bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neutrophil mediated IL-1β processing in Pseudomonas aeruginosa infection is IPAF and Caspase-1 independent and mediated by serine proteases (118.1)
Authors: Karmakar Mausita , Sun Yan , Hise Amy , Rietsch Arne , Pearlman Eric 
Published: January 2023

Abstract
Inflammasome and caspase-1 dependent cleavage of IL-1β to the mature, active form is the predominant, but not sole mechanism of IL-1β processing. To investigate the role of IL-1β, IPAF/NLRC4 inflammasome and caspase-1 in bacterial keratitis, which is an important worldwide cause of blindness, mouse corneas were infected with Pseudomonas aeruginosa invasive strain PAO1 (expressing ExoS, T and Y but not ExoU), and corneal inflammation and bacterial survival were examined. We found that IL-1β-/- mice had significantly fewer infiltrating neutrophils, and significantly higher CFU than C57BL/6 mice. In contrast, there was no difference in either corneal disease or bacterial survival between caspase-1-/-, IPAF1-/- and C57BL/6 mice. In all mouse strains, we found that neutrophils are the major producers of IL-1β during corneal infection, and that although IL-1β processing by macrophages was completely dependent on caspase-1, neutrophil mediated IL-1β processing in vivo was not impaired in caspase-1-/- or in IPAF1-/- mice. In vitro studies showed that inhibition of neutrophil elastase significantly inhibited IL-1β processing by human and mouse neutrophils. Taken together, these results demonstrate a novel caspase-1 independent mechanism of IL-1β processing by neutrophils during bacterial infection.
Improved production of human beta-defensins (HBDs) in grafted site skin tissues of human IMC/mouse chimeras treated with glycyrrhizin (GL) (118.14)
Authors: Okita Yamato , Lee Jong , Nakamura Kiwamu , Kobayashi Makiko , Herndon David , Suzuki Fujio 
Published: January 2023

Abstract
Skin HBDs are very important on the elimination of pathogens at the burn wound infections. Immature myeloid cells (IMC) appearing in tissues surrounding the burn area are shown to be inhibitory on skin HBD production. In this study, the effect of GL on the impaired production of skin HBDs was studied in X-irradiated NOD-SCID IL-2rγ−/− mice (NSG mice) grafted with human IMC and their syngeneic skin tissues. NSG mice were grafted with patient skin (8 × 8 mm unburned skin removed for auto-graft surgery; skin-chimeras) and inoculated i.d. with 1 × 106 cells/mouse of CD34+CD31+ IMC isolated from the same burn patients (skin/IMC-chimeras). These chimeras were treated with 0.2 to 40 mg/kg of GL (Minophagen Pharmaceutical CO., LTD., Tokyo, Japan) 6 and 24 hrs after IMC inoculation. Two days after grafting, tissue specimens excised from grafted sites were homogenized, and the amounts of HBDs in the homogenates were measured. In the results, HBD1 and HBD2 were detected in the skin homogenates of skin-chimeras, while the peptides were not detected in the skin homogenates of skin/IMC-chimeras. However, HBDs were detected in the skin homogenates of skin/IMC-chimeras treated i.p. or i.d. with 3 to 10 mg/kg of GL. The greatest efficacy of GL on recovering HBD production was seen when skin/IMC-chimeras were treated i.d. with 10 mg/kg of GL. These results indicate that the impaired HBD production is improved in skin/IMC-chimeras treated with GL.
Extracellular superoxide dismutase impairs neutrophil function and clearance of Listeria monocytogenes (118.4)
Authors: Break Timothy , Jun Sujung , Indramohan Mohanalaxmi , Dory Ladislav , Berg Rance 
Published: January 2023

