bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of CCL1 antisense ODN on bacterial translocation in mice irradiated with whole body 137Cs γ-rays: induction of M1 macrophages in translocation sites (111.21)
Authors: Kobayashi Makiko , Travis Lauren , Kogiso Mari , Cornforth Michael , Suzuki Fujio 
Published: January 2023

Abstract
M1Mϕ (IL-10-IL-12+ Mϕ) in mesenteric lymph nodes (MLN) of mice have been identified as major effector cells in the host defense against enterococcal translocation and subsequent sepsis. However, M1Mϕ are not easily generated in 5 Gy whole body γ-irradiated mice (WBI-mice) whose M2bMϕ (IL-10+CCL1+LIGHT+IL-12- Mϕ) predominate. M2bMϕ are inhibitory on resident Mϕ conversion to M1Mϕ. In our previous studies, M2bMϕ were not demonstrated in MLN of WBI-mice treated with CCL1 antisense ODN. In this study, therefore, we tried to induce M1Mϕ by enterococcal antigen in MLN of WBI-mice treated with CCL1 antisense ODN. WBI-mice were treated s.c. with CCL1 antisense ODN (10 μg/mouse) twice a day for 2 days starting 2 weeks after γ-irradiation. One day after the final treatment, these mice were stimulated orally with 107 heat-killed E. faecalis. Two days after stimulation, F4/80+ MLN-Mϕ were isolated from these mice and tested for their M1Mϕ properties based on their abilities to express intracellular IL-12, CXCL9 and iNOS mRNA. In the results, Mϕ from WBI-mice treated with scrambled ODN did not express iNOS mRNA, intracellular IL-12 and CXCL9, even when these mice were stimulated with enterococcal antigen. However, iNOS+IL-12+CXCL9+ Mϕ were isolated from the same antigen-stimulated WBI-mice treated with CCL1 antisense ODN. These results indicate that M1Mϕ are inducible by the enterococcal antigen in WBI-mice treated with CCL1 antisense ODN.
Systemic isotretinoin treatment modulates patients’ immune response to P. acnes (111.23)
Authors: Dispenza Melanie , Nelson Amanda , Gilliland Kathryn , Cong Zhaoyuan , Thiboutot Diane 
Published: January 2023

Abstract
Isotretinoin, a pro-drug for retinoic acid, is the only agent that induces a permanent remission of acne, but the mechanism underlying its long-term efficacy is unknown. We hypothesized that modulation of the immune response to the bacterium involved in acne, P.acnes, is key to isotretinoin’s ability to induce long-term or permanent remissions of acne. This study is the first to investigate changes in peripheral immune cells associated with isotretinoin treatment in acne patients in vivo. Peripheral blood samples were obtained from acne patients before starting isotretinoin therapy (baseline) and at 1, 4, 8, and 20 weeks after starting isotretinoin therapy. Monocytes and lymphocytes were isolated, activated in vitro, and analyzed by flow cytometry. Acne patients’ monocytes expressed higher levels of TLR-2 and secreted more IL-1β, IL-6, IL-8, and IL-10 in response to P. acnes than monocytes from normal volunteers. Isotretinoin therapy significantly decreased TLR-2 expression on acne patients’ monocytes compared to their baselines, and this decrease was maintained at six months after the cessation of therapy. Additionally, isotretinoin therapy significantly decreased the secretion of IL-1β, IL-6, IL-8, and IL-10 by untreated and P.acnes-treated monocytes from acne patients compared to baseline. These results suggest that modulation of the immune response to P.acnes may represent one mechanism of isotretinoin’s long-term efficacy.
Lactoferrin inhibits DNA-induced IFN-alpha production by human plasmacytoid dendritic cells (111.4)
Authors: Tewary Poonam , dela Rosa Gonzalo , Rodriguez Luis , Riboldi Elena , Shirota Hidekazu , Patrek Karel , Klinman Dennis , Yang De , Oppenheim Joost 
Published: January 2023

