bluuebunny/crossref_metadata_2025_split huggingface dataset:
Proinflammatory responses of neuroglia cells after radiofrequency fields exposure (P5036)
Authors: Lu Yonghui , Zhong Min , Xu Shangcheng , Zhang Lei , He Mindi , Chen Chunhai , Yu Zhengping , Zhou Zhou 
Published: January 2023

Abstract
Worldwide use of mobile phones has provoked intense concern regarding the potential biological effects of radiofrequency (RF) fields on the brain. Given the important roles of inflammation and immunization in neural physiopathologic processes, we investigated the proinflammatory responses of neuroglia cells after RF exposure. In the present study, we exposed cultured mouse microglia cell line (N9) and mouse astrocyte cell line (CRL-2541) to 1800 MHz RF modulated by 217 Hz for 1, 3, 6, 12 and 24 hours with a special absorption rate (SAR) of 2 W/kg and a duration of 5 min on/10 min off. The RF exposure significantly increased the mRNA levels of tumor necrosis factor-alpha (TNF-α) and interleukin-1beta (IL-1β) in N9 and CRL-2541 cells. Concomitant with this finding, the TNF-α and IL-1β releases were elevated by RF exposure in both neuroglia cell culture mediums. In addition, the RF exposure enhanced the gene and protein expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX 2) in both cell lines. The releases of prostaglandin E2 (PGE2) and nitric oxide (NO), which are the productions of iNOS and COX 2 respectively, were also increased by the RF exposure in the two cell lines. Our results indicate that exposure to 1800 MHz RF (SAR=2 W/kg) may evoke proinflammatory responses in mouse microglia and astrocyte.
NR4A1 (Nur77) dependent monocytes patrol the lung vasculature and inhibit tumor cell invasion (P5068)
Authors: Hanna Richard , Cekic Cagler , Chittezhath Manesh , Herrley Erica , Chodaczek Grzegorz , Biswas Subhra , Hedrick Catherine 
Published: January 2023

Abstract
The nuclear receptor NR4A1 (Nur77) is expressed in monocytes and macrophages, yet its function in regulating inflammation associated with cancer is uncertain. Our previous studies identified that Nur77 regulates the development of patrolling Ly6C- monocytes and is involved in the resolution of inflammation. In the current study, we sought to determine how absence of Nur77 in hematopoietic cells impacts tumor growth and metastasis. Mice deficient in Nur77 showed a significant increase in growth and lung metastasis of syngeneic B16F10 melanoma. Increased tumor seeding of the lung was visible after only 4 days post IV tumor transfer, and appears to be specific to the lung. In vivo imaging reveals that Nur77-defficient mice have a drastic reduction in cells patrolling the lung vasculature, and that these patrolling monocytes establish early immune interactions with tumor cells and granulocytes in the lung. Furthermore, over-expression of Nur77 in human monocytes inhibited angiogenesis and invasion of human tumor cells in co-culture assays. We conclude that the absence of Nur77-regulated patrolling monocytes in combination with polarization of myeloid cells towards a pro-inflammatory and pro-angiogenic phenotype contributes to early tumor cell invasion of the vasculature and growth in the lung. These studies indicate that Nur77 is a novel target for modulating the inflammatory phenotype of monocytes and macrophages in inflammatory diseases, including cancers.
Prostaglandin D2 ameliorates acute lung inflammation by activating Nrf2 independent of 15-deoxy-Δ12,14-PGJ2. (P5040)
Authors: Kim Kyun Ha , Han Wei , Sadikot Ruxana , Christman John , Breyer Richard , Chan Jefferson , Urade Yosihiro , Oh Yu-Kyoung , Blackwell Timothy , Joo Myungsoo 
Published: January 2023

