bluuebunny/crossref_metadata_2025_split huggingface dataset:
Overexpression of B7-H1 on epidermal keratinocytes promotes squamous cell carcinoma formation. (87.28)
Authors: Cao Yujia , Zhang Lu , Ritprajak Patcharee , Hashiguchi Masaaki , Azuma Miyuki 
Published: January 2023

Abstract
B7-H1 is inducible in various tumor cells and inflammatory tissue cells. We established B7-H1 transgenic mice (Tg), which overexpressed B7-H1 in keratinocytes (KCs). KC-associated B7-H1 directly regulated effector CD8+ T cells at the local inflammatory sites in contact hypersensitivity. Malignant tumor-formation is closely correlated with inflammatory responses. In this study, we investigate the roles of KC-associated B7-H1 in MCA-induced squamous cell carcinoma (SCC) formation. Intradermal injection of MCA preferentially induces SCC. We compared histology and inflammatory status between control and B7-H1Tg mice. Seven days after MCA injection, control BALB/c mice showed severe inflammatory responses with rapid expansion of epidermal cells, more infiltrations in the dermis, and higher cytokine expression. In contrast, B7-H1Tg mice showed less infiltration and expansion of epidermal cells, and exhibited poor alignment and higher chromatin condensation in the basal cells. After 7 wks, B7-H1Tg showed significantly higher incidence of SCC. Our results demonstrated that overexpression of B7-H1 on KCs promotes SCC formation, although the B7-H1/PD-1-mediated interactions between infiltrated cells and epidermal cells regulates inflammatory responses at early time points. The exhibition of higher incidence of SCC in B7-H1Tg mice suggests intrinsic changes in epidermal KCs by B7-H1-transduction rather than PD-1-dependent action.
Phenotypic analysis of spinal cord infiltrating CD4+ T lymphocytes during nerve injury induced neuropathic pain (87.4)
Authors: Cao Ling , Draleau Kyle , Slaiby Aaron , Minzy Courtney 
Published: January 2023

Abstract
We previously demonstrated that CD4+ T cells contribute to the maintenance of L5 spinal nerve transection (L5Tx) induced neuropathic pain in BALB/c mice. It is proposed that a particular subtype(s) of the L5Tx-induced spinal cord infiltrating CD4+ T cells mediates this maintenance of neuropathic pain via T cell - glial interactions. Here, we determined the subtype of L5Tx-induced spinal cord infiltrating CD4+ T cells. There were significantly higher numbers of T-Bet+ lumbar spinal cord infiltrating CD4+ T cells in the L5Tx group compared to the sham group at day 7 post-L5Tx, the peak time for detecting lumbar infiltrating CD4+ T cells, while no significant GATA3+ CD4+ T cells were observed. There were no significant differences in the levels of T-Bet+ or GATA3+ CD4+ T cells in the spleen or lumbar lymph nodes detected at this time. Interestingly, although no significantly higher levels of IFNγ were found in L5Tx mice in the lumbar spinal cord post-surgery, there was a notable increase in splenic levels of IFNγ in the L5Tx group at day 3 post-L5Tx compared to both sham and naïve mice. As we also have data indicating no differences in Th17 responses between groups, altogether our data suggests the involvement of Th1 cells in L5Tx-induced neuropathic pain and that the maintenance of neuropathic pain is likely a Th1-mediated process. Specific downstream responses mediated by these infiltrating Th1 cells require further investigation.
MicroRNAs (miR16 and miR146a) regulation of lupus development in NZB/W F1 mouse model (87.9)
Authors: Yuan Yao , Kotenko Sergei , Laurindo Fernanda , Salerno Erica , Raveche Elizabeth 
Published: January 2023