Abstract
Bacterial as well as self DNA is released at infection sites due to cell lysis. This DNA induces the production of IFN-α by TLR9+ Plasmacytoid dendritic cells (pDCs), which in turn can lead to exacerbated tissue damage as seen in psoriasis and lupus. Antimicrobial peptides like cathelicidins enhance the production of IFN-α, but little is known about the effect of other antimicrobial proteins stored in neutrophils. Here we present the inhibitory capacity of lactoferrin on DNA-induced IFN-α production by human pDCs. Confocal microscopy images showed lactoferrin binding to extracellular DNA molecules or CpG oligonucleotides, preventing their uptake by pDCs, and the subsequent activation of TLR-9. Flow cytometry experiments with labeled CpGs to analyze internalization dynamics indicate that lactoferrin prevented cathelicidin-DNA complexes from being internalized, circumventing over-activation of TLR-9. Moreover, when lactoferrin was supplemented in the diet, mice orally treated with the irritant DSS presented lower IFN-α levels in the mesenteric lymph nodes than controls. Therefore, we propose that lactoferrin acts as a scavenger molecule for DNA motifs, potentially reducing the undesirable effects of high levels of IFN-α.
M1 macrophage induction in severely burned mice treated with CCL1 antisense ODN (111.9)
Authors: Asai Akira , Herndon David , Kobayashi Makiko , Suzuki Fujio 
Published: January 2023

Abstract
We have reported that M2bMϕ, an inhibitor cell for M1Mϕ generation, are generated in mice 1 to 3 weeks after severe burn injury. CCL1 released from M2bMϕ acts as an autocrine signaler for keeping their suppressor cell properties. In this study, we tried to induce M1Mϕ in burned mice treated with CCL1 antisense ODN. BALB/c burned mice (25% TBSA, 3rd degree flame burn) were treated s.c. with 10 μg/mouse of CCL1 antisense ODN twice a day for 2 days beginning 13 days after burn injury. F4/80+ peritoneal Mϕ isolated from mice 12 hrs after the final treatment were tested for their M2bMϕ properties based on the expression of LIGHT mRNA and intracellular IL-10. These burned mice were then stimulated with heat-killed MRSA for M1Mϕ induction. Mϕ were considered as M1Mϕ if they expressed iNOS mRNA and intracellular IL-12. CCL1 was not detected in sera of burned mice treated with CCL1 antisense ODN. Mϕ from these mice did not express LIGHT mRNA and IL-10, while LIGHT+ IL-10+ Mϕ were isolated from burned mice treated with scrambled ODN. Further, iNOS+ IL-12+ Mϕ were induced by the bacterial antigen in burned mice subjected to the gene therapy. These results indicate that M2bMϕ are eliminated by CCL1 antisense ODN in severely burned mice, and M1Mϕ are induced in these mice stimulated with the antigen. CCL1 antisense ODN gene therapy may improve host’s antibacterial innate immunity severely suppressed in burned individuals.
Molecular dissection of T-cell differentiation defects in the old CD8 T cell (113.12)
Authors: Renkema Kristin , Rudd Brian , Li Gang , Samadder Partha , Smithey Megan , Nikolich-Zugich Janko 
Published: January 2023

Abstract
One in eight people are 65 years and older in the United States; this population is expected to double within the next 50 years. Alarmingly, infectious diseases remain amongst the leading causes for death in people over 65 years old. Widespread defects in the immune system have been found to increase with age, including qualitative and quantitative decline with adaptive immunity. CD8 T cells have been found to decrease in both number and function in aged mice. We recently found that in response to systemic Listeria monocytogenes (Lm) infection, old mice mobilize fewer Lm-specific CD8 T cells. Moreover, these cells exhibited lower effector cytokine production, and are less polyfunctional. We evaluated the expression of key transcription factors crucial to effector CD8 T cell development in adult and old CD8 T cells in the mouse. We found that in response to in vivo stimulation, old CD8 T cells exhibited altered expression of T-homeobox transcription factors , correlating with lower expression of interferon-gamma (IFNγ), tumor necrosis factor alpha (TNFα) and granzyme B. Altered transcriptional activation may constitute a common denominator underlying suboptimal function of old CD8 T cells in response to primary infection. Experiments are in progress to correct these defects and improve function of aged CD8 T cells.
Lipopolysaccharide-induced molecular interactions of the TLR4 signaling complex and the BK potassium channel (113.16)
Authors: Davis Ryan , Kozina Carol , Branda Steve , Rempe Susan 
Published: January 2023

