bluuebunny/crossref_metadata_2025_split huggingface dataset:
NOD2 promotes protective responses and recovery from Candida tropicalis infection in dextran sodium sulfate (DSS) colitic mice
Authors: Buela Kristine-Ann G. , De Salvo Carlo , Havran Hannah , Hager Christopher , Di Martino Luca , Cominelli Fabio , Ghannoum Mahmoud , Pizarro Theresa 
Published: January 2023

Abstract
Although it is well established that the gut microbiome plays an important role in GI health and disease, recent studies also underscore the complexity and contribution of intestinal fungal communities by, for example, promoting dysbiosis in mouse models of colitis and Crohn’s disease patients, which both have higher levels of Candida tropicalis (Ct) vs controls. Also, proteins encoded by IBD susceptibility loci, such as pattern recognition receptors (PRRs), not only recognize bacterial products, but in the case of NOD2, also detects the fungal cell wall component, chitin. Yet, how PRRs regulate intestinal fungal immunity and how fungi impact colitis is poorly understood. Herein, we show that while Ct infection does not exacerbate colitis in WT controls, Nod2−/− mice show a higher fungal burden and delayed recovery after DSS challenge, indicating NOD2’s protective role and ability to promote fungal clearance during experimental colitis. In the absence of NOD2, epithelial barrier function is compromised, with increased immune cell infiltration and muscle wall thickening. Nod2−/− mice specifically infected with Ct, and not other commensal species, express reduced colonic IL-6 (promotes Th17 and ILC3s), as well as IL-22 and IL-17 (cytokines that maintain epithelial barrier integrity), and show a decreased frequency of MLN-derived IL-17+ ILC3s vs WT, suggesting that delay in fungal clearance and recovery from colitis in Nod2−/− mice may be due to the inability to mount protective type 3 immune responses. Overall, these findings reveal that opportunistic fungal infections during colitis impede gut mucosal healing, and that NOD2 may not only impact the gut microbiome, but also the mycobiome, possibly through an IL-17-mediated mechanism.
Alveolar macrophages provide an early Mycobacterium tuberculosis niche and initiate dissemination
Authors: Cohen Sara Beth , Gern Benjamin H , Delahaye Jared L , Plumlee Courtney R , Gerner Michael Y , Urdahl Kevin B 
Published: January 2023

Abstract
Mycobacterium tuberculosis (Mtb) infection is initiated in the distal airways, a site patrolled by alveolar macrophages (AM), and infection outcomes are governed by early immune events that remain poorly understood. We show that Mtb replicates almost exclusively within airway-resident AM during the first week after aerosol exposure. Although AM are typically thought to reside within the alveolar lumen, confocal imaging demonstrated that Mtb-infected AM establish a novel niche within the lung interstitium, where they undergo proliferation and physically associate with recruited monocyte-derived cells (MC). Localization of AM to the interstitium precedes subsequent Mtb uptake by MC and neutrophils and is driven by non-hematopoietic MyD88/IL-1R inflammasome signaling and the Mtb ESX-1 secretion system. The interstitial localization of infected AM occurs in the absence of recruited monocytes and neutrophils, suggesting that this pulmonary niche may result from AM-intrinsic egress from the alveolar space rather than inflammation-driven alveolar consolidation. Comparisons of the transcriptomes of infected AM localized to the airway or interstitium by RNA-sequencing revealed unique transcriptional profiles in the two populations, suggesting that these two AM subsets may be functionally distinct. For example, Mtb-infected AM in the interstitium dramatically upregulated interferon-response genes, lending support to the idea that these cells are in unique lung environments. Thus, crosstalk between Mtb-infected AM and non-hematopoietic cells establishes pulmonary Mtb infection by promoting the translocation of infected cells from the alveoli to lung interstitium, facilitating dissemination to other myeloid subsets.
Addition of rexinoids during T cell activation enhances mucosal-homing receptor expression and migratory ability of effector cells in vitro
Authors: Manhas Kavita , Marshall Pamela , Wagner Carl E , Jurutka Peter W , Blattman Joseph N 
Published: January 2023

