bluuebunny/crossref_metadata_2025_split huggingface dataset:
A CCR2/CCR5-dual antagonist, BMS-A, offers a potential novel oral therapy for the treatment of autoimmune disease (92.6)
Authors: Zhao Qihong , Pang Jian , McIntyre Kim , Gilloolly Kathleen , Townsend Robert , Postelnek Jennifer , Grafstrom Robert , He Bokang , Ford Gregory , Conarello Stacey , Xie Jenny , Davies Paul , Barrish Joel , Trzaskos James , Salter-Cid Luisa , Mckinnon Murray , Mandlekar Sandhya , Carter Percy 
Published: January 2023

Abstract
CCR2 and CCR5 are two chemokine receptors that are important in the pathogenesis of animal models of autoimmune diseases. Since the two receptors play complementary roles in the immune system, targeting both receptors simultaneously might afford greater efficacy than targeting either alone. The present study describes the identification and characterization of BMS-A, an orally bioavailable small-molecule CCR2/5-dual antagonist. BMS-A was identified as active against CCR2 and CCR5 in radioligand binding assays. Functional assays and biochemical studies demonstrate that it is a potent, selective, competitive, and reversible antagonist against both receptors. It is also a pan-antagonist in that it inhibits functional responses triggered by all ligands of both receptors. When studied in vivo in CCR2-dependent homeostatic and inflammatory models in mouse as well as monkey, BMS-A potently inhibits monocyte trafficking. Its in vivo activity against CCR5-mediated inflammatory processes was established in a CCR2-null mouse model of inflammation, wherein it further reduces macrophage infiltration into tissue. In mouse models of autoimmune disease, such as collagen-induced arthritis, BMS-A robustly reduces the clinical score and tissue destruction, as well as local and systemic inflammation. Thus, BMS-A is potentially a novel oral therapy for the treatment of autoimmune disease.
5-Lipoxygenase mediates IL-4-induced ROS generation and MCP-1 expression in human aortic endothelial cells (93.12)
Authors: Kim Paul H. , Lee Won Hee , Lee Yong Woo 
Published: January 2023

Abstract
Pro-oxidative and pro-inflammatory pathways in vascular endothelium have been implicated in the critical early pathological events in atherosclerosis. The present study was designed to investigate the role of 5-lipoxygenase (5-LOX) in IL-4-induced reactive oxygen species (ROS) generation and MCP-1 expression in vascular endothelium. Real-time RT-PCR and ELISA showed that IL-4 significantly up-regulated the mRNA and protein expression of MCP-1 in primary human aortic endothelial cells (HAEC) and mouse aortas. To determine whether 5-LOX is involved in IL-4-induced MCP-1 expression, HAEC were pre-treated with nordihydroguaiaretic acid (NDGA), a selective 5-LOX inhibitor, for 30 min and then exposed to 10 ng/ml of IL-4. Inhibition of 5-LOX by NDGA significantly attenuated IL-4-induced overexpression of MCP-1 mRNA and protein in HAEC. Additionally, dihydroethidium (DHE) and dichlorodihydrofluorescein (DCF) fluorescence staining showed that pre-treatment of HAEC with NDGA significantly suppressed IL-4-induced ROS generation. Our results suggest that IL-4 induces ROS generation and MCP-1 expression in vascular endothelium through 5-LOX-dependent pathway. These data may contribute to understanding the cellular and molecular mechanisms involved in IL-4-mediated progression of atherosclerosis. (This work was supported by NIH/NHLBI [Grant#R15HL085229] and NSF MILES IGERT).
Therapeutic use of proteasome inhibitors in bacterial superantigen- and LPS-induced acute systemic inflammatory response syndromes (93.13)
Authors: rajagopalan govindarajan , Tilahun Ashenafi Y , David Chella S 
Published: January 2023