Abstract
TLR4 signaling plays a central role in pathogen recognition and is fundamental to innate immunity. However, positive feedback in the systemic inflammatory response to TLR4 stimulation, manifest as sepsis, is a significant concern in managing infection. Thus pharmacological targets for modulating feedback in the immune response are desirable as next-generation therapies. Ion channels provide a ubiquitous mechanism for influencing cellular activation by controlling electrochemical polarization, and may be useful for amelioration of septic shock. Correspondingly, a recent report by Scheel and coworkers suggests that TLR activation of macrophages requires the function of BK potassium channels. On the molecular level, the formation of the LPS-induced TLR4 signaling complex requires intimate interactions of the co-receptors CD14 and MD2. However, our recent in vivo studies of TLR4 diffusion prior to and following LPS-stimulation in HEK293 suggest that several components in addition to these fundamental units may also be involved. In fact, increased FRET efficiency observed in LPS-stimulation of cells co-transfected with fluorescent constructs of TLR4 and the BK potassium channel suggest direct interactions of the signaling complex with this ion channel. Finally, we present results detailing the impact of association with the TLR4 signaling complex on calcium-activation of the BK channel. These data suggest that the BK channel may play an important role TLR4 feedback.
Control of T cell metabolism and regulatory T cell generation by a DRAK2/p70S6K1 signaling axis (113.19)
Authors: Hernandez Jeniffer , Michalek Ryan , Weist Brian , Newton Ryan , Limon Jose , Carrillo Mayra , Paterson Elyse , Nguyen Long , Fruman David , Rathmell Jeffrey , Walsh Craig 
Published: January 2023

Abstract
The delicate balance between effector T cells (Teff cells) and regulatory T cells (Treg cells) is crucial for preventing autoimmunity while maintaining efficient immune function. Mice deficient in the serine/threonine kinase, Dap Related Apoptosis inducing Kinase 2 (DRAK2), are resistant to T cell-mediated organ-specific autoimmune diseases yet retain antiviral immunity. Here we show that DRAK2 dictates the fate of a naïve T cells by regulating their metabolism. This is achieved through amplifying the activity of p70S6K1 in a parallel manner to mTORC1, which leads to an increase in glycolytic metabolism, a process required for Teff cell survival. In addition, we find that the inhibition of the DRAK2/p70S6K1 axis promotes the generation of Treg cells similar to mTORC1 inhibition with rapamycin. By regulating T cell metabolism and Treg cell generation, the DRAK2/p70S6K1 signaling axis orchestrates the balance between Teff cells and Treg cells. Blockade of DRAK2, which is most highly expressed in lymphocytes, may offer an alternative and selective approach vs. rapamycin in the suppression of autoimmunity.
The protein tyrosine phosphatase, SHP-1, is an intrinsic central regulator of dendritic cell function (113.8)
Authors: Levitt Jonathan , Ramachandran Indu , Spencer David 
Published: January 2023