Abstract
Since anti-inflammatory activity of prostaglandin D2 (PGD2) is attributed to 15-deoxy-Δ12,14-PGJ2, a byproduct of PGD2, we explored the hypothesis that PGD2, independent of 15-deoxy-Δ12,14-PGJ2, activates NF-E2-related factor 2 (Nrf2), an anti-inflammatory transcription factor, contributing to suppression of lung inflammation in acute lung injury (ALI). Intratracheal delivery of PGD2 decreased neutrophilic infiltration, MPO activity, and the production of pro-inflammatory cytokines in LPS-treated lungs. In contrast, lipocalin-prostaglandin D synthase (L-PGDS) KO mice that produce less PGD2 showed prolonged lung inflammation, highlighting the importance of L-PGDS and PGD2 in suppressing lung inflammation. Two log10 less of PGD2 than 15-deoxy-Δ12,14-PGJ2 was sufficient for activating Nrf2 in RAW 264.7. Similarly, PGD2 was more potent than 15-deoxy-Δ12,14-PGJ2 in expressing Nrf2 dependent genes in mouse lungs. While overexpression of DP1, a receptor of PGD2, enhanced PGD2-mediated Nrf2 activation, siRNA silencing DP1 expression reduced its activation, suggesting that PGD2 uses DP1 in activating Nrf2. Furthermore, PGD2 synergistically suppressed neutrophil infiltration when nrf2 was functionally complemented to the lung of the nrf2-/- mice. Our results show that PGD2 activated Nrf2 independent of 15-deoxy-Δ12,14-PGJ2 and involved DP1. We suggest that PGD2 has a potent anti-inflammatory activity, which is at least in part mediated by activating Nrf2.
Influence of ovariectomy on the cytokine release in acute lung injury induced by LPS in mice (P5052)
Authors: Gimenes-Junior Joao , Vitoretti Luana , Accetturi Beatriz , Lino-dos-Santos-Franco Adriana , Ligeiro-de-Oliveira Ana , Peron Jean , Aloia Thiago , Palermo-Neto Joao , Oliveira-Filho Ricardo , Tavares-de-Lima Wothan 
Published: January 2023

Abstract
Acute respiratory distress syndrome is a multifactorial disease characterized by acute lung injury, hypoxemia and polymorphonuclear cells infiltration. Clinical and experimental evidences indicate that female sex hormones may greatly influence lung inflammation. Previous data from our group revealed that ovariectomy (OVx) blunted LPS-induced lung inflammation in mice after 24 h. Here, we expanded the study and assessed the influence of OVx on the release of cytokines by lung cells after LPS. 7 day-OVx female C57BL/6 mice were subjected to intranasal instillation of LPS or saline. Non-manipulated animals were subjected to the same procedures and served as controls (Sham-OVx). 24 h thereafter, animals were euthanized and lungs removed. The levels of IL-1β, IL-17, IFN-γ and IL-10 were measured. Ovaries removal per se did not alter the cytokines levels in the lung compared with the control group. Moreover, intranasal instillation of LPS increased the cytokines released in the lungs from both OVx and Sham-OVx groups compared to controls. On the other hand, LPS challenged animals had more IL-1β, IL-17 and IFN-γ within the OVx group. This was associated with significantly higher levels of IL-10 in the same group. Lack of female sex hormones led to an increased release of pro-inflammatory cytokines by the lungs, demonstrating its role in modulating the development of acute lung injury induced by LPS in mice.
Role of GM-CSF and IRF5 in steroid refractory asthma (P6247)
Authors: Gordon Rachael , Raundhal Mahesh , Wenzel Sally , Ray Anuradha , Ray Prabir 
Published: January 2023

