bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic deletion of chemokine receptor Ccr6 decreases atherogenesis in ApoE-deficient mice (117.2)
Authors: Wan Wuzhou , Lim Jean , Lionakis Michail , Rivollier Aymeric , McDermott David , Kelsall Brian , Farber Joshua , Murphy Philip 
Published: January 2023

Abstract
Background—The chemokine receptor CCR6 and its ligand CCL20 are both expressed in human atheroma; however, their functional roles in atherogenesis remain undefined. Here, we addressed this question in the apolipoprotein E-deficient (ApoE-/-) mouse model of atherosclerosis. Methods and Results—Both Ccr6 and Ccl20 are expressed in atherosclerotic aorta from ApoE-/- mice. Atherosclerotic lesion area in the aorta in Ccr6-/-ApoE-/- mice was ~40% and ~30% smaller than in Ccr6+/+ApoE-/- mice at 16 and 24 weeks of age, respectively. In addition, lesions of Ccr6-/-ApoE-/- mice had 44% less macrophage content compared to Ccr6+/+ApoE-/- mice. Since monocytes are the source of lesional macrophages, we tested whether monocytes express Ccr6 and the effect of Ccr6 deletion on monocyte function. We found that Ccr6 was expressed on a subset of primary mouse monocytes and on the mouse monocyte/macrophage cell line RAW 264.7. The receptor was functional, as defined by Ccl20-induced chemotaxis of primary monocytes from wild type but not Ccr6-/- mice; moreover, Ccl20 induced monocytosis in ApoE-/- mice in vivo. Consistent with this, we observed 30% fewer monocytes in the circulating blood of Ccr6-/-ApoE-/- mice, mainly due to fewer CD11b+Ly6Chigh inflammatory monocytes. Conclusions—We conclude that Ccr6 promotes atherosclerosis in ApoE-deficient mice. This may be due in part to Ccr6 support of normal monocyte levels in blood in the model, as well as direct Ccr6-dependent monocyte migration.
Acute exercise alters the Type 1/Type 2 cytokine balance in both low (CD27+) and highly (CD27-) differentiated subsets of CD4+ and CD8+ T cells (117.23)
Authors: LaVoy Emily , Lowder Thomas , Simpson Richard 
Published: January 2023

Abstract
Highly differentiated T cells are preferentially mobilized into the peripheral blood in response to exercise, which may explain some of the observed changes in immune function that occur with strenuous exercise. Although acute exercise has been shown to alter the type1/type2 cytokine balance, no study has attempted to document if this is due to increased frequency of highly differentiated T cells in the periphery. Eight trained male cyclists (Age: 31±6.1 yrs) cycled for 60-min at 95% maximal steady state. Blood samples collected before, immediately after, and 1h after exercise were prepared for cell culture and flow cytometry analysis. Proportions of highly differentiated (KLRG1+CD28-;CD45RA+CD27-) T cells increased immediately after exercise. This was accompanied by decreased intracellular expression of IL-2, IL-4, IL-6, TNF-α, and IFN-γ, and increased IL-10 in T cells following mitogen stimulation. Cytokine changes with exercise were similar in both CD27+ (low differentiated) and CD27- (highly differentiated) cells. Independently of exercise, CD27+ cells produced more IL-2 and IL-6 but less TNF-α and IFN-γ than CD27- cells. These data indicate that acute exercise alters the type1/type2 cytokine balance in response to mitogen stimulation, but independently of altered proportions of low and highly differentiated T-cells. Future work will attempt to establish mechanisms for this response and the role that type 1/type 2 cytokine shifts might play in athlete infection risk.
Paracrine IL-33 stimulation enhances lipopolysaccharide-mediated macrophage activation (117.30)
Authors: Ohno Tatsukuni , Nakae Susumu , Azuma Miyuki 
Published: January 2023