Abstract
SLE is a heterogeneous autoimmune disease and the specific cause remains unknown. B and T cell abnormalities are considered to play a central role in SLE. More recently, microRNAs (miRNAs), a group of small (~22nt) non-coding RNAs have been studied in SLE patients. miR16, targeting Bcl-2, regulates cell apoptosis.miR-146a, which plays a role in downregulation of type I interferon signaling, is found to be decreased in SLE. In NZB/W F1 mouse lupus model, these two particular microRNAs will be investigated in order to identify the microRNAs in regulation of balancing of B and T cell immunity. In preliminary studies, we treated B/W mice with IFNα or IFNλ for 12 week period and IFNα treated group, but not the IFNλ group developed much earlier and more severe lupus-disease than others. We found that spleen cells from IFNα or IFNλ treated B/W mice had similar level of miR16 and miR146a with control B/W, and all the B/W mice showed a pronounced underexpression of these two miRs comparing to C57 mice. By flow cytometry, only IFNα treated group cells showed hyper-activation of B and T cells, and decreased regulatory B. Thus, it is likely that due to the failure to turn off activation of type I interferon signaling in B/W mice by miR146a and anti-apoptotic effects in activated B cells resulting from low level miR16 may drive the acceleration of lupus-disease in the lupus-prone B/W mice.
Altered response of CD4+ T cells to TGF-β and IL-6 in the absence of the vitamin D receptor (88.9)
Authors: Yu Sanhong , Cantorna Margherita 
Published: January 2023

Abstract
Th17 cells play critical roles in autoimmunity. The active form of vitamin D, 1,25(OH)2D3, has been shown to directly regulate T cell function, but the role of vitamin D and vitamin D receptor (VDR) in the differentiation of Th17 cells is not very clear. Induction of Th17 cells using TGF-β and IL-6 resulted in twice as many Th17 cells in VDR KO cultures as WT. The increased frequency of Th17 cells in VDRKO cultures was not a result of higher expression of retinoic acid receptor-related orphan receptor-γT (ROR-γT). 1,25(OH)2D3 deficient CD4+ T cells also overproduced IL-17. Treatment of WT CD4+ T cells with 1,25(OH)2D3 significantly inhibited the generation of Th17 cells. The number of Treg cells in Th0 cultures of CD4+ cells from VDR KO mice was higher, compared to WT. TGF-β addition to the cultures induced Tregs in both the VDR KO and WT cultures, but there were significantly more Tregs in WT than VDR KO cultures. Addition of both TGF-β and IL-6 to WT CD4 cultures caused a 4-fold reduction in Treg cells. The reduction of Tregs by TGF-β and IL-6 in VDR KO cultures was only 2-fold. VDR KO T cells cultured with TGF-β and IL-6 produced significantly more IL-10 than their WT counterparts. Our data suggest the 1,25(OH)2D3 and signaling through the VDR are important regulators of Th17 differentiation. Furthermore, VDR KO T cells have altered responses to TGF-β and IL-6 that resulted in increased numbers of both Th17 and Treg cells.
Epithelial STAT3 activation is associated with expression of the antimicrobial peptide S100A7 (89.14)
Authors: Hulse Kathryn , Norton James , Harris Kathleen , Conley David , Chandra Rakesh , Kern Robert , Peters Anju , Grammer Leslie , Cohen Elyse , Singh Rashmi , Carter Roderick , Suh Lydia , Schleimer Robert 
Published: January 2023