Abstract
Certain vitamins directly impact immune cell migration, indicating potential to function as a vaccine adjuvant. We previously showed that all-trans retinoic acid (ATRA), the biologically active form of vitamin A, modifies gut-homing receptor expression on effector T cells upon binding to the retinoic acid receptor (RAR), which joins with the retinoid X receptor (RXR) to function. Giving ATRA during vaccination also resulted in enhanced mucosal protection following viral challenge in murine models. While promising, certain factors limit adding ATRA to a vaccine, including its instability and poor solubility. Rexinoids, synthetic ligands for the RXR, may mimic or better ATRA immune effects by enhancing RAR-mediated transcription. Their improved stability and solubility also indicates a greater potential for clinical use. Here we explored the ability of different rexinoids to program effector T cell expression of gut-homing receptors CCR9, a4b7, and CD103. Naïve T cells from transgenic mice were activated with appropriate peptide and set concentration of each rexinoid. Flow cytometric analysis showed increased expression of gut-homing receptors in the presence of select rexinoids, indicating their ability to act as an ATRA mimic. A cooperative relationship was seen between other rexinoids and ATRA as co-culturing with suboptimal doses of each showed enhanced receptor expression, suggesting they could potentially act with ATRA normally found in serum. Some rexinoids also promoted better effector T cell migration compared to ATRA, following analysis of a transwell migration assay. Overall, our findings support the prospective use of rexinoids as adjuvants during vaccination.
Metabolic utilization of propanediol by adherent-invasive E. coli regulates intestinal tissue immunity
Authors: Viladomiu Monica , Metz Maeva L , Lima Svetlana F , Chou Lance , Guo Chun-Jun , Simpson Kenneth W , Scherl Ellen J , Longman Randy 
Published: January 2023

Abstract
Crohn’s Disease (CD) has been associated with alterations in the intestinal microbiota, but the microbial mechanisms that regulate host immunity are largely unknown. We have recently shown that Adherent-Invasive E. coli (AIEC), which are enriched in CD patients, are sufficient to induce intestinal Th17 cells. Although AIEC lack pathogenic factors including type III secretion systems, many CD-derived isolates express virulence-associated metabolic enzymes including propanediol dehydratase (PduC), which enables AIEC to use fucose-derived propanediol as an alternate carbon source. We found that pduC is enriched in the microbiome and among E. coli genomes in CD patients compared to healthy controls. To evaluate the physiologic contribution of propanediol utilization to AIEC Th17 induction, we generated a pduC-deficient mutant of a CD-derived, AIEC isolate. Deletion of pduC resulted in reduced, inflammatory Th17 cells and attenuated weight loss following T cell transfer colitis. Using genetic mouse models, we found that CX3CR1+ mononuclear phagocytes are required for AIEC-mediated Th17 induction and IL-10 is required to restrain pduC-dependent colitis. Using a catalytically-inactive mutant, we determined that PduC metabolic activity was required for this immune phenotype. Cell-free supernatants from WT AIEC (but not the isogenic, pduC-deficient clone) promoted ex vivo Th17 cell polarization and metabolomics analysis (LC-MS) of these supernatants defined PduC-dependent metabolites capable of promoting Th17 polarization. These studies reveal a link between AIEC metabolism and inflammatory Th17 cells with the potential to serve as a therapeutic target in the treatment of CD.
Lymphotoxin-beta receptor expression by neutrophils prevents metabolic activation and colitis pathogenesis
Authors: Riffelmacher Thomas , Giles Daniel , Zahner Sonja , Andreyev Alexander , McArdle Sara , Perez Tamara , van der Gracht E.T.I. , Morris Venetia , Tumanov Alexei , Kronenberg Mitchell 
Published: January 2023

Abstract
Inflammatory bowel disease, while multifactorial, is largely characterized by exacerbated intestinal immune activation. However, the critical mechanisms regulating immune activation remain to be fully defined. We have previously reported that a member of the TNF superfamily, TNFSF14 (LIGHT), and its interaction with the lymphotoxin beta receptor (LTβR), is required for preventing severe disease in a mouse model of dextran sulfate sodium (DSS) induced colitis. Thus, we aimed to determine the cell type and mechanism critical to LTβR mediated suppression of DSS-induced colitis. Employing the use of LTβRfl/fl mice and tissue-specific Cre-mediated deletion, we found that neutrophils were the critical LTβR expressing cell type. Deletion of LTβR expression in neutrophils (LtbrΔneut)resulted in exacerbated DSS-induced colitis and drastically increased colonic neutrophil accumulation. Mechanistically, RNA-Seq analysis of neutrophils revealed transcriptional alterations in genes associated with cellular metabolism, and mitochondrial function. Ex vivo studies of bone marrow neutrophils from LtbrΔneut, compared to Cre- controls, revealed increased mitochondrial mass and number, as well as elevated mitochondrial ROS production in neutrophils lacking the receptor. Subsequent metabolic studies demonstrated that LTβR deficient neutrophils exhibited elevated mitochondrial respiration and glycolysis. Interestingly, these increased levels of mitochondrial mass, ROS production and glycolytic activity persist in LtbrΔneut colonic neutrophils during DSS-induced colitis. In sum, our results demonstrate that neutrophil LTβR signaling plays a critical role in the immune activation associated with DSS-induced colitis.
Intestinal colonization with IL-10 inducing adherent E. coli protects from intestinal inflammation and tumor development
Authors: Diehl Gretchen , Ruiz Daniel Zegarra , Kim Dasom , Norwood Kendra , Hill Andrea A. , Morales Fatima Beatriz Saldana 
Published: January 2023