Abstract
BACKGROUND: IL-33, a member of the IL-1 family of cytokines, provokes Th2-type inflammation accompanied by accumulation of eosinophils through IL-33R, which consists of ST2 and IL-1RAcP. We previously demonstrated that macrophages produce IL-33 in response to LPS. Some immune responses were shown to differ between ST2-deficient mice and soluble ST2-Fc fusion protein-treated mice. Even in anti-ST2 antibody (Ab)-treated mice, the phenotypes differed between distinct Ab clones, because the characterization of such Abs (i.e., depletion, agonistic or blocking Abs) was unclear in some cases. METHODOLOGY/PRINCIPAL FINDINGS: To elucidate the precise role of IL-33, we newly generated neutralizing monoclonal Abs for IL-33. Exogenous IL-33 potentiated LPS-mediated cytokine production by macrophages. That LPS-mediated cytokine production by macrophages was suppressed by inhibition of endogenous IL-33 by the anti-IL-33 neutralizing mAbs. CONCLUSIONS/SIGNIFICANCE: Our findings suggest that LPS-mediated macrophage activation is accelerated by macrophage-derived paracrine IL-33 stimulation.
Distribution of cells and cytokines in the spleen of dogs naturally infected with Leishmania chagasi (117.31)
Authors: Silva Joselli , Andrade Alan , Santana Claudia , Tavares Veras Patricia , Vassalo José , Conrado-Dos Santos Washington 
Published: January 2023

Abstract
Visceral leishmaniasis is associated with architectural disorganization of the splenic tissue in human and in dogs. In this study we estimate the changes in the number of Ki-67+ (proliferating cells), CD3+ (T cells), α-CD79+ (cells B) and S100+ (follicular dendritic cells) and in the expression of CXCL13, LTα, TNF, IFN-gamma, IL10, TGFbeta, CCR7, CCL19, CCL21 in the spleens of dogs from an endemic area of visceral leishmaniasis, with organized or disorganized splenic architecture. The number of T cells, B cells, proliferating cells and follicular dendritic cells was lower in the lymphoid follicle of the animals with disorganized splenic tissue than in animals with organized splenic tissue (P &lt; 0.01). The number of B cells was also reduced in the MZ of animals with disorganized splenic tissue (P &lt; 0.01). B cells (P &lt; 0.01) and proliferating cells (P &lt; 0.05) density was lower in the lymphoid follicles of animals with disorganized splenic tissue. CXCL13 (P &lt; 0.02) and LT-α (P &lt; 0.05) expressions were lower in the spleens of animals with disorganized splenic tissue than with organized splenic tissue. There is a correlation between the disorganization of the splenic tissue and abnormal cell distribution and expression of cytokines involved in architectural organization of the splenic lymphoid tissue. These alterations of the spleen may impair leukocyte cooperation against infection by ,Leishmania and other pathogens.
Trans-signaling mediates some key actions of interleukin-6 in the central nervous system (117.6)
Authors: Campbell Iain , Lim Sue , Frausto Ricardo , Rose-John Stefan , Scheller Jürgen 
Published: January 2023

Abstract
IL-6 which is implicated in the pathogenesis of immunoinflammatory disorders of the CNS, signals via binding to either the membrane bound IL-6Rα (classical signaling) or soluble (s)IL-6Rα (trans-signaling) that then form a complex with gp130 to activate the JAK/STAT and SHP2/MAPK pathways. Here we determined the relative importance of classical- versus trans-signaling in mediating IL-6 actions in the CNS. Bigenic mice were generated with CNS-restricted, astrocyte-targeted production of IL-6 and the specific inhibitor of IL-6 trans-signaling, sgp130-Fc (termed GFAP-IL6/sgp130 mice). Transgene-encoded IL-6 mRNA levels were similar in the brain of GFAP-IL6 and GFAP-IL6/sgp130 mice. However, GFAP-IL6/sgp130 mice had decreased pY-STAT3 in the brain due to a marked reduction in the total number of pY-STAT3-positive cells and the absence of detectable pY-STAT3 in specific cell types. These changes in pY-STAT3 were associated with disproportionate reductions in various inflammatory markers as well as reduced vascular pathology and blood-brain barrier leakage. Degenerative changes in the cerebellum characteristic of GFAP-IL6 mice were almost absent in GFAP-IL6/sgp130 mice. The findings suggest that in the CNS: (i) sgp130-Fc is able to block IL-6 trans-signaling, (ii) trans-signaling is important for IL-6 cellular communication with selective cellular targets and, (iii) the blocking of trans-signaling may prove to be an effective means for alleviating the detrimental effects of IL-6.
In vivo consequences of liver-specific interleukin-22 expression: implications for human liver disease progression (117.7)
Authors: Park Ogyi , Wang Hua , Weng Honglei , Li Hai , Yin Shi , Feigenbaum Lionel , Ki Sung-Hwan , Yoo Seong Ho , Dooley Steve , Wang Fu-sheng , Young Howard , Gao Bin 
Published: January 2023

