Authors: Ulrich Benjamin Joseph , Kaplan Mark H. 
Published: January 2023

Abstract
The development of Th subsets results from cellular and cytokine cues that are present in the inflammatory environment. The developing T cell is able to integrate multiple signals from the environment, and those signals sculpt the cytokine-producing capacity of the effector T cell. Even when cytokines activate similar intracellular signaling pathways, the T cell can discriminate the cytokine signal to generate distinct outcomes. IL-9-secreting Th9 cells regulate multiple immune responses, including immunity to pathogens and tumors, allergic inflammation, and autoimmunity. In combination with IL-4, both TGFβ and Activin A promote IL-9 production, yet it is not clear if both cytokines generate Th9 cells with identical phenotype and function. We observed that in contrast to TGFβ that efficiently represses Th2 cytokines in Th9 cultures, Activin A produced a multi-cytokine phenotype with secretion of IL-4, IL-5, IL-13, IL-10, in addition to IL-9. Ongoing experiments will define the function of these populations of cells in vivo. These observations suggest that although TGFβ and IL-4 were identified as cytokines that stimulate optimal IL-9 production, they might not be the cytokines that generate optimal function from Th9 cells in immunity and disease.
Egr2 is required for the activation of the TH17 pathogenetic program
Authors: Gao Yuanyuan , Wang Yan , Bouladoux Nicolas Jean , Belkaid Yasmine , Lazarevic Vanja 
Published: January 2023

Abstract
CD4+ TH17 lineage are a heterogenous population of CD4+ effector cells; some of which have been guardians of tissue homeostasis while others have been linked to tissue inflammation and autoimmunity. TH17 cells can alter their differentiation program ultimately giving rise to either protective non-pathogenic or pro-inflammatory pathogenic cells. Molecular switches that control the development of “pathogenic” versus “non-pathogenic” TH17 cells remain largely unknown. In this study, we identified the transcription factor Egr2 as a critical regulator of the TH17 pathogenic program. We found Egr2 was transiently expressed in the early-intermediate stage (24–48 hours) of TH17 differentiation. When ectopically expressed under TH17-polarizing conditions, Egr2 significantly enhanced the expression of TH17 signature genes in a RORγt-dependent manner. Although Egr2 was dispensable for TH17 lineage commitment, its expression was required for the generation of pathogenetic TH17 cells. Mice with T cell-specific deletion of Egr2 were less susceptible to experimental autoimmune encephalomyelitis (EAE) than WT mice. Myelin-specific Egr2-deficeint TH17 cells failed to induce a chronic inflammatory response in the CNS. Transcriptional analysis revealed that Egr2 promoted the pathogenicity of TH17 cells by regulating the expression of pathogenicity-associated genes. Interestingly, Egr2 was not required for the effector function of protective gut-resident TH17 cells in response to Citrobacter rodentium challenge. These findings indicate that Egr2 represents an attractive candidate for the therapeutic targeting of pathogenic TH17 cells while preserving tissue-protective functions of TH17 cells at barrier sites.