Abstract
Colorectal cancer (CRC) is the third most common and third most deadly cancer in the US. Chronic intestinal inflammation corresponds with advanced disease stage and decreased survival in CRC. Intestinal inflammation corresponds with changes in the microbiota, including expanded proteobacteria, such as E. coli. This altered microbiota is thought to support inflammation and disease progression in both CRC and inflammatory bowel disease (IBD). However, how individual microbes interact with host cells and the pathways they activate remains incompletely defined. We characterized immune effects after colonization with individual isolates from a panel of human mucosally associated E. coli. In contrast to our expectations, a subset induced intestinal macrophage production of IL-10, protecting from colitis. Further characterization of a single isolate revealed colonization with this isolate limited tumor incidence in a model of inflammation associated colorectal tumors. Intestinal macrophages, macrophage production of IL-10, and epithelial expression of IL-10 receptor were all required for anti-inflammatory and anti-tumor effects. Colonization with an isogenic mutant E. coli that lacked a single gene important for epithelial attachment did not induce IL-10 and amplified intestinal tumors with increased tumor infiltration of anti-inflammatory immune cells. While the inherent diversity of the microbiota makes it difficult to pinpoint singular pathways of tumorigenesis, we have identified a regulatory loop between adherent microbes, intestinal epithelium and intestinal immune cells which promotes barrier integrity and limits tumor development, identifying novel ways to therapeutically target inflammation and CRC.
B cell-specific S1P1 deletion reshapes both B and T cell activation profiles in hypersensitivity pneumonitis
Authors: Huppé Carole-Ann , Lecours Pascale Blais , Morissette Mathieu , Marsolais David 
Published: January 2023

Abstract
Hypersensitivity pneumonitis (HP) is a TH1/TH17-polarized chronic disease caused by repetitive exposure to airborne agents. Efficient acquired B cell responses are thought to sustain pulmonary inflammation in HP. We found that an S1P1 pharmacological ligand prevented the reactivation of hypersensitivity upon airway antigenic exposure, which translated into a decrease of antigen-specific antibodies. Given that mice with B cell-specific S1P1 deletion (B-S1P1KO) feature altered bone marrow egress, lower peripheral B cell levels, as well as a defect in antigen uptake, we hypothesized that S1P1 deletion on B cell could mitigate HP progression. B-S1P1KO mice were exposed three times a week for three weeks to an HP-causing agent, Methanosphaera stadtmanae (MSS), and were euthanized 24 hours or 4 days after the last exposure for flow cytometry analyses. Lymphocyte populations in the lung of B-S1P1KO mice were more activated in response to MSS compared to the control strain. Indeed, we observed an increase surface expression of CD80, CD86 on B cells and surprisingly, an increase of surface levels of CD69, CD44 and CD25 on T cells. MHCII levels at the B cell surface were reduced in B-S1P1KO mice, compared to the control strain, while there were no differences in MHCII expression on dendritic cells or macrophages. B cell-specific S1P1 deletion increased the frequency of B cells with the ability to produce pro-inflammatory cytokines (IFNg+, IL-4+ and IL-6+). Concomitantly, the frequency of both B cells and T cells with the ability to produce IL-10 was reduced. Thus, B cell-specific S1P1 deletion induces a proinflammatory B cell phenotype in the HP lung and reduces regulatory populations.
Heterogeneity of regulatory T cells during lung inflammation
Authors: Huang Weishan , Ye Kaixiong , Nidetz Natalie F , McGee Michael C , Islam Rezwanul , Limper Candice B , August Avery 
Published: January 2023