Abstract
Asthma is a heterogeneous, inflammatory disease of the airways characterized by reversible airflow obstruction and bronchoconstriction. 10% of asthma patients are categorized as severe asthmatics (SA), showing mixed neutrophilic/eosinophilic infiltrate, which is poorly responsive to corticosteroids (CS). Elevated levels of inflammatory cytokines, including GM-CSF, IL-6 and IL-17, are found in the airways of SA. Recently, GM-CSF alone or in combination with LPS, was shown to augment expression of IRF5 in macrophages (Mϕ), promoting Th17-driving cytokines. These observations led us to hypothesize that GM-CSF plays an important role in mediating CS-refractory IL-6 production from Mϕ. In RAW 264.7 cells, LPS-induced IL-6 production was inhibited 65% by CS. However, when LPS was combined with GM-CSF at 20 or 200 ng/ml, CS poorly suppressed IL-6 production (17 % and 10.5% respectively). IRF5 expression was detected in LPS+GM-CSF-treated RAW cells and its expression was augmented in the lung-draining lymph nodes of mice exposed to the allergen, house dust mite. Interestingly, IRF5 expression was significantly higher in bronchoalveolar lavage cells isolated from human SA as compared to that in cells from milder, CS-responsive asthmatics or from healthy controls. These observations suggest an important role of GM-CSF and IRF5 in mediating CS-refractory IL-6 production in innate immune cells that in turn promote CS-unresponsive Th17 development and neutrophilic airway inflammation.
Natural EBV infection in humans induces an expression profile similar to cytokine storm illnesses that is unique from other acute viral infections (P6326)
Authors: Dunmire Samantha , Odumade Oludare , Porter Jean , Bacheler Emily , Balfour, Jr. Henry , Hogquist Kristin 
Published: January 2023

Abstract
Herpesvirus infections are common in humans, and while generally not lethal, lead to lifelong infection associated with cancer and autoimmune disease. To better understand immunity to persistent viral infection, we performed a prospective study in otherwise healthy college students of naturally acquired infection by the gamma herpesvirus, Epstein Barr virus (EBV). Transcriptome analysis defined a striking and reproducible profile during acute infection regardless of disease severity and included genes related to cell cycle, interferon response, and immune function. Even with the highly sensitive approach taken, however, no lasting gene changes were apparent during latent infection. Comparing the EBV response profile to multiple other acute viral infections revealed similarity only to Dengue virus. The signature shared by EBV and Dengue was also present in inflammatory syndrome patients. Interestingly, while EBV induced a type I interferon response, a subset of interferon induced genes, including MX1 and OAS1, were not upregulated, despite these genes being conventional contributors in a type I interferon response. Furthermore, IL1B was downregulated, together suggesting potential mechanisms of viral antagonism. These data provide an important first description of the response to natural herpesvirus infection in humans during multiple stages of infection.
Neutralizing KC (CXCL1), but not IL-6 ameliorates recurrent HSK in vivo. (P6340)
Authors: Stuart Patrick , Yin Xiao-Tang , Del Rosso Chelsea , Potter Chloe , Potter Chloe , West Devin 
Published: January 2023

Abstract
Herpetic stromal keratitis (HSK) is the leading cause of infectious blindness in developed nations and occurs following infection with herpes simplex virus. The mechanism underlying this disease is immune-mediated, involving neutrophils, macrophages, cytokines, and chemokines. We hypothesized that neutralizing the proinflammatory cytokine IL-6 or the chemokine KC (murine CXCL1) would significantly reduce disease in an animal model of HSK. Latently infected mice were reactivated 6 weeks following infection with UV-B light to stimulate recurrent disease. At that time, we administered mAbs against IL-6, KC and control IgG via intraperitoneal injection. We monitored recurrent infection by daily testing tear film for virus for 7 days following reactivation. Corneal disease was evaluated weekly for five weeks. Data shows that neutralizing KC resulted in lower opacity and neovascularization scores for all time points measured when compared to controls. Surprisingly, unlike what is seen in acute HSK, neutralizing IL-6 did not decrease disease. Futhermore, treatment with anti-KC results in significantly less neutrophilic infiltrate of infected corneas. We conclude that CXCL1 and not IL-6 is important in developing recurrent HSK. Furthermore, these results further demonstrate that recurrent and acute HSK share some but not all aspects of disease, and that one common thread is the crucial role that neutrophils play in this potentially blinding disease.
RIG-I receptor regulation of T cell immunity during virus infection (P4361)
Authors: Suthar Mehul , Ramos Hilario , Brassil Margaret , Netland Jason , Chappell Craig , Blahnik Gabrielle , McMillan Aimee , Diamond Michael , Clark Edward , Bevan Michael , Gale, Jr. Michael 
Published: January 2023

