bluuebunny/crossref_metadata_2025_split huggingface dataset:
Autoimmune manifestations in aged mice arise from early-life immune dysregulation
Authors: Karnell Jodi , Mahmoud Tamer I. , Wang Jingya , Wang Qiming , Wang Shu , Naiman Brian , Gross Philip , Brohawn Philip Z. , Morehouse Christopher , Aoyama Jordan , Wasserfall Clive , Carter Laura L , Atkinson Mark A. , Serreze David V , Braley-Mullen Helen , Mustelin Tomas Mikael , Kolbeck Roland , Herbst Ronald , Ettinger Rachel 
Published: January 2023

Abstract
Autoantibodies that arise in autoimmunity can be present years to decades prior to the onset of disease manifestations. This suggests that the initial autoimmune trigger involves a peripheral lymphoid component, which ultimately drives disease pathology in local tissues later in life. Here we show Sjögren’s Syndrome manifestations that develop in aged NOD.H-2h4 mice were driven by and dependent on peripheral dysregulation that arose in early life. Specifically, elimination of spontaneous germinal centers that developed in spleens of young NOD.H-2h4 mice by transient blockade of CD40 ligand (CD40L) or splenectomy abolished Sjögren’s pathology of aged mice. Strikingly, a single injection of anti-CD40L at 4 weeks-of-age prevented tertiary follicle neogenesis and greatly blunted the formation of key autoantibodies implicated in glandular pathology. Microarray profiling of salivary gland characterized the expression pattern of genes that increased with disease progression and showed early anti-CD40L greatly repressed B cell function, while having a broader effect on multiple biological pathways including IL-12 and interferon signaling. Importantly, a single, prophylactic treatment with anti-CD40L also inhibited the development of autoimmune thyroiditis and diabetes in NOD.H-2h4 and NOD mice, respectively, supporting a key role for CD40L in the pathophysiology of several autoimmune models. These results suggest that early peripheral immune dysregulation gives rise to autoimmune manifestations later in life and for diseases pre-dated by autoantibodies, early prophylactic intervention with biologics may prove efficacious.
The role of infiltrating macrophages and IL-6 production on seizure development after viral infection
Authors: DePaula-Silva Ana Beatriz , Hanak Tyler J. , Doty Daniel J. , Sim Jordan T. , Libbey Jane E. , Fujinami Robert S. 
Published: January 2023

Abstract
Epilepsy is a chronic neurological disorder characterized by recurrent seizures. Seizures, which are often associated with viral encephalitis, occur in response to imbalances between excitatory and inhibitory inputs within the brain. Patients with viral encephalitis are 16 times more likely to develop epilepsy. It is estimated that around 65 million people worldwide suffer from epilepsy. Although treatments to prevent seizures are available, 30% of the patients do not respond to the medication. In order to develop new immunomodulatory treatments that could lead to an eventual cure for seizures/epilepsy, a better understanding of the seizure development mechanism is required.
We have developed an experimental model of virus-induced seizures/epilepsy. In our model, C57BL/6J mice are infected intra-cranially with the Daniels strain (DAV) of Theiler’s murine encephalomyelitis virus. Between 3 and 10 days post infection (d.p.i.), around 50% of the infected mice will develop spontaneous acute seizures and approximately 50% of these mice develop epilepsy. Because seizures begin to develop at 3 d.p.i we believe it happens as a consequence of the activation of the innate immune response. We found that seizures are correlated with an increase in myeloid cells infiltrating into the brain. Also, the pro-inflammatory cytokines IL-6 and TNF alpha were elevated at 3 d.p.i. IL-6 knockout mice infected with DAV experienced significantly fewer seizures. Because infiltrating macrophages are the main producers of IL-6, we depleted macrophages from mice and we infected them with DAV. We did not observed seizures in animals depleted of macrophages, suggesting macrophages are playing a central role in the development of seizures after viral infection.
Role of SLAMF immunoregulatory molecules in MS disease processes
Authors: Mizrahi Jordan S , Park John Jaewon , Masvaker Ruturaj , Bielekova Bibi 
Published: January 2023