Abstract
It is well established that reactive oxygen species (ROS) play a critical role during immune responses against pathogens. Extracellular superoxide dismutase (ecSOD) regulates extracellular concentrations of ROS and protects tissues during non-infectious inflammatory insults. However, how ecSOD activity impacts immune responses directed against pathogenic microorganisms has not been thoroughly investigated. We utilized mice with varying levels of ecSOD activity to investigate the involvement of this enzyme in innate immune responses against Listeria monocytogenes. Our data demonstrate that ecSOD activity negatively impacted host survival and bacterial clearance from the spleen and liver. Paradoxically, ecSOD activity was associated with increased percentages of neutrophils in the livers of mice prior to, and during infection. Neutrophils from livers of mice with high ecSOD activity were altered in their ability to produce various molecules important for bacterial clearance. Additionally, ecSOD activity was associated with a higher percentage of neutrophils that phenotypically resembled myeloid-derived suppressor cells. Neutrophil depletion studies revealed that high ecSOD activity resulted in neutrophils with no protective capacity, whereas neutrophils from mice lacking ecSOD provided superior protection compared to neutrophils from wild-type mice. Collectively, our data demonstrate that ecSOD activity inhibits innate immune responses, thus impairing bacterial clearance.
Regulation of the inflammatory response: enhancing neutrophil infiltration under chronic inflammatory conditions (118.5)
Authors: Bian Zhen , Guo Yanan , Ha Binh , Zen Ke , Liu Yuan 
Published: January 2023

Abstract
Neutrophil (PMN) infiltration plays a central role in inflammation and is a major cause of tissue damage. Thus, PMN infiltration must be tightly controlled. Using zymosan-induced peritonitis as an in vivo PMN infiltration model, we show in this study that PMN response and infiltration were significantly enhanced in mice experiencing various systemic inflammation including colitis and diabetes. Adoptive transfer of leukocytes from mice with inflammation into healthy recipients or from healthy into inflammatory recipients followed by inducing peritonitis demonstrated that both circulating PMN and tissue macrophages were altered under inflammation and that they collectively contributed to enhanced PMN infiltration. Detailed analyses of dextran sulfate sodium (DSS)-elicited colitis revealed that enhancement of PMN infiltration and macrophage function occurred only at the post-acute/chronic phase of inflammation and was associated with markedly increased IL-17A in serum. In vitro and ex vivo treatment of isolated PMN and macrophages confirmed that IL-17A directly modulates these cells and significantly enhances their inflammatory responses. Neutralization of IL-17A eliminated the enhancement of PMN infiltration and IL-6 production and also prevented severe tissue damage in DSS-treated mice. Thus, IL-17A produced at the chronic stage of colitis serves as an essential feedback signal that enhances PMN infiltration and promotes inflammation.
Immunomodulatory effects of Simvastatin in Rheumatoid arthritis synoviocytes are mediated via BNIP3 (119.1)
Authors: Khan Mohammad Saeed , Al-Karakooly Zeiyad , Ali Nawab , Kannan Krishnaswamy 
Published: January 2023

Abstract
We investigated the anti-inflammatory effects of Simvastatin (SMV) in vitro, in fibroblast-like synoviocyte (FLS) cell lines from control and RA subjects, in the presence of an activated TLR2 signaling pathway. Cells (10^5 cells/well) were grown in 12-well culture plates and treated with SMV in triplicates for 4 hours and then treated with TLR2 ligand (Pam3CSK4) for 24-hours. Cytotoxicity was assessed by Alamar-blue assay, interleukin-6 (IL-6) by ELISA, reactive oxygen species (ROS) and apoptosis by flow cytometry. Inositol phosphates (IPs) were measured by labeling IPs with tritium in cell culture, followed by anion exchange chromatography and analyzed in a beta scintillation counter. Gene expression analysis of 84-ROS associated genes was performed using a real time PCR array profiling kit from SABiosciences. SMV caused dose-dependent cytotoxicity in both cell lines and this was due to apoptosis. Basal apoptosis was higher in normal than RA-FLS (14% vs 4.3%). ROS was increased modestly (5% basal to 12%). IL-6 increased and IP-1 and IP-2 decreased with SMV treatment. Gene expression of GSR, TXNRD1, PRDX1, SOD2, MT3 and PTGS2 were significantly upregulated. BNIP3 expression was increased 2200-fold in RA-FLS after SMV/TLR2 treatment. These findings indicate that SMV induce FLS apoptosis in RA by upregulating BNIP3 and FLS react to survive by increasing IL-6, decreasing IP-1 and IP-2 and upregulating anti-oxidant genes.
Defective regulatory T cells function and spontaneous colitis induced by protein phosphatase 4-deficiency (120.14)
Authors: Liao Fang-Hsuean , Lin Yu-Jun , Hsing En-Wei , Hsou Wan-I , Jhou Yi-Jyun , Tan Tse-Hua , Huang Ching-Yu 
Published: January 2023