Abstract
Bacterial superantigen-induced toxic shock syndrome (TSS) and sepsis are characterized by a profound systemic inflammatory response. Given the important role of NF¿B pathway in inflammation, we investigated whether a clinically approved proteasome inhibitor, Bortezomib, capable of inhibiting NF¿B pathway, be of therapeutic use in such conditions using HLA class II transgenic mice. Bortezomib significantly blocked staphylococcal enterotoxin B (SEB)-induced T cell activation and cytokine production in vitro. In SEB-induced TSS, in vivo administration of Bortezomib significantly reduced serum levels of several pro-inflammatory cytokines and chemokines. Nevertheless, 100% of SEB challenged mice treated with Bortezomib succumbed to TSS, and Bortezomib sensitized mice to TSS at concentrations of SEB which are otherwise non-lethal (i.e., as low as 2 μg/mouse), even when administered 24 hours after exposure to SEB. Sensitization to TSS by Bortezomib was not due to the pro-apoptotic effects of Bortezomib. Serum biochemical parameters and histopathological findings suggested acute liver failure as the possible cause of mortality. In sepsis model, whereas LPS alone (10 μg/mouse) was seldom lethal, it was uniformly lethal when administered along with Bortezomib. In conclusion, Bortezomib sensitizes mice to certain acute systemic inflammatory diseases.
Supported by R01AI068741 and AI 72211
Systemic Inflammation in Murine Choroidal Neovascularization (CNV) (93.14)
Authors: Raikwar Himanshu P , Coughlin Beth , Rohrer Baerbel M 
Published: January 2023

Abstract
Laser-induced photocoagulation of RPE-Bruch's membrane is a conventional method of inducing CNV in mice, which resembles in many aspects the pathology of human exudative age-related macular degeneration (AMD). The presence of complement components and inflammatory cells in the CNV and AMD lesions support an "inflammation-related theory of AMD". Here we further examined the inflammatory processes in experimentally-induced CNV in mice. The spleens of CNV mice were enlarged on day 6, with a corresponding increase in weight and cellularity of spleenic mass. In particular the CD11b (monocyte/macropgage) population was increased. At the protein level, T-bet, transcription factor for IFNγa proinflammatory/Th1 cytokine, was upregulated in the spleen. Furthermore serum levels of IFNγand anaphylotoxin were elevated in CNV mice. Taken together, CNV seems to involve both the innate (complement system) and adaptive (Th1) immune response, acting both locally within the eye as well as systemically. Distinguishing the different contributions of local and systemic effects to CNV might aid in the design of treatment strategies.
This work was supported in part by the Foundation Fighting Blindness, and an unrestricted grant to MUSC from Research to Prevent Blindness, Inc., New York, NY. BR is a Research to Prevent Blindness Olga Keith Weiss Scholar.
Anti-inflammatory Adjuvants in Resuscitation Fluids Improves Survival in Experimental Hemorrhage (93.15)
Authors: Dong Weihong , Cai Bolin , Pena Geber , Pisarenko Vadim , Lee Marlon , Ramos Laura , Deitch Edwin , Ulloa Luis 
Published: January 2023

Abstract
Conventional resuscitation fluids reestablish tissue perfusion, but they fail to prevent lethal inflammatory responses. We reasoned that ethyl pyruvate (EP) can provide a therapeutic anti-inflammatory potential to improve survival during resuscitation. Survival, organ damage, inflammatory responses and characteristic pathways were analyzed after resuscitation of hemorrhagic rodents and swine. All control rodents and swine without resuscitation died within the first 6 hrs after hemorrhage. Resuscitation with Hextend reestablished arterial blood pressure and tissue perfusion, yet 90% of the animals died within 6 hrs after hemorrhage. All the animals treated with 50 mM EP survived hemorrhage. EP prevented systemic inflammation and improved survival in a concentration dependent manner. Unlike Hextend, resuscitation with EP ablated TNF and HMGB1 production, preserved the intestinal epithelium, and prevented bacterial endotoxin in the serum. From a molecular perspective, EP inhibited NF-kB and PARP activation without affecting IKBa activation in major organs and culture of macrophages. USAMRMC#05308004, AHA06352230N, NIH-GM084125.
Visualizing the rapid and localized keratinocyte expression of dendritic epidermal T cell antigens in response to wounding (93.3)
Authors: Komori Heather Kiyomi , Witherden Deborah A , Teyton Luc , Havran Wendy L 
Published: January 2023

Abstract
Within the skin, dendritic epidermal T cells (DETC) function at the interface of innate and adaptive immunity, playing important roles in homeostasis, tumor surveillance and wound repair. Central to their role in wound repair is stimulation of DETC through their monoclonal Vγ3Vδ1 T cell receptor (TCR) by an uncharacterized antigen expressed on stressed keratinocytes. While only DETC proximal to the wound site become activated, expression patterns and kinetics of antigens that stimulate DETC activation are uncharacterized. Using soluble DETC TCR tetramers, we show that the DETC TCR binds to a glycosylated, cell surface expressed, protein that is constitutively expressed by transformed epithelial cell lines in vitro. Additionally, in situ studies show that DETC TCR ligands are rapidly upregulated by keratinocytes proximal, but not distal to, wound edges. Following antigen expression, DETC become activated and antigen expression is subsequently down-modulated. Furthermore, inhibition of TCR-ligand interactions using DETC TCR tetramers delays wound repair in vivo, highlighting the importance of rapid, TCR mediated, DETC activation by keratinocytes for proper wound healing. This study represents the first visualization of DETC TCR ligand expression by keratinocytes in murine skin and provides a mechanism for the rapid and localized activation of DETC in response to wounding. Supported by the National Institutes of Health (AI064811 to W.L.H, A142267 to L.T.), and the National Science Foundation Graduate Research Fellowship to H.K.K.
Beneficial effects of fullerene derivative on lipopolysccharide-induced pro-inflammatory pathways in human aortic endothelial cells (93.9)
Authors: Lee Won Hee , Kim Paul H. , Lee Yong Woo 
Published: January 2023

