bluuebunny/crossref_metadata_2025_split huggingface dataset:
SerpinB1 is essential for regulation of neutrophil extracellular trap (NET) generation (118.3)
Authors: Farley Kalamo , Stolley James , Zhao Picheng , Cooley Jessica , Remold-O'Donnell Eileen 
Published: January 2023

Abstract
NETosis, a programmed death pathway induced in mature neutrophils by pathogens and inflammatory mediators, can be either a protective process that prevents spread of microbial infection or a pathological process that causes severe tissue damage and inflammation. Little is known about the mechanisms that regulate such a diverse functional spectrum. Previously we demonstrated serpinB1 null mice are highly susceptible to pulmonary Pseudomonas aeruginosa infection due to increased pathology mediated neutrophilic death. Using in vitro and in vivo approaches we examine the regulatory role of SerpinB1 in NETosis. We found bone marrow or LPS-derived serpinB1 null neutrophils are remarkably prone to NETosis in both NADPH-dependent and independent manner. A regulatory role for SerpinB1 in NETosis is also supported by the increased number of neutrophils with expanded nuclei, likely representing chromatin decondensation, and by finding that exogenous rSERPINB1 abrogates NET production. Importantly, during P. aeruginosa lung infection 4 times more NETs were harvested from serpinb1-/- mice than WT mice. The total number of in vitro activated serpinB1-/- neutrophils that died was not different from wild-type, indicating that the primary protective role of SerpinB1 is determining whether activated neutrophils die by the highly injurious NETs mechanism or by a less phlogistic mode, generating apoptotic-like cells with shrunken appearance and small nuclei.
Treatment of Atopic Dermatitis by Bone Marrow-derived Clonal Mesenchymal Stem Cells (119.3)
Authors: Jeon Myung-Shin , Na Kwangmin , Yoo Hyun Seung , Choi Mi-Sook , Lee Hyeon Sook , Kim Hyo Jin , Lim Hyun-Ja , Yi TacGhee , Choi Gwang Seung , Song Sun U 
Published: January 2023

Abstract
Mesenchymal stem cells (MSCs) can perform immunomodulatory activities, including suppression of T- and B-cell proliferation. MSCs have been primarily studied for their suppression of pro-inflammatory Th1 responses, but their therapeutic effects on atopic dermatitis (AD), which is a Th2-dominant disease, have not been reported. In this study, using an ovalbumin-induced mouse AD model, we investigated whether MSCs reduce the allergic inflammation in AD. We used mouse bone marrow-derived clonal mesenchymal stem cells (mcMSCs) isolated by our newly established isolation protocol termed the subfractionation culturing method (SCM). When injected intravenously into animals between antigen challenges, mcMSCs were found to inhibit the majority of AD-specific pathological changes by decreasing cell infiltration in skin lesions and reducing serum level of IgE. To explore the mechanism of this effect, we investigated the effects of mcMSCs on IgE production in B cells. We found that mcMSCs significantly inhibited IgE production when B cells were stimulated either by lipopolysaccharide (LPS) or anti-CD40 antibodies in the presence of interleukin (IL)-4. In addition, allogeneic mcMSCs can inhibit both isotype class switching and terminal differentiation of B cells probably by inhibiting NF-κB activation. These results suggest that mcMSC-based cell therapy is a promising therapeutic modality for AD treatment.
Context dependent differentiation of resident and inflammatory intestinal macrophages from a common monocyte precursor (120.1)
Authors: Mowat Allan , Scott Charlotte , Bain Calum 
Published: January 2023

Abstract
Macrophages (mϕ) are essential for homeostasis and protective immunity in the intestine, but also drive pathology in inflammatory bowel disease. It is not clear whether these different functions are due to distinct populations of mϕ, or if the same cell change. We show here that two populations of mϕ exist within the mouse colon, based on the levels of CX3CR1 expression. Most resting mϕ express CX3CR1 at much higher levels than any other tissue mϕ and also express CD11c. These resident mϕ produce a balanced mixture of TNFα and IL10 constitutively, but respond poorly to stimulation via TLR, despite expressing all TLR. During acute DSS colitis, mϕ expressing lower levels of CX3CR1 come to dominate. These “inflammatory” mϕ produce TNFα predominantly and respond via TLR. Using a combination of gene profiling, immunophenotyping and adoptive transfer models, we show that CX3CR1int mϕ in both healthy and inflamed intestine are derived from Ly6Chi CCR2+ monocytes that upregulate CX3CR1 after entering the intestine, sequentially acquiring F4/80 and class II MHC expression. Under resting but not inflammatory conditions, the newly arrived monocytes differentiate further, becoming CX3CR1hi, producing IL10, expressing CD163 and CD206 and becoming TLR unresponsive. These results provide novel evidence that “resident” and “inflammatory” mϕ in the intestine derive from the same monocyte precursor whose ultimate fate is determined locally and depends on the presence or absence of inflammation
Retinoic acid is a specific IgA isotype switching factor (120.11)
Authors: Kim Pyeung-Hyeun , Seo Goo-Young , Kim Hyun-A , Lee Mi-Ra , Park Mi-Hee 
Published: January 2023