Abstract
Dendritic cells (DCs) initiate proinflammatory or regulatory T cell responses, depending on their activation state. Despite extensive knowledge of DC-activating signals, mechanisms of DC-inhibitory signals are less well understood. We show that the SH2-domain-containing protein tyrosine phosphatase, SHP-1, is an important inhibitor of DC signaling that targets multiple activation pathways. Downstream of TLR4, SHP-1 showed increased interactions with several proteins including IRAK-4, and modulated LPS signaling through the inhibition of NF-κB, AP-1, ERK and JNK activity, while enhancing p38 activity. In addition, SHP-1 inhibited pro-survival signaling modulated through AKT activation. Further, SHP-1 inhibited CCR7 protein levels and CCR7 mediated cytokine expression. Inhibition of SHP-1 in DCs enhanced proinflammatory cytokines, IL-6, IL-12 and IL-1β, promoted survival and increased the rate DC migration from the periphery to draining lymph nodes. In vivo administration of SHP-1-inhibited DCs loaded with antigen, significantly induced the expansion of antigen-specific cytotoxic T cells and inhibited Foxp3+ regulatory T cell proliferation compared to unmodified DCs. When used in a vaccination protocol, SHP-1-inhibited DCs significantly reduced progression of pre-established mouse melanoma and prostate tumors. Taken together, these data demonstrate that SHP-1 is an intrinsic global regulator of DC function, controlling many facets of T cell-mediated immune responses.
Regulation of thymocyte positive selection and motility by GIT2 (113.9)
Authors: Phee Hyewon , Dzhagalov Ivan , Mollenauer Marianne , Wang Yana , Irvine Darrell , Robey Ellen , Weiss Arthur 
Published: January 2023

Abstract
Thymocytes are highly motile cells that migrate under the influence of chemokines in distinct thymic compartments as they mature. The motility of thymocytes is tightly regulated; however, the molecular mechanisms that control thymocyte motility are not well understood. Herein, we report that G protein-coupled receptor kinase-interactor 2 (GIT2) is required for efficient positive selection. Interestingly, GIT2-/- double positive (DP) thymocytes display increased Rac activation, actin polymerization and migration towards SDF-1 and CCL25 in vitro. Using two-photon laser scanning microscopy, we found that scanning activity of GIT2-/- thymocytes is severely compromised in the thymic cortex. Moreover, the GIT2-/- thymocytes accumulated at discrete small regions throughout the cortex including areas adjacent to SDF-1 positive blood vessels and interacted with them extensively. The impaired scanning activity of GIT2-/- thymocytes was accompanied by impaired positive selection in TCR transgenic GIT2-/- mice, suggesting GIT2 plays a key role in controlling chemokine-mediated motility of DP thymocytes and ultimately regulates positive selection.
Regulation of the development of acute hepatitis by IL-23 through IL-22 and IL-17 production (114.13)
Authors: Mingli Xu , Noriko Morishima , Izuru Mizoguchi , Yukino Chiba , Koji Fujita , Masahiko Kuroda , Yoichiro Iwakura , Daniel J Cua , Koji Yasutomo , Junichiro Mizuguchi , Takayuki Yoshimoto 
Published: January 2023

Abstract
IL-23 plays a critical role in the expansion of highly pro-inflammatory Th17 cells secreting IL-17 and IL-22. Recently, we demonstrated that Notch signaling drives IL-22 secretion through the aryl hydrocarbon receptor (AHR) and plays a protective role in Con A-induced hepatitis. In the present study, we investigated a role for IL-23 in the hepatitis using IL-23p19- and IL-17-deficient mice. In WT mice, injection of Con A induced up-regulation of various cytokines including IL-23p19, IL-22 and IL-17. In IL-23p19-deficient mice, exacerbated hepatitis was observed and serum IL-22 and IL-17 levels were greatly reduced, while IL-17-deficient mice showed ameliorated hepatitis. Injection of exogenous IL-22 protected p19-deficient mice from the hepatitis, whereas injection of exogenous IL-23 greatly enhanced serum levels of not only IL-22 but also IL-17, and much less effectively protected from the hepatitis in IL-17-dependent and -independent manners. Finally, it was revealed that STAT3, STAT4 and Notch contributed to the production of both cytokines and that AHR was important for only IL-22 production in response to Con A and IL-23 in liver mononuclear cells. These results suggest that IL-23 plays a protective role in the hepatitis through IL-22 production and also a pathological role via IL-17-dependent and -independent mechanisms.
Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity (114.16)
Authors: Puel Anne , Cypowyj Sophie , Bustamante Jacinta , Wright Jill , Liu Luyan , Lim Hye Kyung , Migaud Mélanie , Israel Laura , Chrabieh Maya , Audry Magali , Gumbleton Matthew , Toulon Antoine , Bodemer Christine , El-Baghdadi Jamila , Whitters Matthew , Paradis Theresa , Brooks Jonathan , Collins Mary , Wolfman Neil , Al-Muhsen Saleh , Galicchio Miguel , Abel Laurent , Picard Capucine , Casanova Jean-Laurent 
Published: January 2023