Abstract
Psoriasin (S100A7) is a potent antimicrobial peptide produced by epithelial cells. Previous work by our group has demonstrated a significant reduction in both the expression of S100A7, and the activation of STAT3 (pSTAT3) in tissue samples from patients with chronic rhinosinusitis with nasal polyps (CRSwNP) compared controls. To investigate whether these two independent observations were linked, we examined the relationship between pSTAT3 and S100A7 expression in primary human bronchial (NHBE) and nasal epithelial cells (NEC). NHBEs or NECs were stimulated with a variety of known STAT3 activators in the presence or absence of TNF. STAT3 activation was assessed by western blot analysis of phospho-STAT3, while S100A7 gene and protein expression were analyzed by qRT-PCR and ELISA, respectively. Among the stimuli tested, IL-22 was the most effective inducer of S100A7 in NHBEs and NECs, and this response was enhanced by TNF (22.3 ng/mg protein and 321.2 ng/mg protein, respectively). Moreover, IL-22 induced phosphorylation of STAT3, and co-incubation with STAT3 inhibitor V resulted in &gt; 75% inhibition of S100A7 protein expression. Interestingly, the TLR3 activator dsRNA, also potently induced S100A7 expression, but this induction was only slightly attenuated by inhibition of STAT3. These data suggest that STAT3 plays a role in the activation and expression of S100A7 in airway epithelial cells, and may be relevant to innate immunity in the airways.
Salivary gland NK cells are phenotypically and functionally unique (89.20)
Authors: Reilly Emma , Tessmer Marlowe , Brossay Laurent 
Published: January 2023

Abstract
NK cells and CD8+ T cells play vital roles in containing and eliminating systemic cytomegalovirus. However, CMV has a tropism for the salivary gland acinar epithelial cells and persists in this organ for several weeks after primary infection. Here we characterize a distinct NK cell population that resides in the salivary gland, uncommon to any described to date, expressing both mature and immature NK cell markers. Notably, naïve salivary gland NK cells have a reduced expression of CD27, are nearly absent of the inhibitory receptor KLRG1, yet are mostly CD11b positive. Using RORγt reporter mice and nude mice, we also show that the salivary gland NK cells are not lymphoid tissue inducer (LTi) NK-like cells and are not thymic derived. During the course of MCMV infection, we found that salivary gland NK cells detect the infection and acquire activation markers, but have limited effector functions in vivo. Salivary gland NK cell effector functions are not regulated by iNKT or Treg cells, which are mostly absent in the salivary gland. Additionally, we demonstrate that peripheral NK cells are not recruited to this organ even after the systemic infection has been controlled. Altogether, these results indicate that latency in SMG may result from both the presence of unfit NK cells and the lack of recruitment of peripheral NK cells.
Immunomodulation of the epithelial cell responses by CD80 blockade and disease amelioration in experimental colitis. (89.3)
Authors: Srinivasan Mythily , Dudhgaonkar Shailesh 
Published: January 2023

Abstract
Under physiological conditions the intestinal epithelium adapts to a constantly changing environment of the intestinal luminal content including the enteric bacteria. The colonic epithelial cells (CEC) respond to microbes through a family of tightly regulated toll like receptors (TLR) that constantly survey their surroundings for potential threats. In inflammatory bowel diseases (IBD) abnormal response to bacteria mobilizes immune effector cells to the intestinal mucosa, chiefly the CD4+ T cells which perpetuate sustained inflammation. Successful therapeutic strategies for IBD should therefore suppress lymphocytic responses; promote epithelial healing and re-establishment of intestinal homeostasis. Inhibition of T cell activation suppresses inflammatory cytokines in animal models of IBD. Here we investigated the effects of a synthetic peptide that blocks T cell costimulation, the CD80-CAP, on the CEC responses in experimental colitis. We observed that the CEC from CD80-CAP treated mice exhibited significantly reduced pro-inflammatory responses and a skewing towards anti-inflammatory cytokine response. Importantly, the CD80-CAP treatment also resulted in concomitant restoration of TLR-2, TLR-3, TLR-4 and TLR-5 mRNA in the CEC of colitic mice to physiologic levels. Taken together our data suggest that the CD80-CAP administration suppress inflammation and modulate epithelial cell responses potentially facilitating re-establishment of mucosal homeostasis in experimental colitis.
Inflammation-induced Expression of Immunoreceptor Tyrosine-based Inhibition Motif (ITIM)-less SIRPα Enhances Neutrophil Transmigration (89.39)
Authors: Guo Ya-Lan , Chen Yi-Tien , Soto Ileana , Zen Ke , Liu Yuan 
Published: January 2023