Abstract
Interleukin 22 (IL-22), which acts as either a pro-inflammatory or anti-inflammatory cytokine in various disease models, is markedly upregulated in chronic liver diseases, including viral hepatitis B and C infection. In this report, we demonstrate a strong correlation between IL-22 expression in the liver with active, inflammatory human liver disease. To clarify the role of IL-22 upregulation in the pathogenesis of liver diseases, liver specific IL-22 transgenic (IL-22TG) mice, under the control of albumin promoter, were developed. Despite elevated IL-22 serum levels ranging from 4000 to 7000 pg/ml, IL-22TG mice developed normally without obvious adverse phenotypes or evidence of chronic inflammation. Most interestingly, IL-22 TG mice were completely resistant to Concanavalin A-induced T cell hepatitis with minimal effect on liver inflammation and had accelerated liver regeneration after partial hepatectomy. Although they did not spontaneously develop liver tumors, IL-22 TG mice were more susceptible to diethylnitrosamine-induced liver cancer. Microarray analyses revealed that a variety of anti-oxidant, mitogenic, acute phase genes were upregulated in the livers from IL-22TG mice compared with those from wild-type mice. These findings indicate that localized production of IL-22 in the liver promotes hepatocyte survival and proliferation but primes the liver to be more susceptible to tumor development without significantly affecting liver inflammation.
IL-21R is required for the systemic accumulation of activated B and T lymphocytes in MRLlpr mice (117.9)
Authors: Andreyeva Tatyana , Rankin Andrew , Guay Heath , Herber Deborah , Carrier Yijun , Mayra Senices , Stedman Nancy , Ryan Mark , Bloom Laird , Medley Quintus , Collins Mary , Nickerson-Nutter Cheryl , Young Deborah , Dunussi-Jannopoulos Kyri 
Published: January 2023

Abstract
IL-21 is a pleiotropic cytokine that can influence the activation, differentiation and expansion of B and T cells. Lupus prone MRL/MpJ-Faslpr/lpr/J (MRLlpr) mice have been shown to develop renal pathology and autoantibodies in an IL-21 dependent manner. We generated MRLlpr mice deficient in IL-21 receptor (MRLlpr.IL-21R-/-) to assess the impact of loss of IL-21R signaling on the systemic B and T cell lymphoaccumulation and activation that occurs in MRLlpr mice. Consistent with therapeutic blockade of IL-21, MRLlpr.IL21R-/- mice developed reduced proteinuria, renal pathology and serum IgG autoantibody levels. Lymphoaccumulation was significantly reduced in MRLlpr.IL-21R-/- mice, as evidenced by decreased lymphadenopathy and splenomegaly. Importantly, spontaneous germinal center formation and plasma cell accumulation were absent in IL-21R deficient MRLlpr mice. In addition, activated CD4+ CD44+ CD62Llo T cells failed to accumulate. We also demonstrate that T extrafollicular helper cells, which are a subset of activated CD4+ T cells that are reported to be the primary inducers of antibody production in MRLlpr mice, require IL-21R for their generation. T helper cell differentiation was also found to be impacted by loss of IL-21R, as IFN-γ producing CD4+ T cells were significantly reduced in MRLlpr.IL21R-/- mice. Together, our data highlight that IL-21 promotes multiple pathogenic B and T cell effector responses in MRLlpr mice.
Autoimmunity-associated LYP regulates T cell receptor signaling and thymus development (148.21)
Authors: Wang Yaya , Sawatzke Kristy , Zhou Wenbo , Ellingson Sonja , Peterson Erik 
Published: January 2023