Abstract
Inflammation in vascular endothelium has been implicated in the critical early pathological events in atherosclerosis. The present study was designed to examine the hypothesis that fullerene derivative, polyhydroxylated fullerene [C60(OH)18±22], may attenuate pro-inflammatory pathways in human aortic endothelial cells (HAEC). The quantitative real-time RT-PCR, enzyme-linked immunosorbent assay (ELISA), and cell-based enzyme-linked immunosorbent assay (CELISA) showed that pre-treatment of HAEC with increasing concentrations of polyhydroxylated fullerene (5, 25, and 50 μM) significantly and dose-dependently attenuated lipopolysaccharide (LPS)-induced up-regulation of mRNA and protein expression of pro-inflammatory mediators such as interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin. Our results suggest that polyhydroxylated fullerene may play a potential protective role in the progression of atherosclerosis via its anti-inflammatory action. Additionally, it will provide insights to novel preventive and therapeutic approaches for atherosclerosis specifically targeted against pro-inflammatory pathways in vascular endothelium (This work was supported by the Institute for Critical Technology and Applied Science).
CXCR3-dependent mechanisms are required for plasma cell recruitment into the CNS (94.18)
Authors: Marques Cristina P. , Sedlack Stefanie N. , Stohlman Stephen A. , Bergmann Cornelia C. 
Published: January 2023

Abstract
CXCR3 and its ligands, CXCL-9, -10, and -11 regulate T cell trafficking to sites of infection, but their role in recruiting antibody secreting cells (ASC) is unknown. Neurotropic coronavirus induces CXCR3 ligands early during infection, and CXCL10 remains elevated throughout CNS persistence. In addition, lymph nodes reveal increased CXCR3 expression on ASC prior to their accumulation in the CNS. CXCR3-dependent ASC recruitment was thus studied in CXCR3-/- mice, as well as following CXCL10 neutralization. Infected CXCR3-/- mice exhibited increased mortality and clinical disease. Uncontrolled CNS virus replication compared to wt mice coincided with a decrease in lymphocyte recruitment and increased T and B cell accumulation in lymph nodes. Both total and virus-specific ASC in the brain were reduced by ~80%. In contrast, CXCL10 inhibition in wt mice did not significantly alter CNS inflammation or morbidity. Furthermore, Ab treatment increased the relative frequency of B cells, CD138+ plasma blasts, and both total and virus-specific ASC in the CNS. Nevertheless, CD4 T cell percentages remained reduced. Thus, although the absence of CXCR3 reduced ASC recruitment to the CNS, CXCL10 blockade did not inhibit protective ASC accumulation. CXCL10-independent ASC recruitment to the CNS suggests CXCL9-mediated support of local CNS humoral immunity.
Supported by NIH AI 47249
Role of inducible costimulator and inducible costimulator ligand in bleomycin-induced lung and skin fibrosis model (94.22)
Authors: tanaka chichiro , Fujimoto Manabu , Sato Shinichi , Takehara Kazuhiko , Hasegawa Minoru 
Published: January 2023