Abstract
Retinoic acid (RA) is known to have several activities which lead to potent mucosal IgA response. In the present study, we obtained several evidences that RA can act as a specific IgA isotype switching factor. RA, though less effective than TGF-β1, significantly increased IgA secretion and Ig germ-line α transcripts (GLTα) by LPS-activated mouse spleen B cells, while concurrently decreasing other isotypes secretion and GL transcripts. Based on limiting dilution analysis, RA increased the frequency of IgA secreting B cell clones by two-fold. This was not accompanied by increased numbers of IgA secreting cells/clone. Further, RA increased the activity of GLα promoter reporter by 3-fold and this was further increased by TGF-β1. Herein, RA-induced GLα expression was diminished by a TGF-β receptor I inhibitor (SB431542) and overexpression of DN-Smad3. Nevertheless, site-directed mutagenesis revealed that putative Smad3 binding elements (SBEs) are not relevant to RA-inducible promoter activity. Interestingly, RA-induced GLα transcription and IgA secretion were virtually disappeared by LE540, a RA receptor (RAR) antagonist. In addition, p38 inhibitor (SB203580) and ERK inhibitor (PD98059) diminished RA-induced GLα transcription and IgA secretion. In addition, we found that RA can induce p38MAPK/ERK phosphorylation. Taken together, these results suggest that RA induces GLα transcription through diverse pathways including RAR, Smad3, and p38MAPK/ERK, leading to IgA isotype switching.
Alcohol consumption is associated with tissue-specific alterations of myeloid-derived suppressor cells. (120.19)
Authors: Brand Rhonda , Stottlemyer J. Mark , Falo Louis 
Published: January 2023

Abstract
Alcohol consumption results in defects in immune function. The role of myeloid-derived suppressor cells (MDSC) and regulatory T-cells (Treg) in suppression of immune responses has been established. MDSCs in particular have been implicated in the suppression of both adaptive and innate immune responses. To develop a better understanding of the mechanisms by which alcohol effects immune function, we evaluated the effects of alcohol suppression specifically on MDSC and Treg populations. Previous studies suggest that ethanol consumption can result in tissue-specific inhibition of the antigen presentation function of dendritic cells and other APC populations. We used the Lieber-DeCarli liquid ethanol diet feeding model, which generates oxidative stress and liver steatosis, to examine the effect of alcohol consumption on MDSC and regulatory T cell populations in the spleen and serum. We found that the Lieber-DeCarli liquid ethanol diet had no effect on either circulating or splenic Treg populations, a result consistent with previous reports using a non-liver damaging ethanol feeding model (Meadows-Cook diet). On the other hand, we observed a specific increase in splenic MDSCs after ethanol exposure. These results suggest that alcohol ingestion induces regional changes in MSDC populations that may correlate with observed regional immune effects.
Monocyte-derived inflammatory dendritic cells expressing CX3CR1hi control urinary tract infection in mice. (120.25)
Authors: Partida-Sanchez Santiago , Horvath Dennis , Cortado Hanna , Li Birong , Flaño Emilio , Justice Sheryl 
Published: January 2023