Abstract
Previous studies by us and others have demonstrated that SIRPα, an immunoreceptor tyrosine-based inhibition motif (ITIMs)-containing cell surface receptor, regulates neutrophil (PMN) and monocyte transmigration in response to inflammatory stimuli. In this study, we further characterized leukocyte SIRPα and found that PMN express multiple forms of SIRPα including the typical SIRPα with a long cytoplasmic domain containing the full ITIMs (ITIM+SIRPα) and shorter, ITIM-depleted SIRPα (ITIM-SIRPα). Importantly, our studies in both human and inflammatory animals revealed that, while ITIM+SIRPα is generally expressed in PMN of healthy donors, active inflammatory conditions induce diminishing of ITIM+SIRPα but a dominant expression of ITIM-SIRPα. In vitro and in vivo functional assays indicate that, compared to PMN from healthy donors bearing ITIM+SIRPα, PMN with chiefly ITIM-SIRPα display a higher tendency of activation and exhibit enhanced transmigration under inflammation. However, despite the differences in the intracellular domains, purified ITIM+SIRPα and ITIM-SIRPα from healthy and inflammatory donors had similar extracellular binding with the ligand CD47. In addition, our results suggest that conversion of SIRPα into ITIM-less receptor is through inflammation-induced proteolytic cleavage in PMN and such process serves as an important mechanism to enhance inflammatory response and dynamically modulate PMN transmigration.
Complement anaphylatoxin function and signaling in the CNS (89.48)
Authors: Ingersoll Sarah , Martin Carol , Martin Brian 
Published: January 2023

Abstract
Demyelination of the CNS in autoimmune diseases is known to involve several immune effector mechanisms, including complement. The brain is considered an immunoprivileged site; however, complement proteins are produced locally by glial cells. We are investigating the roles of C3a and C5a on glial cell activation and their overall role in demyelination and remyelination pathology. Using the cuprizone model to induce demyelination, we found that transgenic mice expressing C3a or C5a in the CNS had exacerbated demyelination and slightly delayed remyelination in the corpus callosum compared to wild type mice. C3a and C5a transgenics had increased cellularity in the corpus callosum. Using immunofluorescence, it was shown that microglia and astrocyte levels were increased in the brains of transgenic mice during peak demyelination. To study the role of anaphylatoxins on individual glial subsets, we created novel adenoviral vectors to express murine C3a or C5a. ERK1/2, were phosphorylated when BV-2 microglia were stimulated with C5a, but not C3a. JNK and ERK1/2 were phosphorylated in primary astrocytes treated with C3a or C5a. Additionally, C5a was able to induce chemtoaxis in J774 macrophages; however, we did not see significant migration of astrocytes or BV-2 microglia in vitro. Overall, our findings show that anaphylatoxin production in the brain plays a negative role during demyelination, most likely due to an increase in inflammatory cells in demyelinated areas of the brain.
Human innate immune cells that engage soluble beta-1,3/1,6 glucans: Role for complement receptor 3 (CR3, CD11b/CD18) (89.53)
Authors: Vasilakos John , Bose Nandita , Chan Anissa , Danielson Michael , Dudney Christine , Elmasry Natalie , Gorden Keith , Guerrero Faimola , Magee Andy , Maristany Carolyn , Walsh Richard , Will Paul , Wurst Lindsay 
Published: January 2023