Abstract
Inducible costimulator (ICOS) is a CD28 homolog with an expression restricted to T cells, and its only interaction partner, ICOS ligand (ICOSL), is highly expressed on B cells, macrophage, and dendritic cells. To assess the role of ICOS-ICOSL signaling pathway in tissue fibrosis, bleomycin-induced lung and skin fibrosis model was examined in mice deficient for ICOS and/or ICOSL. Daily subcutaneous injection of bleomycin induced fibrosis in the lungs and skin. The loss of ICOS improved the survival rate as a result of ameliorated inflammatory cell infiltration, collagen deposition, and proinflammatory cytokine expression. By contrast, the deficiency of ICOSL or both ICOS and ICOSL reduced the survival rate in consequence of aggravated inflammation and tissue fibrosis. Interestingly, ICOSL expression on macrophage and B cell was ~300% elevated in ICOS-deficient mice compared with wild type mice during this process. Thus, ICOSL expression levels inversely associated with the severity of this mouse model. These findings suggest that ICOSL expression on antigen presenting cells has regulatory roles independent of ICOS-ICOSL pathway for the development of bleomycin-induced tissue fibrosis.
Monocyte chemoattractant protein-1 (MCP-1), not MCP-3, is the primary chemokine required for monocyte recruitment in thioglycollate-induced peritonitis (94.5)
Authors: Yoshimura Teizo , Takahashi Munehisa , Galligan Carole , Tessarollo Lino 
Published: January 2023

Abstract
In this study, we generated a novel MCP-1-deficient (designated as MCP-1Ä/Ä) mouse model using the Cre/loxP system. As expected, MCP-1 was not produced by LPS-activated MCP-1Ä/Ä macrophages; however, the production of MCP-3 was unexpectedly increased. In contrast, macrophages from another mouse line with a neo gene cassette in intron 2 produced a significantly lower level of MCP-1 and MCP-3. Decreased MCP-3 production was also detected in previously generated MCP-1-deficient mice by the insertion of a neo gene cassette in exon 2 (designated as MCP-1 KO). Altered MCP-1 and/or MCP-3 production was observed in vivo in each mouse model in response to intraperitoneal injection of thioglycollate (TG). The up- and down-regulation of MCP-3 production in MCP-1Ä/Ä and MCP-1 KO mice, respectively, provided us with a unique opportunity to evaluate the role for MCP-3 in the recruitment of monocytes. Despite the increased MCP-3 production in MCP-1Ä/Ä mice, TG-induced monocyte accumulation was still reduced by about 50% compared to WT mice, which was similar to the reduction detected in MCP-1 KO mice. Thus, up-regulated MCP-3 production did not compensate for the loss of MCP-1, and MCP-3 appears to be a less effective mediator of monocyte recruitment than MCP-1 in this model. Our results also suggest the participation of other mediators regulating the recruitment of monocytes in this model.
CCL20 and beta-defensin induce arrest of human Th17 cells on inflamed endothelium under flow conditions (95.1)
Authors: Yssel Hans , Ghannam Soufiane , Giot Jean-Philippe , Jorgensen Christian , Pène Jérôme 
Published: January 2023

Abstract
CCR6 is a chemokine receptor that is specifically expressed at the cell surface of Th17 cells, a population of cytokine producing CD4+ T cells with strong inflammatory properties. Ligand-mediated triggering of chemokine receptors is involved in T lymphocyte migration towards and diapedesis into inflamed tissue. Here, we have determined the involvement of CCR6 in this process by analyzing the capacity of CCR6-specific ligands to induce arrest of Th17 lymphocytes onto endothelial cells in vitro under flow conditions. We show that under inflammatory conditions both CCL20 and beta-defensin-2 are capable to induce arrest of tissue-derived Th17, but neither Th1 nor Th2, cells on HUVEC, stimulated with IL-1beta and TNF-alpha 48 h prior to the adhesion assay. Chemokine-induced arrest of Th17 cells was found to be dependent, at least in part, on the expression of CD54. Although specific for Th17 cells, CCR6 expression is not a stable trait, as antigen-specific stimulation resulted in the inhibition of cell surface expression of CCR6 with a complete loss of expression observed after 76h of stimulation. CCR6 expression was restored following subsequent culture in vitro which was intrinsic to Th17 cells and which was independent of the addition of cytokines to the culture medium. As CCL20 is not only secreted by inflamed endothelium, but is also produced rapidly by activated Th17 cells, these results show that CCR6 plays an important role in the migratory capacity of human Th17 cells towards inflamed tissue and, furthermore, that antigen-specific activation induces a transient state of non-responsiveness to CCR6-specific ligands.
The key to the blood brain door: Differential signaling of the adenosine receptor subtypes regulates lymphocyte entry into the central nervous system at the choroid plexus (95.12)
Authors: Mills Jeffrey H , Mueller Cynthia , Bynoe Margaret S 
Published: January 2023