Abstract
Phagocytes are essential for protecting the urinary tract from bacterial infections. Although neutrophils are required for clearing of bacteria during urinary tract infection (UTI), the function of monocyte-derived macrophages and dendritic cells (DCs) is less clear. To determine the role of monocyte-derived phagocytes, we used CD11b-DTRTg mice and selectively depleted CD11b+ blood monocytes prior to inoculation of uropathogenic Escherichia coli (UPEC) into the bladder. We then monitored monocyte-derived macrophages and DCs during the course of UTI. We found that conditional CD11b ablation effectively depleted a population of CXC3CR1+high, but not CX3CR1+low cells in the bladder and kidney. Interestingly, CX3CR1+high cells expressed low levels of F4/80 but expressed CD11c, and other DC markers, suggesting they were monocyte-derived DCs. UPEC induced bacterial burden was significantly elevated in the kidneys of CD11b-depleted mice at 48 hrs post-infection, when compared to controls. Furthermore, CX3CR1 KO mice were unable to clear UPEC 48 hrs post-infection; instead, bacteria spread from the bladder to the kidney, similarly to CD11b monocyte depleted mice. CX3CR1+high DCs, but not CX3CR1+low macrophages isolated from infected bladders produced abundant amounts of IL-6 and TNF-α pro-inflammatory cytokines. Our studies indicate that a monocyte-derived novel DC subset expressing CX3CR1 is required for preventing bacterial spreading, and the clearance of bacteria in the kidney.
Hsp90 and autoantibodies expression in periodontal disease (120.29)
Authors: Aguilera-Galaviz Luis , Hernandez-Montoya Martha , Lopez Luna Maria , Garcia Iris , Aceves-Medina Maria 
Published: January 2023

Abstract
In Periodontal disease (PD)several studies suggest, that exaggerated host immune and inflammatory response is considered as a potential risk for developing cardiovascular diseases, alter the course of diabetes, osteoporosis and premature babies during pregnancy. Objetives: the baseline of this study was to detect the presence of auto-antibodies and Hsp90 expression in healthy and systemic compromised patient. Methods: 32 patients with periodontitis were evaluated and 20 healthy people, blood sample to set up IFI for ANCA, antiepithelial antibodies, ANA and WB to determine the molecular profile using keratinocyte extract RT-PCR for Hsp 90 was performed in periodontal tissue. Results: 57% were positives for ANCA, the total of sera were positives for nuclear and/or cytoplasmic antibodies and 57% presented anti-epithelial antibodies, the sera from these patients recognized proteins in a wide range of molecular weight keratinocytes extract, and 30 and 70 kD in mouse skin extract, Hsp90 expression was considerably highest in PD patient and systemic compromise. Conclusions: The immune response in periodontal disease is influenced by the microflora, the production of antibodies against self structures, could be involved in the pathogenic mechanism; these autoantibodies are associated with necrotic or apoptotic phenomena. Metabolic activity of microorganism should be involved in cross reactions and antigen procesesing in situ could stimulate self reactive lymphocytes.
GITR on the surface of antigen presenting cells, but not on T cells, regulates the pathogenesis of CD4+ T cell-mediated experimental colitis (120.3)
Authors: Liao Gongxian , Berger Scott , Detre Cynthia , de Waal Malefyt Rene , Herzog Roland , Bhan Atul , Terhorst Cox 
Published: January 2023

Abstract
The receptor GITR is thought to function on the surface of regulatory and activated effector CD4+ T cells. To better understand the role of GITR in in vivo immune responses, we use an established experimental colitis model. Chronic enterocolitis was induced by the transfer of wt or GITR−/− CD4+ T cells into either GITR−/− x Rag−/− or Rag−/− recipients. When non-fractionated CD4+ cells from either wt or GITR−/− donors were transferred, colitis unexpectedly developed in GITR−/− x Rag−/−, but not in Rag−/− recipients. In these mice, the percentage of Treg and Th17 cells is decreased, whilst that of Th1 cells increased. Furthermore, Tregs fail to prevent colitis in GITR−/− x Rag−/− recipients. This is not due to an aberrant function of GITR−/− Treg or Teff cells, but is caused by an imbalance in the number of tolerogenic CD103+ and PDCA1+ plasmacytoid dendritic cells in the GITR−/− mouse. This in turn impairs Treg development and expands the Th1 population in GITR−/− x Rag−/− recipients upon the transfer of non-fractionated CD4+ cells. We conclude that for the induction of colitis, GITR is dispensable on the surface of Treg and Teff cells, nor do GITR-L / GITR interactions on T cells play a role in controlling the disease. GITR, however, controls in vivo DC and monocyte development and in its absence aggravated chronic enterocolitis is caused by an imbalance of colitogenic Th1 cells and regulatory T cells.
Tonsil-derived mesenchymal progenitor cells acquire a follicular dendritic cell phenotype under cytokine stimulation (120.34)
Authors: Woo So-Youn , Kim Ji-Yon , Cho Kyung-Ah , Kim Han Su , Ryu Kyung-Ha 
Published: January 2023