Abstract
Beta-1,3/1,6 glucans (BGs) are a diverse class of PAMPs. Structurally, BGs can vary on the basis of chain length, types of linkages, branching, and tertiary structure. BGs have been reported to activate various types of innate immune cells; most studies demonstrate the use of particulate BGs activating murine immune cells. Unlike particulate BGs, most soluble BGs demonstrated minimal activities typically associated with innate immune cell activation, such as induction of cytokines. Hence, little is known regarding the types of human immune cells or receptors that engage soluble BGs, and if structurally distinct BGs differ in their cell selectivity or receptor requirements. The objective of this study was to determine the types of human immune cells that soluble BGs bind to, and to determine the receptors required for binding. Since BGs have been implicated in interacting with Dectin-1 and CR3 expressing cells, we hypothesize that human innate immune cells that express these receptors will bind soluble BGs. Specific binding of BGs was evaluated by flow cytometry on primary human immune cells and cell lines using BG specific antibody and DTAF-labeled BGs. In addition, these studies were conducted using three structurally distinct, purified, and chemically characterized BGs. Key findings demonstrate that on cells that express both CR3 and Dectin-1, CR3 is a critical receptor for binding soluble BGs and not all BGs bind equivalently to human innate immune cells.
Galectin expression and modulation by viruses in fish cell lines (89.54)
Authors: Jackson Shawn , de las Heras Sanchez Ana , Ahmed Hafiz , Vakharia Vikram , Vasta Gerardo 
Published: January 2023

Abstract
The galectin family of β-galactoside-binding proteins is evolutionarily conserved. In homeotherm vertebrates, galectin-virus interactions can affect viral infectivity and/or pathogenicity. We hypothesize that in teleost fish, galectin interactions with viral proteins modulate viral infectivity. We examined fish cell lines for expression of galectin-like molecules, and assessed changes in expression of identified galectins as well as of cytokines in response to viral infection. Minnow (EPC), trout (RTG-2), bluegill (BF-2), salmon (CHSE-214, ASK), zebrafish (ZFL), and catfish (COO, 42TA, G14D, 28S.3, 1G8, and 3B11) cells were tested. A proto-type galectin-like protein is expressed in EPC, RTG-2, and ZFL cell lines, and a chimera-type in EPC and RTG-2 cell lines. All tested cell lines express mRNA that exhibits high conservation with the zebrafish Drgal1-L2 proto-type galectin. Ten of the 12 cell lines express Drgal1-L3-like mRNA, 7 express Drgal1-L1-like mRNA, and 6 express Drgal1-L4-like mRNA. With the exception of 3B11, all tested cell lines express Drgal3-L1-like mRNA. Eight of the 12 express Drgal3-L2-like mRNA. Two of the 12 cell lines expressed Drgal9-like mRNA. Following infection of EPC cells with IHNV or IPNV, we observe modulations in expression of proto-type and tandem-repeat-type galectin-like molecules. We see modulations in expression of various cytokines, including type I and II interferons and TNF family members.
KIR2DS1 positive Natural Killer cells from individuals expressing cognate HLA ligand are tolerant. (89.58)
Authors: Pittari Gianfranco , Selvakumar Annamalai , Liu Xiao-Rong , Dupont Bo 
Published: January 2023

Abstract
Inhibitory KIR-HLA interactions are critical for NK tolerance to self. KIR2DS1 is the only activating counterpart of inhibitory KIRs to have ligand specificity for HLA class I, recognizing HLA-C group 2. Since KIR and HLA genes segregate independently, individuals that carry KIR2DS1 may have HLA-C antigens of the HLA-KIR ligand group C2. We here report that 2DS1 positive NK cells from such individuals are tolerant to such self HLA antigens. We demonstrate that the mechanism for tolerance is different for individuals homozygous or heterozygous for the HLA ligand. NK clones have been generated from KIR2DS1-positive and HLA-C2 homozygous, HLA-C1/C2 heterozygous or HLA-C1 homozygous individuals. Their response against HLA-KIR ligand group C2-expressing targets and their KIR repertoire have been assessed. NK clones expressing KIR2DS1 display anti-HLA-C2 alloreactivity but are tolerant to HLA-C2 if this is a self antigen. This hyporesponsiveness to C2 in C2/C2 homozygous donors is also observed for NK clones lacking 2DL1. In turn, the co-expression of inhibitory KIRs with ligand specificity for self HLA class I including C2 is an important mechanism for tolerance in HLA-C1/C2 heterozygous individuals. This is the first demonstration of activating NK receptor tolerance to cognate self MHC ligand. NK clones expressing only the activating receptor and not the homologous inhibitory receptor are readily identified. Remarkably, NK clones with self HLA ligand specificity are not deleted.
Human gastrointestinal stem cell (hGISC) derived non-transformed epithelial cells but not malignant colonic adenocarcinoma cell line HT29 respond to combined innate and adaptive immunostimulation by producing high levels of nitric oxide. (90.14)
Authors: Panja Asit , Joseph Ansamma , Panja Aparna , Harrison David 
Published: January 2023