Abstract
Chronic mucocutaneous candidiasis disease (CMCD) is characterized by recurrent or persistent infections of the skin, nails, oral and genital mucosae caused by Candida albicans and, to a lesser extent, Staphylococcus aureus, in patients with no other infectious or autoimmune manifestations. We report two genetic etiologies of CMCD: autosomal recessive deficiency in the cytokine receptor, interleukin-17 receptor A (IL-17RA), and autosomal dominant deficiency of the cytokine IL-17F. IL-17RA deficiency is complete, abolishing cellular responses to IL-17A and IL-17F homo- and heterodimers. By contrast, IL-17F deficiency is partial, with mutant IL-17F-containing homo- and heterodimers displaying impaired, but not abolished activity. These experiments of nature indicate that human IL-17A and IL-17F are essential for mucocutaneous immunity against C. albicans, but otherwise largely redundant.
TNFαRII expressing FoxP3+ T reg cells have a reversible defect in their ability to suppress the autoimmune disease thyrocyte epithelial cell hyperplasia/proliferation (115.17)
Authors: Kayes Timothy , Braley-Mullen Helen 
Published: January 2023

Abstract
Most IFN-γ-/- NOD.H-2h4 mice given 0.05% NaI in their water develop an autoimmune thyroid disease characterized by infiltrating lymphocytes, expression of TNFα and TGFβ, production of anti-thyroglobulin antibodies, and uncontrolled proliferation of TEC, resulting in destruction of the gland and loss of function. IFN-γ-/- NOD.H-2h4 mice have elevated FoxP3+ CD4+ T reg in cervical LN and spleen (25-40%, and 25-35% of CD4+ T cells) dependent on age, presence of severe disease, and absence of IFN-γ. T reg cells from mice with severe TEC H/P exhibit a suppressive phenotype with expression of high levels of FoxP3, CD25, and TNFαRII (p75), and they suppress anti-CD3 mediated proliferation of T cells in vitro. Splenocytes from mice with severe TEC H/P transfer severe TEC H/P to IFN-γ-/- SCID recipients following 72 hr culture. During culture, percentages of T reg decrease, allowing transfer of severe TEC H/P. However, in recipient mice, percentages of T reg increase, and despite increased numbers of T reg in LN and spleen, the mice develop severe TEC H/P. This data suggests there may be a defect in the ability of these T reg to suppress TEC H/P, either because of an intrinsic defect in the T reg or because effector cells are resistant to suppression. The defect is reversible as addition of IL-2 (100 U/ml) to the culture increases T reg percentages, and inhibits transfer of TEC H/P, restoring the ability of T reg to suppress TEC H/P in recipient SCID mice.
Viral vector mediated tolerance induction in experimental autoimmune encephalomyelitis by dendritic cell targeted expression of a self-antigen (115.2)
Authors: de Andrade Pereira Bruna , Fraefel Cornel , Ackermann Mathias , Dresch Christiane 
Published: January 2023