Abstract
Protein phosphatase 4 (PP4) is essential during early T cells development. To assess the function of PP4 in peripheral T cells, we generated conditional PP4 knockout mice with CD4-cre transgene (CD4cre-PP4f/f). In these mice a partial block of thymocyte development was manifested as a ~40-60% reduction of peripheral T cells. Further studies showed that PP4 deletion resulted in poor T cell proliferation, inefficient Treg polarization, decreased Treg cell number and reduced Treg suppression activity. In vivo, CD4cre-PP4f/f mice exhibited defective T-dependent antibody production. More interestingly, by 5-month old ~50% of the CD4cre-PP4f/f mice developed spontaneous colitis with wasting syndrome, and showed increased percentages of IFNgamma+, IL-6+, or IL-17A+-producing cells in intra-epithelial lymphocytes and lamina propria lymphocytes. When investigating the pathogenesis of colitis, we found that transferring PP4-deficient CD4+CD45RBhigh cells failed to induce colitis in RAG-/- recipients, whereas antibiotics treatment could reverse the wasting syndrome. Combined with the defects in Treg and antibody production, these results are consistent with the possibility that PP4 deficiency reduced the efficiency of mucosal immunity against commensal bacteria, causing uncontrolled gut inflammation that eventually develop into colitis. The spontaneous colitis in CD4cre-PP4f/f mice may thus serve as an unique model for studying the pathogenesis of human inflammatory bowel disease.
EBI2 expression is associated with B cell inflammation in human sinuses (120.35)
Authors: Hulse Kathryn , Zhong Qiu , Mahdavinia Mahboobeh , Norton James , Kern Robert , Conley David , Chandra Rakesh , Tan Bruce , Peters Anju , Grammer Leslie , Harris Kathleen , Seshadri Sudarshan , Carter Roderick , Suh Lydia , Schleimer Robert 
Published: January 2023

Abstract
Epstein-Barr virus-induced G-protein coupled receptor 2 (EBI2) is important for the migration of B cells and induction of extrafollicular plasma cells within secondary lymphoid tissues. Recent studies from our group have demonstrated that many molecules associated with B cell survival and plasma cell differentiation (e.g. BAFF and immunoglobulins) were elevated in nasal polyps from patients with chronic rhinosinusitis (CRS). To investigate whether B cells or EBI2 played a role in CRS pathogenesis, expression of B cell- and EBI2-related genes in nasal tissue from normal controls and CRS patients with (CRSwNP) or without (CRSsNP) nasal polyps was assessed. EBI2 mRNA was quantitated by qRT-PCR, EBI2 protein was measured by western blot, and B cell subsets were characterized by flow cytometry. Expression of EBI2 mRNA was significantly elevated in polyp tissue (p&lt;0.001) and correlated with mRNA expression of CD20 (r=0.71; p&lt;0.0001) and CH25H, an enzyme responsible for production of an EBI2 ligand (r=0.65; p&lt;0.001). EBI2 protein was also elevated in polyps (p&lt;0.01, n=10). In addition, B cells (CD20+) and plasma cells (CD138+) were significantly elevated in polyps compared to nasal tissue from normal controls (p&lt;0.05). Collectively, these data suggest that elevated EBI2 may facilitate B cell migration and differentiation in the nasal mucosa, especially nasal polyps. These findings provide new insights into the pathogenesis of CRS and may indicate potential new therapeutic targets.
Examining the role of T cell co-receptors CD4 and CD8 in T cell activation by using high-affinity T cell receptors (121.28)
Authors: Marshall Elizabeth , Weber K. Scott , Donermeyer David , Allen Paul , Kranz David 
Published: January 2023