Abstract
Lymphocyte entry into the central nervous system (CNS) is a highly regulated process which serves to promote tissue repair (when required) while protecting against potentially fatal inflammation. As the formation of extracellular adenosine (catalyzed from ATP by CD39 and CD73) during inflammation serves as a negative-feedback signal to prevent excessive cell damage, our results suggest that adenosine receptor (AR) signaling also regulates CNS lymphocyte infiltration. We have recently shown that CD73 and AR signaling are required for CNS lymphocyte entry during experimental autoimmune encephalomyelitis (EAE), the animal model of autoimmune inflammatory disease Multiple Sclerosis. We now show that CD39, CD73, and the A1- and A2A-AR subtypes are found clustered in the CNS only at the choroid plexus, a structure which regulates lymphocyte migration from the blood to the cerebrospinal fluid. Moreover, while A1- and A2A-AR activation have functionally opposing cellular effects (cAMP studies), mice given A2AAR antagonists are protected against EAE and CNS lymphocyte infiltration while A1AR-/- mice develop severe EAE. Additionally, AR signaling can induce lymphocyte transmigration across an in vitro choroid plexus transwell barrier while A2AAR activation promotes the upregulation of ICAM-1. Therefore, we conclude that AR signaling at the choroid plexus mediates CNS lymphocyte entry. AI 57854 and NS 063011
T cell migration to synovial joints is not necessary for the development of proteoglycan-induced arthritis (95.5)
Authors: Egelston Colt , Angyal Adrienn , Glant Tibor T , Mikecz Katalin 
Published: January 2023

Abstract
Rheumatoid arthritis (RA) is largely mediated by autoantibodies, the production of which is supported by autoreactive T cells. Previous reports in RA and its animal models also suggest that T cells present in the joints can locally propagate arthritis. To identify T cells migrating to the joints before and during arthritis development, we transferred fluorescence-labeled T cells and unlabeled antigen-presenting cells from BALB/c mice with proteoglycan-induced arthritis (PGIA) to syngeneic immunodeficient mice, and then monitored the recruitment of donor T cells in the ankle joints of the recipients using in vivo two-photon microscopy, immunohistochemistry, and flow cytometry. Despite the development of arthritis in the recipient mice, we found very few donor T cells in their joints after cell transfer. Furthermore, treatment of recipient mice with FTY720, an inhibitor of lymphocyte egress from lymphoid organs, which effectively depleted T cells in both peripheral blood and joints, failed to inhibit PGIA development. In contrast, arthritis did not occur in recipient mice after injection with donor cells depleted in T cells in vitro prior to transfer. Our results suggest that while lymphoid organ-homing T cells are required for the adoptive transfer of PGIA, the few T cells that migrate to the joints do not play a significant role in arthritis development.
Work supported by the NIH and the Grainger Foundation.
T cells regulate interstitial lung disease via expression of integrins (95.9)
Authors: Luzina Irina G. , Todd Nevins W. , Atamas Sergei P. 
Published: January 2023

Abstract
Interstitial lung disease, a combination of pulmonary inflammation and fibrosis, is deadly and occurs idiopathically or as a complication of autoimmune rheumatic diseases (scleroderma, rheumatoid arthritis, poly- and dermatomyositis, lupus). T cells often accumulate in the lungs of such patients. Previous reports suggested that αV-containing integrins may activate TGF-β and facilitate fibrosis. Whether pulmonary T cells utilize such integrins in interstitial lung disease is not clear. Expression of integrins αVβ3 (ITGAVB3) or αVβ5 (ITGAVB5) on pulmonary T cells was observed by double-stain immunofluorescence confocal microscopy in six out of six patients with scleroderma lung disease, as well as in the animal models of pulmonary CCL18 overexpression that manifests in selective T lymphocytic infiltration of the lungs and T cell-dependent pulmonary fibrosis. Flow cytometry of bronchoalveolar lavage T cells confirmed expression of integrins on more than 10% (up to 50%) of pulmonary T cells in 14 of 25 scleroderma patients and in all CCL18-overexpressing mice; Q-PCR experiments confirmed elevated integrin mRNAs in purified BAL T cells. There was no expression of ITGAVB3 or ITGAVB5 on T cells from the lungs of healthy volunteers or control mice. Injections of anti-ITGB3 blocking antibody or genetic deficiency of ITGB3 protected mice from CC18-induced inflammation and fibrosis. Jurkat cells that were forced to overexpress ITGAVB3 or ITGAVB5 induced Smad2 phosphorylation and nuclear translocation, and increases in collagen and α-smooth muscle actin expression in co-cultures with primary lung fibroblasts. Blocking anti-TGF-β antibodies attenuated such regulation in cell co-cultures. Thus, expression of integrins on pulmonary T cells contributes to interstitial lung disease by promoting T cell infiltration, TGF-β activation, and fibrosis.