Abstract
Tonsils comprise part of the mucosal immune system and contain lymphocytes, macrophages, and follicular dendritic cells (FDCs). FDCs are located in the B cell area of the follicles of secondary lymphoid organs, such as the spleen, tonsils, or lymph nodes, and they trap and retain immune complexes on their surfaces to regulate B cell activation and maturation. Stromal cells from the palatine tonsils are often used for FDC in vitro studies, and it has been reported that human palatine tonsils may be a good source of multipotent mesenchymal cells. Therefore, we assessed whether tonsil-derived mesenchymal stromal cells could differentiate into a FDC-like phenotype. We discovered that stromal cells isolated from human tonsils not only had the potential to differentiate into various cell types of mesenchymal origin, but they also could differentiate into FDC-like cells under cytokine stimulation in vitro.
Regenerating islet-derived 3-gamma regulates pulmonary Th17 immunity by altering the gut microbiome (120.37)
Authors: McAleer Jeremy , Choi Sun Mi , Chen Kong , Binnie Matthew , Sheppard Dean , Qin Shulin , Reinhart Todd , Davila Eduardo , Hooper Lora , Ouyang Wenjun , Kolls Jay 
Published: January 2023

Abstract
Regenerating islet-derived 3-gamma (Reg3g) is a 17kDa lectin produced by intestinal paneth cells and has bactericidal activity against gram-positive organisms. Here, we find that lung infection with Staphylococcus aureus induces the expression of reg3g and reg3b in a MyD88-dependent manner. Expression of reg3b in the lung was localized to large airway cells, and increased following treatment with IL-17 and IL-22. Further, recombinant Reg3g had strong binding to S. aureus and growth inhibition in vitro. In vivo studies indicated that reg3g-/- mice were capable of clearing S. aureus infection, and produced significantly more IL-17 than control B6 mice. This was associated with increased segmented filamentous bacteria colonization in the gut of Reg3g-/- mice. To test the hypothesis that Reg3g regulates lung Th17 immunity by altering the gut microbiome, mice were treated with antibiotics prior to immunization with ovalbumin plus cholera toxin. Antibiotic treatment reduced lung Th17 numbers in Reg3g-/- mice to the level observed in B6 mice. Finally, gut vaccination with heat-killed Klebsiella pneumoniae increased Th17 cytokine expression in the lung and protected against live challenge, demonstrating the intestinal niche can augment pulmonary immunity. These data demonstrate dual roles for Reg3g in host defense: 1) direct anti-microbial activity against S. aureus, and 2) decreasing SFB levels in the gut, which could negatively impact Th17-mediated host defense.
Increased localization of Regulatory T cells in Hilar Lymph Node during the resolution of an ovalbumin induced - murine model of Allergic Airway Disease (120.38)
Authors: Natarajan Prabitha , Guernsey Linda , Secor Eric , McNamara Jeffery , Schramm Craig , Thrall Roger 
Published: January 2023

Abstract
In our biphasic ovalbumin (OVA)-induced allergic airway disease (AAD) model, short-term exposure of mice for 7 to 14 days to OVA via aerosol results in AAD, whereas continued daily exposure for 42 days leads to resolution of disease and development of local inhalational tolerance (LIT). In our earlier studies, we have shown from adoptive transfers that hilar lymph node (HLN) B cells isolated from LIT mice suppress development of AAD via TGF-β expression and had regulatory function. We also showed, in-vitro, that these cells induced conversion of effector T cells (Teffs) to regulatory T cells (Tregs) in a TGF-β dependent manner. In the present study, we investigated the association of Tregs and B cells within HLN of AAD and LIT mice. We demonstrated a significant increase in number of Tregs localized in B cell zones and T-B border in HLN of mice at LIT as compared to AAD qualitatively from confocal images. Quantification of Tregs using Imaris software in HLN yielded similar results. We studied the expression of chemokine receptors: CXCR4 and CXCR5 on Tregs via flow cytometry and showed a significant increase in number of Tregs expressing CXCR4 and CXCR5 in HLN from mice at AAD and LIT as compared to naive and sensitized groups. This observation correlated with the results obtained using confocal microscopy. Hence, we conclude that HLN regulatory B cells directly interact with Teffs converting them into Tregs in the B cell zones and contribute to the resolution of disease.
Inducible nitric oxide synthase inhibition protects mice from chlorine-induced airway dysfunction and inflammation. (120.39)
Authors: O'Koren Emily , Potts Erin , Foster W. , Gunn Michael 
Published: January 2023