Abstract
The recognition of foreign antigens by T cells is accomplished through the binding of the T cell receptor (TCR) in collaboration with co-receptor (CD4 or CD8) recognition of MHC. It is clear that CD4 and CD8 function by binding to their cognate MHCs and by delivering the kinase Lck to the TCR complex for initiation of signaling, however, the mechanistic details of this process remain unclear. For example, it remains unknown if co-receptors must engage the same MHC as the TCR, or if engagement of a nearby non-cognate MHC molecule is sufficient to initiate signaling. To examine the details of co-receptor function, we used a class II MHC specific TCR system consisting of a wild-type (KD 20 μM) and high-affinity variant (KD 25 nM). A panel of T cell hybridomas was generated expressing either the wild-type or high-affinity TCR paired with either the CD4 or CD8 co-receptor. The low-affinity, but not the high-affinity, TCR required cognate CD4 for activity. Unexpectedly, non-cognate CD8 was able to enhance the activity of the low-affinity TCR, and CD8:class I MHC interactions were required for activity mediated by the high-affinity TCR. Unexpectedly, CD8 also operated by preventing apoptosis of the antigen presenting cells (APCs). These data show that CD8 can act by binding to non-cognate MHC, and that its functions extend to the prevention of apoptosis of APCs. The findings thus provide a framework for a new model of co-receptor function.
Ablation of PDK1 reduces CD4 T cell proliferation and alters cytokine production (121.6)
Authors: Yu Minjun , Ghosh Sankar , Farber Donna 
Published: January 2023

Abstract
In CD4 T cells, phosphoinositide-dependent protein kinase 1(PDK1) plays a crucial role in activating AGC kinases including Akt, p70 ribosomal S6 kinase, PKCθ, which control downstream proliferation, protein synthesis and NF-κB activation. We used mice with conditional expression of PDK1 (PDK1 floxed) and an YFP reporter (PDKF/FR26YFP) to assess the effect of PDK1 deletion on effector and memory CD4 T cell persistence, homeostasis and function. CD4 T cells were activated by anti-CD3/anti-CD28 antibodies and treated with TAT-Cre fusion protein. PDK1 knockdown was confirmed by PCR and western blotting of YFP+ cells which also showed reduced p70 S6 kinase phosphorylation. Transfer of primed PDK1 deficient effector T cells into Rag2-/- mice resulted in reduced persistence. This reduced persistence was associated with decreased proliferative turnover both in vivo and in vitro, but not an increase in apoptosis, as assessed by annexin V staining. PDK1 deficient effector and memory CD4 T cells reduced IL-2 production but IFN-γ production was intact. These results suggest that the PDK1 selectively controls effector CD4 T cell proliferation and IL-2 production with potential effects on memory CD4 T cells persistence in vivo.
Ikaros regulates naive CD8+ T cell autocrine IL-2 production and differentiation (121.7)
Authors: O'Brien Shaun , Thomas Rajan , Wells Andrew 
Published: January 2023