Abstract
In our proteomic analysis of cerebrospinal fluid (CSF) we found signaling lymphocyte activation molecules family (SLAMF) upregulated in multiple sclerosis (MS) patients in comparison to controls. The goal of this project is to explore the role of SLAMF molecules in MS.
To identify immune cells that express and secrete SLAMF molecules in the intrathecal (CSF) environment, we performed immunophenotyping of matched blood and CSF leukocytes and dynamic in-vitro experiments, co-culturing leukocytes with EBV and CMV viral lysates. This antigen-specific activation of a sizeable proportion of T and B cells allowed the investigating of changes in surface expression and secretion of SLAMF molecules.
SLAMF2 was broadly expressed, however CSF CD8+ T cells and monocytes had higher SLAMF2 expression in comparison to blood. Stimulation down-modulated SLAMF2 on T cells, but upregulated it on B cells. SLAMF3 was expressed on cells of adaptive, but not innate immunity and CD4+ T cells expressed higher levels of SLAMF3 in CSF than in blood. Upon activation, SLAMF3 expression did not change and the soluble form did not accumulate in supernatants. SLAMF5 was broadly expressed, with particularly higher levels on cells of innate immunity (monocytes and dendritic cells). CSF T and B cells had lower SLAMF5 levels than blood T&B cells. SLAMF6 was strongly expressed on T, B and NK cells; its expression levels did not vary between compartments or upon activation. Finally, SLAMF7 was expressed on cytotoxic T cells, NK cells and plasma cells, with significant upregulation on all antigen-presenting cells upon activation. We explored its role in cytotoxicity, but found no effect of SLAMF7 blockade or sSLAMF7 addition on NK-mediated killing of MHC-I-deficient targets.
Sex-specific regulation of CNS autoimmunity by the signal lymphocytic activation molecule (Slam) locus
Authors: Raza Abbas , Case Laure K , Osmanski Erin , Krementsov Dimitry N , Boyson Jonathan E , Teuscher Cory 
Published: January 2023

Abstract
Multiple sclerosis (MS) is a demyelinating inflammatory disease of the central nervous system (CNS). Epidemiological studies have documented a 3–6 fold increase in MS incidence and prevalence in females over the last half-century, while remaining relatively stable in males. This establishes that gene×environment×sex interactions contribute to MS susceptibility. Genome-wide association studies (GWAS) of MS patients identified multiple candidate genes, including a locus containing the signal lymphocytic activation molecule (SLAM) family of receptors, a region rich in immune-relevant genes that is highly conserved between humans and mice. There are two major Slam haplotypes segregating in laboratory mice. Slam haplotype-1 is present in C57BL/6 (B6) mice and haplotype-2 is expressed in most other common inbred laboratory strains, including 129 mice. The congenic B6.129c1 mouse possesses the 129-derived Slam haplotype-2 locus on the B6 background, which allows for assessing the potential contribution of SLAM family genes to MS susceptibility using the myelin oligodendrocyte (MOG) model of experimental autoimmune encephalomyelitis (EAE). We show that male B6.129c1 congenic mice demonstrate significant protection against MOG-EAE, but only in males. Furthermore, draining lymph nodes from immunized B6.129c1 males, but not females, had increased Foxp3+ regulatory T cells (Treg) and IL-10 levels compared with B6, suggesting that SLAM/Slam haplotypes regulate autoimmunity by modulating the generation of immunoregulatory cells in a sex-specific manner. Taken together, our results support a role for the SLAM locus is MS pathogenesis, and reveal a novel sexual dimorphism in the genetic control of this autoimmune disease
A role for the NLR family members NLRC4 and NLRP3 in sterile inflammasome activation in glial cells
Authors: Guo Haitao , Freeman Leslie , David Clément N , Brickey Willie J , Jha Sushmita , Ting Jenny P 
Published: January 2023