Abstract
Inhalation of toxic chlorine (Cl2) gas causes an oxidative injury to the upper airways that results in epithelial damage, elevated airway hyperreactivity (AHR), and hypoxia in both humans and mice. We hypothesize that activated resident immune cells, specifically alveolar macrophages, respond to Cl2 gas injury by releasing effector molecules like TNF-alpa and iNOS, and that blocking the excess buildup of harmful effector molecules after injury will decrease inflammation and improve overall lung function. We targeted iNOS, an inflammation-induced enzyme that catalyzes the release of nitric oxide (NO) from L-arginine. We observed that Cl2-exposed iNOS-/- mice were completely protected from elevated AHR and hypoxia and exhibited decreased cytokine inflammation, BAL inflammatory infiltrates, and alveolar leakage. We then evaluated the effect of a small molecule inhibitor of iNOS, 1400w, on lung function and inflammation after Cl2 exposure. Mice treated with 1400w, starting 3hr post Cl2 exposure, exhibited the same protected responses as iNOS-/- deficient mice. AHR was decreased by 98%; arterial blood oxygen saturation levels were almost at normal levels, and pro-inflammatory cytokine levels, alveolar leakage, and BAL inflammatory infiltrate numbers were approximately reduced by half compared to PBS-treated Cl2-exposed control mice. Our findings demonstrate that iNOS inhibition is a promising therapeutic target for Cl2 injury.
Commensal bacteria regulate Treg abundance in a gnotobiotic model of food allergy. (120.6)
Authors: Feehley Taylor , Stefka Andrew , Tripathi Prabhanshu , Antonopoulos Dionysios , Chang Eugene , Theriault Betty , Nagler Cathryn 
Published: January 2023

Abstract
Increasing evidence points to a central role for commensal bacteria in the regulation of immune-mediated disease. We postulated that microbiota-derived signals govern susceptibility to allergic responses to food. We find that CD4+Foxp3+Tregs are significantly reduced in the colonic lamina propria (cLP) (but not the spleen or MLN) of mice that have been rederived germ free. Peanut specific IgE and IgG1 responses are significantly increased in response to intragastric sensitization of germ free mice. Depletion of the microbiota by treatment with an antibiotic cocktail also alters the response to allergic sensitization; increased Bacteroidetes (Bacteroideaceae) and reduced Firmicutes (Lachnospiraceae) correlate with the depletion of colonic Tregs and susceptibility to allergic sensitization in antibiotic-treated mice. We used selective media to culture bacteria representative of each of these families from the feces of SPF mice to examine their influence on allergic susceptibility. We hypothesized that certain bacterial families promote Treg induction, increasing protection against allergy. We find that Tregs are not induced in mice monocolonized with Bacteroides uniformis; sensitization of these mice results in PN specific IgE and IgG1 responses similar to germ free mice. Ongoing experiments are examining whether dual colonization with Lachnospiraceae (Coprococcus spp) restores the Treg compartment in the cLP and/or if Treg transfer protects against allergic sensitization.
Identifying the function of Notch1 in T-cell activation (121.1)
Authors: Dongre Anushka , Osborne Barbara 
Published: January 2023

Abstract
The Notch receptor is activated by ligands that belong to the Delta or Jagged family. Ligand binding is followed by proteolytic cleavages resulting in the release of intra-cellular Notch which translocates to the nucleus and functions as a transcriptional activator. While the role of Notch in thymocyte maturation has been studied, the precise role of Notch in T-cell activation and cellular metabolism remains incompletely understood. Evidence from our lab has suggested that TCR mediated activation leads to the generation of active Notch and inhibition via Gamma Secretase Inhibitors (GSI) decreases T cell activation and proliferation. However, since GSI’s are known to have multiple substrates, whether such a decrease in activation is indeed dependent on Notch or is simply a GSI mediated effect needs to be examined. To determine the role of Notch in T cell activation we conditionally deleted Notch1 in peripheral T cells. Our data demonstrate that CD4 cells have reduced expression of activation markers accompanied by a decrease in IL-2 and IFN-Gamma secretion as well as impaired proliferation in the absence of Notch1. Notch1 was also required for polarization towards Th1. Furthermore, absence of Notch1 decreased pAkt-S473 implying reduced mTORC2 activity. Our data implicate the importance of Notch1 in T cell function. Future studies are aimed to delineate the role of non-canonical Notch1 signaling in T cells and how it may influence molecular pathways downstream of the TCR.