Abstract
West Nile Virus (WNV) is an RNA virus that is the leading cause of mosquito-borne encephalitis in the United States. Recently, we demonstrated that MAVS, the central adaptor molecule of the RIG-I like receptor (RLR) signaling pathway, is essential role in programming innate and adaptive immune defenses to control WNV infection. However, the role of the individual RLRs in directing immunity during virus infection has not been clearly defined. WNV infection of Lgp2-/- mice showed increased mortality which corresponded to enhanced virus replication and reduced antigen-specific CD8+ T cells in the CNS at late times during infection. While LGP2 was determined to be non-essential in innate immune responses to WNV infection, LGP2 was required for controlling antigen-specific CD8+ T cell survival and effector functions during virus infection. Adoptive transfer studies of WT and Lgp2-/- CD8+ T cells into Rag-/- mice demonstrated that LGP2 functions in a cell-intrinsic manner to regulate T cell sensitivity to CD95-mediated cell death. Biochemical studies showed that LGP2 expression in CD8+ T cells is regulated through crosstalk between the T cell receptor signaling and interferon signaling pathways. Mechanisms by which LGP2 regulates extrinsic apoptosis signaling and T cell survival will be discussed. Overall, these studies demonstrate a novel for LGP2 in regulating T cell immunity and reveals a broader role for RLRs in programming adaptive immune responses during virus infection.
Licensed and unlicensed natural killer cells show differential immunoregulatory and effector mechanisms during viral infection. (P4367)
Authors: Sungur Can , Zamora Anthony , Tang-Feldman Yajarayma , Baumgarth Nicole , Pomeroy Claire , Murphy William 
Published: January 2023

Abstract
Natural killer (NK) cells are innate lymphocytes with anti-viral and tumor capabilities that can be divided into subsets based on receptor expression patterns. If an NK cell expresses an inhibitory receptor that can bind to self-MHC I molecules it is considered to be “licensed” and fully functional; however, if the cell cannot bind to self it is “unlicensed”. We have observed differential effector and immunoregulatory functions of licensed versus unlicensed cells during influenza and murine cytomegalovirus (MCMV) infections in mouse models. We predict that licensed NK cells have anti-viral properties as well as immunoregulatory characteristics by killing T cell populations. The unlicensed NK cells may serve more of a helper cell role by aiding in tissue regeneration and enhancing dendritic cell (DC) numbers. After influenza or MCMV infection, there is a significant reduction in antigen-specific CD4 and CD8 T cell populations in the presence of licensed NK cells based on flow cytometry. Depletion of unlicensed NK cells reduces the number of DCs in the target tissues and lymph nodes. Additionally, the unlicensed NK cells are the primary producers of IL-22 based on intracellular staining in the damaged tissues after viral infection, aiding in tissue regeneration. Collectively, these data suggest a suppressive role for licensed NK cells to reduce the number of T cells, while the unlicensed serve as helper cells to aid in tissue regeneration and DC expansion during infection.
How MAIT cells control the growth of intracellular mycobacteria (P4381)
Authors: Sakala Isaac , Yankelevich Wei-Jen , Kjer-Nielsen Lars , Fairlie David , Rossjohn Jamie , McCluskey James , Hoft Daniel , Hansen Ted 
Published: January 2023