Abstract
Naive CD8+ T cell responses are regulated by signals from antigen, co-stimulatory molecules, and cytokines such as IL-2. CD8 T cells produce IL-2 only transiently after activation, and subsequently become dependent upon CD4+ T cells for their differentiation. The mechanism by which CD8 cells extinguish autocrine IL-2 production is unclear. We find that Ikaros, a DNA binding protein that negatively regulates IL-2 production by CD4+ T cells, also controls autocrine IL-2 production by CD8+ T cells. In an in vitro model devoid of CD4-derived signals, co-ligation of TCR and CD28 led to initial activation and expansion of naive CD8+ T cells, but wild-type cells failed to differentiate into IFN-γ-producing CTL unless exogenous IL-2 was added. Conversely, naive CD8+ T cells with reduced Ikaros activity due to loss of one copy of the ikzf1 gene exhibited sustained autocrine IL-2 secretion and could differentiate in response to TCR and CD28 alone. The IL-2 produced by ikzf1+/null CD8+ cells was required for their CD4-independent differentiation, as neutralizing IL-2 Ab abrogated IFN-γ production, and was sufficient to drive the differentiation of co-cultured wild-type CD8+ cells in a cell-extrinsic manner. These data show that Ikaros negatively regulates autocrine IL-2 production by CD8+ T cells as means to ensure that their differentiation remains dependent upon CD4+ T cell help. Ikaros may therefore be a crucial regulator of autoimmunity and tumor immunity.
Signaling via neurokinin 1 receptor is necessary for the development of efficient Th1 and Th2 immunity (122.2)
Authors: Ho Chin , Sumpter Tina , Tkacheva Olga , Shufesky William , Morelli Adrian , Larregina Adriana 
Published: January 2023

Abstract
The outcomes of the immune response depend on a delicate interaction of the immune and nervous systems. Although pro- and anti-inflammatory neuropeptides are secreted in lymphoid and peripheral organs, and immune cells secrete neuropeptides and express their receptors, the role of these mediators on Th1 and Th2 biased immunity is lacking. It has been postulated that substance P and hemokinin-1, the prototypic pro-inflammatory neuropeptides, promote Th1 biased autoimmunity by agonistic binding of the neurokinin-1 receptor (NK1R). We hypothesized that agonistic binding of NK1R favors Th1 as well as Th2 mediated immunity. To test our hypothesis, we compared delayed type hypersensitivity responses following in vivo treatment of C57BL/6 wild type (WT) or NK1RKO mice with either Th1 (2-4-dinitrochlorobenzene) or Th2 (fluorescein isothiocyanate) sensitizers. We show that NK1RKO mice had impaired development of both Th1 and Th2 immunity. Our results were further confirmed in WT mice treated with either of the NK1R antagonists L733,060 or RP67,580 prior to sensitization. Mechanistic analyses demonstrated that NK1R signaling was necessary to promote acute inflammation in skin and skin-draining lymph nodes as well as for the recall of effector immunity following elicitation. We conclude that NK1R signaling is required for efficient development of both Th1 and Th2 effector immune responses.
Inflammatory cytokines in the pathogenesis of autoimmune type 1 diabetes (123.21)
Authors: Ramanathan Sheela , Bobbala Diwakar , Chen Xi Lin , Mayhue Marian , Leblanc Chantal , Tanaka Toshiyuki , Chen Yi-Guang , Ilangumaran Subburaj 
Published: January 2023

Abstract
Inflammatory cytokines are implicated in the pathogenesis of different autoimmune diseases like Type 1 diabetes, Rhumatoid arthritis and inflammatory bowel disease in humans as well as in animal models. IL-21, and IL-15 are pro-inflammatory cytokines and they exert their biological effects at various stages of the immune responses. We have shown previously that IL-21 can synergize with IL-15 or IL-7 to reduce the threshold of TCR signaling, while simultaneously increasing the production of effector cytokines such as TNFα and IFNγ. IL-21 maps to one of the shared autoimmune disease susceptibility loci in humans and mice. In Non Obese Diabetic (NOD) mouse that develops spontaneous autoimmune type 1 diabetes (T1D), IL-21 is a candidate gene in the Idd3 locus. C57BL/6 derived Idd3 allele protects NOD mouse from T1D. As IL-2 also maps to the same locus, the relative contribution of IL-2 and IL-21 to the disease process is not well understood. It has been shown previously that NOD mouse lacking the receptor for IL-21 does not develop autoimmune diabetes. Here we report that the absence of IL-21 protects the 8.3 TCR transgenic NOD mice from diabetes. Similarly we observed that NOD mice that lack the expression of IL-15 show reduced incidence of type 1 diabetes. Our results suggest that IL-21 and IL-15 may be implicated at different stages of disease development in the NOD mouse model.
CD3 zeta chain deficient T cells instigate multi-organ tissue inflammation (123.35)
Authors: Deng Guo-Min , Beltran Jessica , Mizui Masayuki , Terhorst Cox , Tsokos George 
Published: January 2023