Abstract
The inflammasome is implicated in many inflammatory diseases including neurological diseases but has been primarily studied in the macrophage-myeloid lineage. Here we demonstrate a physiologic role for nucleotide-binding domain, leucine-rich repeat, CARD domain containing proteins, NLRC4 and NLRP3, in brain astrocytes and microglia under the sterile neuroinflammation condition. In vitro, lysophosphatidylcholine (LPC), a molecule associated with neurodegeneration and demyelination, elicits an inflammasome activation dependent on both NLRC4 and NLRP3 in microglia and astrocytes, which are central players in neuroinflammation. Canonical inflammasome components ASC and caspase-1 but not non-canonical inflammasome component caspase-11 is required for LPC-activated inflammasome. Mechanistically, LPC-activated inflammasome also requires cathepsin B protease, calcium mobilization and potassium efflux. In an in vivo cuprizone model of neuroinflammation and demyelination, we found only mice lacking both Nlrc4 and Nlrp3 genes show the significant reduction in astrogliosis and microglial accumulation accompanied by decreased expression of the LPC receptor, G2A, while multiple sclerosis (MS) patient samples show increased G2A. These results reveal that both NLRC4 and NLRP3 are involved in activating LPC-induced inflammasome and are important in astrogliosis and microglial accumulation in a neurological disease model.
Biological evaluation of the MILLIPLEX® map Mouse High Sensitivity T Cell Panel
Authors: Keith Robert H , Grana Paula , Schultz Christian , Bowdish Dawn M.E. , Xiao Qiang 
Published: January 2023

Abstract
Low levels of inflammation are involved in many clinical and sub-clinical disease states like autoimmune diseases. Measuring picogram levels of cytokines is critical for understanding their pathogenesis. Model organisms, such as mice, offer unique challenges of sample availability and detection of low levels of cytokines. We recently developed a Mouse High Sensitivity T Cell Panel multiplex assay for simultaneous measurement of 18 mouse cytokines using Luminex xMAP® technology. In this study, we analyzed mouse cytokine secretions both in vitro, with PMA-, PHA-, LPS-, Con-A, or calcium ionophore-challenged PBMC samples, and in vivo, using LPS-challenged mice and an aged-mouse model. Typically, the response of mouse PBMCs to in vitro stimulants is difficult to study due to low levels of cytokine secretion. Using the MILLIPLEX® map Mouse High Sensitivity T Cell Panel, distinctly different stimulant-dependent cytokine responses were observed. PMA and LPS induced the secretion of IL-1β, IL-5, IL-10, LIX, MCP-1, MIP-2 and LPS. IL-6 was secreted in response to LPS but not PMA. Th17 cell cytokine IL-17A was secreted in response to PHA and Con A but not LPS. Interestingly, low levels of secretion were seen in response to the combination of all stimulants for GM-CSF, IFNγ, IL-1α and IL-2. The in vivo challenge of LPS significantly increased mouse plasma levels of fourteen cytokines. Small increases were also seen for GM-CSF and IL-2, while IL-5 and IL-12 (p70) trended higher. In a mouse model of aging, sex-specific changes of plasma levels were observed for IL-1, IL-5, IL-10, GM-CSF, IFNγ, KC and MIP-2. Thus, the MILLIPLEX® MAP Mouse High Sensitivity T Cell Panel is a useful tool to study low levels cytokines in mouse models of disease and inflammation.
c-Maf positively regulates IL-17-producing iNKT cell-mediated airway neutrophilia
Authors: Yu Jhang-Sian , Hamada Michito , Ohtsuka Shigeo , Yoh Keigyou , Takahashi Satoru , Miaw Shi-Chuen 
Published: January 2023