Abstract
Mucosal associated invariant T cells or MAIT cells have a semi-invariant TCR Vα chain and limited Vβ chains. In addition MAIT cell development is dependent upon the commensal microbiota and the expression of MR1, a highly conserved class Ib molecule of mammals. Mouse and human MAIT cells are activated in an MR1-restricted manner by cells infected with diverse strains for bacteria suggesting a widely shared antigen. Remarkably, human MR1 was recently shown to bind select bacterial vitamin B metabolites capable of activating MAIT cells in an MR1-restricted manner. This finding raised the interesting question of the importance of MR1 presentation of vitamin B metabolites for controlling bacterial infection. To address this question we have developed a mouse model whereby mycobacteria infected macrophages are co-cultured with purified MAIT cells, and control of intracellular bacterial growth is monitored. Using this assay, MAIT cell control of mycobacterial growth was found to depend upon IL-12 secretion by infected macrophages and IFN-γ secretion by MAIT cells. Interestingly, in the absence of infection, MAIT cells secreted IFN-γ in response to recombinant IL-12 alone or antigenic vitamin B metabolites. These findings demonstrate that MAIT cells can be activated by either TCR or non-TCR interactions. The contribution of these two pathways of MAIT cell activation in the context of mycobacterial infection is currently being investigated.
PGI2 inhibits IL-33-induced innate type 2 cytokine responses by natural helper cells (P4343)
Authors: Zhou Weisong , Toki Shinji , Goleniewska Kasia , FitzGerald Garret , Peebles R. 
Published: January 2023

Abstract
Natural helper (NH) cells are newly identified innate lymphoid cells that produce large amounts of type 2 cytokines including IL-5 and IL-13 in response to IL-33. NH cells are critical in protective type 2 immunity against helminth infection and mediate influenza virus-induced airway hypersensitivity. However, how type 2 immune responses of NH cells are regulated is not known. In this study, we tested the hypothesis that prostaglandin I 2, a lipid product formed in cyclooxygenase (COX) pathway in arachidonic acid metabolism, suppresses IL-33-induced type 2 cytokine responses by NH cells. Mouse NH cells (Lin -CD25 +CD127 + cells) were purified by flow cytometric cell sorting from bone marrow and stimulated with IL-33 in the presence of the PGI 2 analog cicaprost or vehicle. We found that cicaprost dose-dependently decreased IL-13 production by NH cells. In addition, when mice deficient of PGI 2 receptor (IP KO mice) were administered with IL-33 to the lung, they had greater IL-5 and IL-13 responses in the lung at 6 h after IL-33 challenge compared to WT mouse controls. These data indicate that PGI 2 and its receptor signaling inhibit NH cell-mediated innate type 2 immune responses and suggest that use of COX inhibiting drugs may increase the risk of developing allergic diseases by augmenting innate type 2 immunity.
Exogenous vitamin D inhibits human pro-inflammatory cytokine responses to TLR-4L but not TLR-8L innate immune activation (P6331)
Authors: Fitch Natascha , Becker Allan , HayGlass Kent 
Published: January 2023

Abstract
Population health studies demonstrate that insufficient/deficient Vitamin D status is strongly associated with increased upper respiratory tract infections. As low vitamin D status is widespread, it is imperative to understand the roles it plays during an immune response. Here we determine the effects of active vitamin D (1,25(OH)2D3) on peripheral blood mononuclear cells (PBMC) cytokine responses elicited by bacterial or viral ligands and explore mechanisms by which vitamin D regulates innate immune responses. Results: PBMC stimulated with TLR-4L and exogenous 1,25(OH)2D3 exhibited decreased pro-inflammatory cytokine production; whereas cultures stimulated with TLR-8L did not exhibit alterations in cytokine production patterns in the presence of supplemental 1,25(OH)2D3. 1,25(OH)2D3 alone slightly reduced TLR-4 but decreased TLR-8 by &gt;75%. Moreover, while TLR-4 ligand stimulation had no effect on VDR levels, TLR-8L stimulation reduced VDR mRNA by 60% (p&lt;0.005). Conclusions: Exogenous 1,25(OH)2D3 markedly reduces inflammatory cytokine production elicited by TLR-4 but not by TLR-8 or RSV activation. TLR-8L strikingly reduce VDR while 1,25(OH)2D3 reduces viral PRR expression, resulting in a synergistic decrease in the capacity of viral stimulated cells to have responses modulated by exogenous vitamin D. The results suggest a need for closer examination of the benefits of exogenous vitamin D supplementation in bacterial versus viral infection.
PGE2 modulates the ability of IFN-γ to inhibit IL-23 production in activated dendritic cells (P6333)
Authors: Rahbari Kate , Adhikary Sabina , Ganea Doina 
Published: January 2023