Abstract
A population of T cells that lack the CD3 zeta (ζ) chain exists in systemic lupus erythematosus (SLE), rheumatoid arthritis, cancer, and infectious diseases. SLE is a chronic autoimmune disease characterized by high production of autoantibodies and multi-organ tissue inflammation. However, the role of CD3ζ chain-deficient T cells in the pathogenesis of these disorders remains unknown. Here we show the role of CD3ζ chain deficient T cells in multi-organ tissue inflammation. We found that CD3ζ -deficient mice spontaneously developed multi-organ tissue inflammation that can be promoted following the injection of poly: (ic) or allogeneic cells. Interestingly, a humoral response did not accompany the cellular response. CD3ζ chain deficient T cells were found defective in activation-induced apoptosis, and to display aggregated lipid rafts in which CD44, and CCR2 colocalized and to produce IFN-γ. Anti-IFN-γ treatment of CD3ζ deficient mice inhibited spontaneous multi-organ tissue inflammation. Promotion and resolution of lipid raft aggregation resulted in enhanced and decreased IFN-γ production suggesting a clear role of aggregated lipid rafts in the production of IFN-γ. Our results demonstrate that CD3ζ chain deficient T cells instigate multi-organ tissue inflammation by enabling lipid raft aggregation. Thus we demonstrate that decreased CD3ζ chain expression in autoimmunity, cancer and infection, contributes independently to inflammation and damage.
Regulation of T cell metabolism and autoimmunity by the orphan nuclear receptor ERRγ (123.47)
Authors: Yin Yiming , Perry Daniel , Perl Andras , Morel Laurence , Telarico Tiffany 
Published: January 2023

Abstract
Autoreactive T cells and abnormal cytokine production are key features of human and mouse systemic lupus erythematosus (SLE). The SLE susceptibility locus Sle1c2 is associated with CD4+ T cell hyperactivation, hyperproliferation and hyperproduction of IFNγ in the NZM2410 mouse model. Sle1c2 contains two genes, only one of which, Esrrg, is expressed in mouse CD4+ T cells. qRT-PCR and Western blot analysis showed that Esrrg is expressed in CD4+ T cells, albeit at a low level. Esrrg expression is significantly decreased in B6.Sle1c2 CD4+ T cells as compared to B6, and negatively correlates with T cell activation. In vitro, Esrrg expression is dramatically decreased after CD4+ T cells are stimulated with anti-CD3/CD28. These data suggest that Esrrg is required to maintain T cells in a quiescent state. Esrrg is a key regulator of cell metabolism. Consistently, Sle1c2 is associated with increased expression of genes involved in the glycolytic pathway, such as MCT4 and Hif1a, which have been previously associated with enhanced T cell effector functions. Sle1c2 is also associated with a decreased mitochondrial mass and functions, which is consistent with Esrrg playing a key role in these processes. Furthermore, treatment of CD4+ T cells with ERRγ agonist and reverse agonist affects T cell survival, proliferation, Foxp3 expression, and IL-2 and IFNγ production. Our study suggests that decreased Esrrg expression contributes to T cell autoimmunity through regulating cell metabolism.