Abstract
c-Maf belongs to the large Maf family transcription factors and plays a key role in regulation of cytokine production and differentiation in TH2, TH17, TFH and Tr1 cells. Invariant natural killer T (iNKT) cells can rapidly produce large quantity of TH-related cytokines such as IFN-γ, IL-4 and IL-17A upon stimulation by its glycolipid antigen α-galactosylceramide (α-GalCer). However, the role of c-Maf in iNKT cells and iNKT cell-mediated diseases remains poorly understood. In this study, we demonstrate that α-GalCer-stimulated iNKT cells express c-Maf transcript and protein. By using c-Maf-deficient fetal liver cell-reconstituted mice, we further show that c-Maf-deficient iNKT cells produce less IL-17A than their WT counterparts after α-GalCer stimulation, but IFN-γ and IL-4 productions were not affected. c-Maf deficiency does not affect the development and activation state of iNKT cells. c-Maf also positively regulates induction of IL-17-producing iNKT (iNKT17) cells by IL-6, TGF-β and IL-1β. c-Maf-deficient iNKT cells express lower RORγt transcripts compared with WT iNKT cells under IL-17-induction condition. Interestingly, c-Maf-deficient iNKT17 cells lose the ability to recruit neutrophils into the lungs. Taken together, c-Maf is a positive regulator for IL-17A production through transactivating RORγt expression in iNKT17 cells. It is a potential therapeutic target in iNKT17 cells-mediated inflammatory disease.
Unexpected STAT3-mediated mechanisms of regulation of effector Th17 function in autoimmunity
Authors: Raphael Itay , McGeachy Mandy J 
Published: January 2023

Abstract
Th17 cells have been linked to the emergence of many autoimmune inflammatory conditions as well as defense against fungal pathogens. Early differentiation and expansion of Th17 cells relies on key cytokines that signal through STAT3, including IL-6 and IL-21. Later STAT3-dependent signals from IL-23 are critical for gain of inflammatory function by effector Th17 cells. Thus, development of drugs that target STAT3 or its upstream receptors are a major research focus to alleviate disease. However, the requirements for STAT3 signaling in effector Th17 cells remain elusive. Here, we developed a model to study the effect of STAT3 deficiency specifically in effector Th17 cells in EAE, an animal model of multiple sclerosis. Our data show that mice lacking STAT3 in effector Th17 cells are resistant to EAE development. Unexpectedly, we demonstrate that in Th17 cells, STAT3 is not required for maintenance of Th17 lineage commitment or Th17 cytokine production in vivo. To determine mechanisms by which STAT3 regulates Th17 effector cells to promote development of autoimmune inflammation, we performed bioinformatics analysis of the transcriptome of effector Th17 cells isolated from lymph nodes (LN) at day 10 (onset) of EAE. This revealed that STAT3 regulates expression of genes associated with particular cell-death pathways, and pathways associated with proliferation and T cell mediated tissue damage. Corresponding to these changes in gene expression, we found that STAT3 deficient effector Th17 cells were reduced in numbers in LN and target tissue during EAE. Our data reveal a hitherto unappreciated mechanism for STAT3 in regulating effector Th17 cells, which have major implications for use of STAT3-targeted therapies.
PD-L1 from HaCaT cells affect melanin production in B16F10 cells under poly(I:C) stimulation
Authors: Woo So-Youn , Park Minhwa , Cho Kyung-Ah , Cho Min-Sun , Lee Kyung Ho 
Published: January 2023