Abstract
A single nucleotide polymorphism (SNP) in the PTPN22 gene, which encodes the lymphoid tyrosine phophatase LYP, is associated with increased risk of Rheumatoid Arthritis and other autoimmune diseases. LYP inhibits T cell receptor (TCR) signaling by dephosphorylation of Lck and Zap70. The disease associated LYP R620W (LypW) protein caused by the missense C1858T SNP in PTPN22 appears to exert “gain-of-function” effects upon TCR activation. Here we show that LypW negatively regulates TCR-induced intracellular Ca2+ flux, tyrosine phosphorylation, MAPK activation, and NFAT response element transactivation in Jurkat cells. The effects of LYP on TCR signaling are dependent on its enzymatic function. Studies from ptpn22−/− mice shows that PTPN22 regulates thymocyte positive selection. To evaluate effects of LypW expression on lymphocyte selection and function, we generated BAC transgenic mice bearing either the major human PTPN22 allele (LypR) or LypW. In contrast to intact positive selection in LypW H-Y TCR transgenic female mice, we observed impaired negative selection in LypW, but not LypR, H-Y male mice. These findings suggest that susceptibility to autoimmune diseases in LypW-carrying people may result from enhanced presence of autoreactive T cell in the peripheral repertoire, due to impaired thymocyte deletion. Together, our data suggest a thymic developmental mechanism whereby a “gain of function” Lyp variant can predispose to autoimmune disease.
Immunogenic potential of mutations in mitochondrial DNA and possible implications in autoimmune disease (148.22)
Authors: Duvvuri Bhargavi , Duvvuri Venkata , Chen Lina , Wang Chao , Jamnik Roni , Grigull Jörg , Watts Tania , Wu Gillian 
Published: January 2023

Abstract
To seek the underlying cause of autoimmune diseases we tested the hypothesis that mutated self proteins from mitochondria are seen as foreign proteins. A total of 21 mitochondrial peptides were identified using epitope prediction tool, SYFPEITHI as likely HLA-A2 restricted peptides. In vitro T cell line assays were conducted based on MHC stabilization of the peptides on T2 cells. Ten peptides were identified and the significant correlations were observed between the insilico and in vitro binding affinities. To determine the frequency of T cellular memory for the identified mutated peptides, PBMCs from healthy donors were tested in INF gamma-ELISpot assays. Frequencies of T cells recognizing mutated self peptide ranged from as few as 10 in 200,000 to 90 in 200,000 of the PBMCs plated. Among A2-donors, significant T cell responses were seen with mean age of 61 years. Of the 21 peptides two peptides, named as P10 and P14 were identified to be immuno-dominant peptides based on the immunogenic response by most of the donors (both A2 and non-A2) tested. To further determine the phenotype of the responding T cells, T cell co-stimulation assays were done for selected peptides based on T2 binding and Elispot assay results. T cell co-stimulation assays further confirmed Elispot results and interestingly, both interferon gamma producing CD8+T cells and CD4+ T cells were identified. We propose and will discuss the role of these immunogenic peptides as “Enemies with-in”.
Up-regulation of MCP-1 and RANTES by cartilage (149.10)
Authors: Merly Liza , Smith Sylvia 
Published: January 2023