Abstract
Multiple sclerosis (MS) is an autoimmune disease characterized by the presence of self-reactive T cells that target myelin components. Immunization of susceptible animals with myelin antigens induces experimental autoimmune encephalomyelitis (EAE), an animal model for MS. The aim of this project was to induce permanent, antigen-specific tolerance in EAE/MS and to address the mechanisms that would contribute to tolerance. The strategy includes the ex vivo modification of autologous hematopoietic stem cells (HSC) with lentiviral vectors that express myelin oligodendrocyte glycoprotein (MOG) under the control of a dendritic cell (DC) specific promoter. After re-infusion, the modified HSC will give rise to antigen expressing DCs. We demonstrated the effectiveness of this strategy for inducing MOG-specific tolerance in EAE, as 100% of the mice that received BM cells transduced with MOG-lentivector were protected. In addition, we show depletion of MOG specific T cells and generation of Foxp3+ regulatory T cells in chimeras that received HSC transduced with MOG-lentivector. As apposed to the protected animals, the diseased control mice showed high levels of IL-1, INF-γ and IL-17. The strategy presented here is particularly promising for clinical applications and important for addressing fundamental questions in immunity and tolerance.
Treatment of autoimmune demyelination by autoregulatory CD8+ T-cells (115.24)
Authors: Ortega Sterling , Tyler Andrew , Kashi Venkatesh , Mendoza Jason , Benagh Andrew , Karandikar Nitin 
Published: January 2023

Abstract
Immune dysregulation is believed to be the causative factor in the debilitating neurological disease Multiple Sclerosis (MS). We have recently shown that neuroantigen-specific auto-reactive regulatory (autoregulatory) CD8+ T-cells are capable of suppressing the murine model of MS, experimental autoimmune encephalomyelitis (EAE), a disease mediated by neuroantigen-specific CD4+ T-cells. We now show that deficiency of CD8+ T-cells correlates with more severe disease and an increase in IL-17+ and TCRVβ8.2+ CD4+ T-cell responses with reduction in IL-10+ CD4+ T-cells. Disease suppression by autoregulatory CD8+ T-cells is dependent on recognition of cognate antigen in vivo in the context of MHC Class I and requires IFN-γ and perforin production by CD8+ T-cells, suggesting a cytotoxic/suppressor mechanism. Suppression mediated by direct CD8-CD4 interactions is suggested by the ability of these cells to inhibit adoptively transferred disease and direct in vitro killing of neuroantigen-loaded CD4+ T cells. Finally, neuroantigen-specific CD8+ T-cells were able to traffic to the central nervous system (CNS) during ongoing inflammation, suggesting both a peripheral and central mechanism of action. These studies define a novel and unexpected immune regulatory function for tissue-reactive “autoregulatory” CD8+ T-cells that can be harnessed for the development of immunotherapeutic intervention in MS and other autoimmune diseases.
Indoleamine 2,3-dioxygenase 1 (IDO1) activity correlates with inflammation in systemic sclerosis (115.5)
Authors: Rutella Sergio , De Santis Maria , Bonanno Giuseppina , Procoli Annabella , Mariotti Andrea , Corallo Maria , Novarese Linda , Bosello Silvia , Scambia Giovanni , De Cristofaro Raimondo , Ferraccioli Gianfranco 
Published: January 2023

Abstract
Background. A contributory effect of IDO1 to inflammatory autoimmune pathologies such as rheumatoid arthritis and systemic lupus erythematosus has been recently described. We aimed to address whether IDO1-driven kynurenine (KYN) production correlates with degree of inflammation and disease extent in systemic sclerosis (SSc). Methods. Peripheral blood was obtained from 27 consecutive patients (median age 62 years, range 22-78; median disease duration = 10 months, range 1-35) with either limited cutaneous SSc (n=17) or diffuse cutaneous SSc (n=10). In 11 of the 27 patients, CD19+ B cells were magnetically purified to estimate IDO1 mRNA levels by quantitative PCR. Results. High serum KYN in SSc (3.17±0.82 μM compared with 1.82±0.37 μM in healthy controls; p&lt;0.0001) positively correlated with serum CRP (r=0.42; p=0.03), an established marker of inflammation. We showed a trend towards higher KYN levels in diffuse SSc compared with limited SSc, although no correlations emerged between KYN release and serological features or lung fibrosis. Interestingly, purified CD19+ B cells expressed IDO1 mRNA, whose copy number correlated with serum CRP (r=0.58; p=0.048) and with the frequency of bona fide CD4+FoxP3+ Treg cells. Conclusions. The generation of KYN and expansion of Treg cells may reflect a counter-regulatory mechanism to limit excessive inflammation in SSc.