Abstract
Gastrointestinal (GI) inflammation is a global health burden. Yet the mechanism of GI inflammation remains undefined. Among proposed mechanisms, increased nitric oxide (NO) production by intestinal epithelial cells (EC) is thought to play a crucial role in inflammatory conditions such as IBD. However, the regulation of NO production in human intestinal epithelium are undefined, thus treatments for these diseases remain inadequate. Therefore, to gain insight about NO production regulation by intestinal EC, we studied the effects of innate (LPS) and adaptive (IFNγ) immunostimulatory agents on a novel hGISC cell system derived non-transformed primary epithelial cells (EC) and compared it to a colonic adenocarcinoma EC line HT29. A macrophage cell line MHS served as a positive control. Cells were cultured with/without LPS (1μg/ml), IFNγ (200 u/ml), or in combination for 24 hours. Culture supernatants were analyzed for NO content by Griess reaction assay. Our results show that neither LPS nor IFNγ alone affect NO production by intestinal ECs. However, NO production by hGISC derived primary ECs was dramatically increased (comparable to the NO level seen in MHS cells) when LPS and IFNγ were added in combination. In contrast, malignant HT29 cells do not show any difference in NO synthesis even when LPS (innate stimuli) and IFNγ (adaptive stimuli) were combined. These findings may help understand the intestinal inflammatory disease mechanisms and development of new treatments.
Cooperation of retinoic acid and Toll-like receptor signaling in induction and function of mucosal dendritic cells (90.5)
Authors: Feng Ting , Qin Hongwei , Benveniste Etty , Cong Yingzi , Elson Charles 
Published: January 2023

Abstract
Mucosal dendritic cells (DCs) play a crucial role in the maintenance of intestinal immune homeostasis. However, how DCs become mucosal DCs is still unclear. In this study, we investigated whether retinoic acid (RA) induced the mucosal DC phenotype and function, and the mechanisms involved in this process. We report here that bone marrow cells expressed RA-synthesizing enzyme aldehyde dehydrogenase family 1a2 (ALDH1a2) and provided RA to DC precursors in the bone marrow microenvironment. RA induced bone marrow-derived DCs (BMDCs) to express gut-homing receptor CCR9 and ALDH1a2. Similar to mucosal DCs, RA-educated DCs (RA-DCs) promoted conversion of Foxp3+ regulatory T cells from naïve Foxp3- precursors, induced B cell IgA secretion, and enhanced lymphocyte gut-homing receptor expression. The effect of RA on educating BMDCs to acquire mucosal DC functionality was dependent on a narrow time window and tight dose. RA inhibited DC SOCS3 expression through direct interference with SOCS3 promoter activity thus enhanced STAT3 activation, which promoted bioactive TGF-β production. In cooperation with RA signaling, commensal microbiota stimulation further enhanced RA-DC ALDH1a2 expression and was required for RA-DC TGF-β production. Our data reveal a mechanism for RA to instruct bone marrow DC precursors to differentiate into mucosal-like DCs. Cooperation of RA signaling and microbiota stimulation is required for the development of fully functional mucosal DCs.