Abstract
Immunomodulation refers to changes in an organism’s immune response by factors that either activate or suppress immune function. In previous studies we have shown the presence of immunomodulatory factor(s) in commercial shark cartilage (SC) extracts. Cartilage extracts induce various inflammatory cytokines and a potent chemokine in human peripheral blood leukocytes (HPBL). The cytokine induction profile of SC-stimulated cells includes potent Th1 type cytokines, such as IL-2, TNFα, IFNγ, and IL-1β, two of which are characteristically involved in inflammatory responses and an inflammatory chemokine, IL-8. To further delineate the HPBL response to SC, supernatants from both short-term and long-term primary HPBL cultures were assayed for two potent mediators, macrophage chemoattractant protein 1(MCP-1) and RANTES, by ELISA. Within 4 hours, SC-treated leukocytes produced significantly (p &lt; 0.05) elevated levels of MCP-1 when compared to cultures treated with medium alone and the response was similar to that seen in LPS-treated cultures. After 24 hours, however, the response to LPS was significantly reduced while the response to SC was consistently maintained through 96 hours. In contrast, the production of RANTES by both un-stimulated and stimulated HPBL was relatively consistent through the first 12 hours of culture. RANTES levels in leukocytes treated with medium alone decreased gradually after 24 hours, while those of LPS- and SC-treated cultures remain elevated.
Notch1 produces a deregulation of CXCR4/SDF-1 chemokine signaling in multiple myeloma cells (149.12)
Authors: Mirandola Leonardo , Apicella Luana , Colombo Michela , Carluccio Silvia , Platova Natalia , Comi Paola , Cobos Everardo , Kast W. , Chiriva Maurizio , Chiaramonte Raffaella 
Published: January 2023

Abstract
Notch deregulation occurs in several solid and hematopoietic tumors. Recently, the Notch receptor oncogenic role has been shown to be critical in multiple myeloma (MM) which frequently displays deregulation of the Notch ligand, Jagged2. MM is a malignant disorder of Ig-secreting plasma cells which accumulate in the bone marrow and cause bone lesions through stimulation of osteoclast activity. Several chemokines and their receptors (CRs) are critical in MM progression. Particularly, the axis SDF1-a/CXCR4 promotes MM cell growth, recruiting in the bone marrow compartment, apoptosis resistance, angiogenesis and osteolysis. This work aims to explore the effects of the Notch oncogenic pathway on the expression and function of a number of CRs and correspondent ligands which display a critical role in MM. Our results indicate that Notch pathway plays a regulative role on the expression and function of CXCR4/SDF-1α axis in different MM cell lines including RPMI-8226, KMS-12 and OPM-2.
Chemokine receptor expression on T and B cells in a murine model of ovalbumin-induced allergic airway disease (149.17)
Authors: Natarajan Prabitha , Guernsey Linda , Secor Eric , McNamara Jeffrey , Schramm Craig , Thrall Roger 
Published: January 2023

Abstract
In our biphasic Ovalbumin (OVA)-induced Allergic Airway Disease model, short-term exposure to OVA aerosols results in Allergic Airway Disease (AAD) whereas continued exposure leads to the resolution of disease and the development of Local Inhalational Tolerance (LIT). We have shown in adoptive transfer studies that Hilar Lymph Node (HLN) B cells of LIT mice suppress development of AAD. To understand trafficking of B cells within HLN, we assessed their expression of CXCR4 and CXCR5 chemokine receptors via flow cytometry in mice at various stages of the model: naïve, sensitized, AAD and LIT. B cell populations were divided into CD5+ and CD5- cells. Our data demonstrates that there was a significant increase in the number and percentage of total B cells expressing CXCR4 in the HLN of mice at AAD and LIT compared to naïve and sensitized mice. We also observed a significant increase in CXCR4 expression on CD5+ B cells compared to CD5- B cells. We also studied the chemokine receptor expression on T cells and observed that Foxp3+ T regulatory cells significantly increased the expression of CXCR4 at AAD and LIT. CXCR4 expression on B cells is required for germinal center development in lymphoid organs. It is unusual to find CD5+ B cells in lymph nodes. We hypothesize that these CD5+ B cells may be directly interacting with effector T cells in a regulatory manner converting them into regulatory T cells within germinal centers and hence contributing to the resolution of AAD.
A persistent loss of cytokine responsiveness defines CD8+ memory T cell function (150.2)
Authors: Perona-Wright Georgia , Kohlmeier Jacob , Mohrs Katja , Cookenham Tres , Woodland David , Mohrs Markus 
Published: January 2023