Abstract
Skin form the physical barrier protected from the stimulants outside. Keratinocytes can sense either harmless commensal organisms or harmful pathogens, and subsequently drive immune response by Toll-like receptors (TLRs). For example, activation of TLR3 has been shown to require barrier repair by stimulate essential genes, including tight junction genes and inflammatory cytokines. Melanocytes reside on the basal layer cells and connect with about 30–40 keratinocytes in the basal layer through dendritic morphology. Most observations refer to transfer of melanosome into keratinocytes but melanogenesis regulator mechanism by soluble factor(s) from keratinocytes is unclear. Upon consideration of the cellular location in the skin and ratio of residing keratinocytes to melanocytes in the epidermis, regulation of melanogenesis by controlling keratinocytes in vivo is challenging. In this study, we investigated whether HaCaT affect melanogenesis under TLR3 stimulation using B16F10 cells, and found that poly(I:C) stimulation induced PD-L1 secretion from HaCaT cells and PD-L1 inhibited expression of melanogenesis-related genes on B16F10 cells.
* This work was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF-2016R1A2B4009182).
Intestinal Regulation of C. albicans by PP Langerin+ DCs
Authors: De Jesus Magdia , Rochac-Argueta Emily , Gallagher Heather 
Published: January 2023

Abstract
As the largest mucosal compartment, the human gastrointestinal tract (GI) is highly colonized with a complex microbial ecosystem that includes fungal organisms. Although fewer in numbers and less extensively studied in the context of the intestinal mucosa, it is unclear whether commensal members such as Candida species play a role in intestinal mucosal immunity. Recent studies have suggested that Candida sp. in the intestinal mucosa are associated with a number of human diseases such as gastric ulcers, Crohn’s disease and Hirschsprung-associated enterocolitis. We have recently identified, a specific non-macrophage dendritic cell (DC) population within intestinal Peyer’s patches (PP) that expresses the C-type lectin receptor (CLR)-Langerin and are able to specifically uptake Candida albicans, Candida tropicalis and yeast purified β-1,3-glucan particles (GPs). We hypothesize that Langerin+ DCs are central in the sampling, presentation and regulation of C. albicans within PPs. To address this hypothesis, we are currently defining the role of Langerin+ DCs in the processing of Candida sp. after uptake using the Langerin-DTR- EGFP mouse model as well as the Langerin-DTR- EGFP-DSS model. We are also characterizing the local gene expression profiles of PP B and T- lymphocytes as well as Langerin+ DCs in response to C. albicans. Additionally, we are investigating whether Langerin+ DCs are a migratory cell subset that not only transports C. albicans near germinal centers but can also take them to tolerogenic sites such as the MLN. These studies will advance our knowledge of how commensal members that are also part of the “mycobiome” are sampled, what mucosal immune responses are elicited and how these fungal organisms are tolerated.
miR155-deficient alleviated intestinal inflammation by downregualting the development and function of CD103+CD11b+DC in the lamina propria of intestine
Authors: Xu Yingping , Zhang Binbin , Zhu Xiaoli , Li Chuanwei , Song Wengang , Tang Hua 
Published: January 2023

Abstract
Inflammatory bowel disease (IBD) refers to inflammatory disorders of the gut with unclear pathogenesis. miR155 expression was increased in IBDs by upregulated Th1/Th17 cell response and proinflammatory factors to promote intestinal inflammation. Dendritic cell (DC) is a heterogeneous subsets in the intestine, and plays important roles in maintaining intestinal homeostasis. However, it is unclear whether miR155 regulate the differentiation and function of intestinal DC subsets to orchestrate inflammation in the intestinal microenvironment. Here, we found defiency of miR155 led to a significantly decreased number of CD103+CD11b+DC in the lamina propria (LP) of intestine at steady state, moreover, the yield of bone marrow-derived CD103+CD11b+DC induced by GM-CSF and Flt3L in vitro was also decreased compared to that of wild type (WT) mice. Further study showed that differency of miR155 had no effect on turnover rate and migration. Interestingly, we found the percentage and number of pre-cDC1 (CD103+DC precursor) in the BM were reduced significantly in the bone marrow of miR155-deficient mice compared to that of WT mice, and the transcriptor IRF4 and Notch2 expression of CD103+CD11b+DC in the LP was also decreased in miR155-deficient mice. In addition, CD103+DC and CD103+CD11b+DC in the LP of miR155-deficient mice exhibited a poor pro-inflammatory phenotype. Taken together, our results identifies a role of miR155 as a critical regular of intestinal homeostasis, which will be helpful for seeking a potential therapeutic target for the treatment of IBD.
Sensory neurons co-opt classical immune signaling pathways to mediate chronic itch
Authors: Oetjen Landon K , Mack Madison R , Whelan Timothy M , Guo Changxiong J , Yang Lihua , Hamilton Samantha L , Wang Peter L , Niu Haixia , Feng Jing , Xu Amy Z , Tripathi Shivani V , Luo Jialie , Brestoff Jonathan R , Schaffer Andras , Hsieh Chyi-Song , Gereau Robert W , Miller Mark J , Hu Hongzhen , Davidson Steve , Liu Qin , Kim Brian S 
Published: January 2023