Abstract
The proinflammatory cytokine IL-23 emerged recently as a key player in autoimmune diseases. Production of IL-23 by pathogen-activated dendritic cells (DC) is regulated by endogenous mediators such as prostaglandin E2 (PGE2) and interferon-γ (IFN-γ). PGE2 stimulates IL-23 and inhibits IL-12 production. In contrast, IFN-γ inhibits IL-23 and stimulates IL-12. In the presence of both PGE2 and IFN-γ, TLR-stimulated DC produce higher levels of both cytokines. Here we analyze the signaling pathways involved in this complex regulation. IRF1, induced by LPS and at high levels by IFN-γ, acts as a positive transcription factor for IL-12p40, and as a negative regulator for IL-23p19. The potent effect of IFN-γ on IRF1 correlates with the inhibition of IL-23 and stimulation of IL-12 in LPS-activated DC. In contrast, PGE2 abolishes IRF1 expression in LPS-stimulated DC, resulting in the inhibition of IL-12 and stimulation of IL-23 production. When both PGE2 and IFN-γ are present, the IRF1 levels are similar to LPS controls, allowing for both IL-23p19 and IL-12p40 expression. In addition, as previously reported by us, the stimulatory effect of PGE2 on p19 transcription is also mediated through the activation of the positive transcription factors CREB and C/EBP. Our findings suggest that the combined presence of PGE2 and IFN-γ in autoimmune conditions results in sustained production of both IL-12 and IL-23, which contribute to the maintenance of a proinflammatory environment.
Flt3 ligand expands and activates myeloid-derived suppressor cells in a STAT3-independent manner (P1074)
Authors: Rosborough Brian , Liu Quan , Raïch-Regué Dàlia , Matta Benjamin , Mathews Lisa , Thomson Angus , Turnquist Heth 
Published: January 2023

Abstract
Introduction: Fms-like tyrosine kinase 3 ligand (Flt3L) promotes dendritic cell (DC) expansion; however, its influence on myeloid-derived suppressor cells (MDSC), an immature population of myeloid cells that suppresses T cell immunity, has not been studied. Methods: BALB/c mice were treated with Flt3L (10 μg/d i.p., 10 d) in the presence or absence of STAT3 inhibitor S31-201 (5 mg/kg/d). Splenic DC and MDSC were isolated by CD11c+ and Gr1+ magnetic bead selection, respectively. Stimulation and suppression of CD3+ T cell responses were assayed by MLR. Syngeneic MDSC were adoptively transferred (5x106) to BALB/c recipients 1 d before C57BL/6 heart transplantation and survival monitored. Results and Conclusions: Flt3L increased MDSC (CD11b+Gr1+) frequency and absolute numbers. MDSC from Flt3L-treated mice potently suppressed CD3+ T cell proliferation greater than control MDSC from naïve splenocytes. Conversely, Flt3L-expanded DC stimulated increased proliferation of allogeneic T cells compared to those from naïve control mice. While STAT3 is considered crucial for MDSC expansion and activation, STAT3 inhibition reduced Flt3L-mediated DC, but not MDSC, expansion. STAT3 inhibition augmented MDSC expansion by Flt3L, without affecting their suppressive capacity. Flt3L-expanded MDSC, but not control MDSC, demonstrated in vivo suppressive activity by prolonging fully MHC-mismatched heart transplant survival. Together, these data identify a novel immunomodulatory function of Flt3L.