Abstract
Cytokines are soluble signaling molecules that orchestrate immune responses, regulating both immune protection and immunopathology. T cell differentiation is characterized by distinctive changes in cytokine production, but less is known about concomitant changes in cytokine responsiveness. Here we report that CD8+ T cell differentiation imposes permanent alterations in the cytokine receptor repertoire. We show that influenza virus-specific CD8+ memory T cells in both humans and mice lose responsiveness to interleukin (IL)-27. This loss is due to persistent downregulation of the shared gp130 cytokine receptor chain on effector and memory T cells and occurs as a direct consequence of antigenic stimulation. Loss of IL-27 responsiveness renders CD8+ memory T cells deficient in their expression of the immunosuppressive cytokine IL-10 during recall responses. Together our data reveal a previously unappreciated feature of CD8+ T cell differentiation, in which the selective and persistent loss of specific cytokine receptors defines the functional potential of memory cells during rechallenge. The altered cytokine responsiveness of effector and memory T cells has fundamental implications for the functional manipulation of these cells in vivo.
IL-2 production in human memory CD8+ T cells depends on ERK1 expression (150.7)
Authors: Kim Tae Kon , Benjamin Cara , Ma Qing , Eric Wieder , Komanduri Krishna 
Published: January 2023

Abstract
Recently, we showed that human late memory (CD45RA+CD27-) CD8+ T cells have a unique cytokine signature characterized by the lack of IL-2 production, and no IL-2/IFNγ co-production. Prior studies have suggested the importance of ERK1/2, in IL-2 production; however, little is known about the individual contributions of ERK isoforms to the functional signatures of human T cell subsets. We developed flow cytometric methods to study the differential expression of ERK1 and ERK2 in CD8+ T cell maturation subsets in association with their cytokine signatures. We found that the expression of total ERK1, but not ERK2 nor Ras/Raf/MEK1/MEK2, are diminished by ~80% (measured by flow cytometry and western blotting) in late memory CD8+ T cells, in comparison to early memory CD8+ T cells. Consequently, the diminished expression of total ERK1 resulted in decreased total and phosphorylated ERK1/2. In addition, total ERK1 expression in CD8+ T cells was bimodal on flow cytometry (ERK1high and ERK1low) and consistently identified the subset of memory CD8+ T cells capable (ERK1high) or incapable of IL-2 production (ERK1low) (mean IL-2 production in ERK1high vs. in ERK1low: 20% vs. 1.5%, (n=9, p=0.0039)). Interestingly, late memory cells transduced with lentivirus-expressing ERK1 cDNA, produced 2.5 times more IL-2 than control (n=3, p&lt;0.05). Collectively, these data suggest that the capacity to produce IL-2 in human memory CD8+ T cells is determined by ERK1 expression.
Mast cell ADAM-10 expression is blocked by IL-10 and may regulate CD23 levels on B cells (151.12)
Authors: Faber Travis , Conrad Daniel , Pullen Nicholas , Ryan John 
Published: January 2023

Abstract
Asthma is an inflammatory lung disease that is caused in part by mast cell activation via IgE antibodies. IgE is produced by B cells, and suppressed when IgE binds to the B cell receptor CD23. Recent data have demonstrated that CD23 expression is blocked by the protease ADAM-10. We demonstrate that mast cells abundantly express ADAM-10 in vitro and in vivo. Surface ADAM-10 expression is suppressed by the cytokine IL-10 via a Stat3-dependent mechanism that also reduces ADAM-10 mRNA expression. Preliminary experiments indicate that ADAM-10 expression may allow mast cells to regulate CD23 levels on B cells. Our data support the hypothesis that ADAM-10 may function in feedback loops regulating mast cell activation.