Abstract
Mammals have evolved neurophysiologic reflexes such as scratching to expel invading pathogens and noxious environmental factors. It is also well established that these responses are associated with chronic inflammatory diseases such as atopic dermatitis. However, the mechanisms by which inflammatory pathways promote sensations such as itch remain poorly understood. Here, we show that the type 2 cytokines interleukin (IL)-4 and IL-13 directly stimulate sensory neurons and that chronic itch is dependent on neuronal IL-4Rα, the shared receptor subunit for IL-4 and IL-13. Based on our understanding of IL-4Rα signaling in immune cells, we hypothesized that downstream Janus kinase (JAK) signaling in sensory neurons would be a critical mediator of itch. Indeed, we find that both systemic JAK inhibition and interruption of JAK signaling in the nervous system can dramatically reduce itch. Further, sensory neuron-specific genetic deletion of JAK1 results in robust abatement of chronic itch in mice. Finally, in proof-of-concept translational studies, patients with recalcitrant chronic itch improved rapidly and dramatically in response to JAK inhibition. Thus, signaling mechanisms previously ascribed to the immune system may represent novel targets within the sensory nervous system for the treatment of pathologic sensory responses. Collectively, these studies reveal an evolutionarily conserved paradigm in which the sensory nervous system employs classical immune signaling pathways to influence mammalian behavior.
Complement protein C1q suppresses macrophage inflammasome activation during clearance of modified LDL
Authors: Manughian-Peter Ayla , Ho Minh Minh , Fraser Deborah A. 
Published: January 2023

Abstract
In the atherosclerotic environment, inflammation plays a major role. Ingestion of modified forms of low-density lipoproteins (such as oxidized LDL) by macrophages promotes macrophage secretion of inflammatory cytokines, which contributes to disease progression. We have previously shown that the complement classical pathway activator, C1q, has a novel, anti-inflammatory role independent of the complement cascade: opsonization of modified LDL with C1q polarizes macrophages towards an anti-inflammatory (M2) phenotype, and dampens the pro-inflammatory (M1) phenotype that is prevalent in the atherosclerotic environment. Differential transcriptomic analysis in human macrophages suggests that C1q may influence macrophage inflammatory phenotype by modulating the levels of components of the NLRP3 inflammasome, a protein complex responsible for activation of inflammatory cytokine IL-1β. To investigate this further, resting or M1-polarized human monocyte derived macrophages (HMDMs) were treated with 10 μg protein/mL oxLDL, with or without 75 μg/mL C1q, and inflammasome gene, protein and activity were measured. Our data suggest that when bound to oxLDL, C1q downregulates NLRP3 inflammasome related genes, and reduces inflammasome activity, leading to a reduction in IL-1β secretion from M1-polarized macrophages. This indicates that this non-complement role of C1q may be important in dampening inflammation in the early atherosclerotic lesion. Discerning the molecular pathways that regulate inflammatory states of macrophages can contribute to the development of therapeutics for chronic inflammatory illnesses such as atherosclerosis.