Abstract
Pulmonary inflammation is the leading cause of respiratory illness worldwide. Although strong T cell responses are desired for defending the hosts against infections, the cytotoxic effector function of the innate and adaptive immune responses can lead to the development of pulmonary immunopathology, which may lead to death. While T cells produce inflammatory cytokines during infections and allergies, they can also produce the immunomodulatory cytokine IL-10, which is critical for limiting the immunopathology caused by the excessive effector immune responses. However, the composition of IL-10-producing lymphocyte population and their molecular signatures are unclear. Using mouse models that report the production of IL-10 by GFP and expression of T regulatory cell marker Foxp3 by RFP, mouse models of lung inflammation (including allergic asthma, hypersensitivity pneumonitis, and flu), transcriptomic analyses at the population and single cell levels, and transgenic mouse models that are impaired in T cell-derived IL-10 production, we found that, in the disease models used, regulatory T cells in the mouse airway are mainly comprised of CD4+ Foxp3+, CD4+ Foxp3− and CD8+ subsets, and they differ under different disease conditions. Furthermore, within each subset, IL-10-producing T cells exhibit significant molecular heterogeneity. Information gained from this dataset provides insights into the T cell subset heterogeneity and signature markers, and shed light for future strategic design for therapeutic development utilizing the immunomodulatory features of T cells for the treatment of pulmonary immunopathology.
Distinct memory γδ T cell subsets are fine-tuned by TCR engagement and soluble signals to shape IFNγ and IL-17A responses
Authors: Khairallah Camille F , Imperato Jessica N , Yang Daniella , Qiu Zhijuan , Sheridan Brian S 
Published: January 2023

Abstract
Unconventional T cells are essential for tissue homeostasis and protection against invading pathogens at barrier sites. γδ T cells are enriched at these interfaces where they can form memory populations that can be either beneficial or detrimental depending on the functional response elicited. However, our understanding of the factors regulating memory γδ T cell generation, activation and function remains limited. Foodborne Listeria monocytogenes (Lm) infection of Batf3−/− mice revealed a critical role for Batf3-dependent dendritic cells in the generation and function of adaptive γδ T cells. In line with this observation, IFNγ and IL-17A production and IFNγ/IL-17A co-production by memory γδ T cells were induced by heat-killed Lm after 24 hours in culture, and these responses were inhibited after MHC-II or CD11c depletion. The induction of cytokine production was tightly associated with Zap70/Syk phosphorylation, indicative of TCR activation. Although IL-12 is usually associated with type 1 responses, neutralization of IL-12/23p40 dramatically impaired IL-17A production whereas IFNγ response was only marginally affected. Surprisingly, classical TH17 polarizing cytokines had little impact on IL-17A production. Despite this conventional-like response, memory γδ T cells remained able to quickly produce IL-17A in response to supernatant or live Lm independently of TCR signaling. Thus, adaptive γδ T cells are a functionally diverse population that encompasses innate- and adaptive-like responses that are fine-tuned by the γδTCR and soluble signals. These insights may facilitate the development of new strategies eliciting specific functional subsets of memory γδ T cells tailored to various intestinal disease settings.
ST2-expressing B1 B cells acquire an anti-inflammatory capacity during pregnancy in mice
Authors: Valeff Natalin Jimena , Ventimiglia Maria Silvia , Quadrana Florencia , Jensen Federico 
Published: January 2023

Abstract
In the context of pregnancy, it is known that IL-33 induces the production of anti-inflammatory molecules by decidual B1 cells, protecting against preterm birth (PTB) in human and mouse. We have previously showed that expression of IL-33 receptor, Il1rl1 (ST2) is significantly upregulated in splenic B cells during mid pregnancy, predominantly in B1 cell subset. Furthermore, using an LPS induced PTB mouse model, we observed increased numbers of splenic and decidual ST2-expressing B1 cells in the acute phase of PTB as compared to term pregnant females.
We aimed to investigate here the anti-inflammatory properties of ST2-expressing B1 cells during pregnancy. Total splenocytes from pregnant (P) and non-pregnant (NP) mice were isolated and cultured for 24h with/without LPS (10 μgr/ml), ST2 expression and cytokine production by ST2+ B1 cells was evaluated by flow cytometry. B1 cells from P mice stimulated with LPS showed significantly higher levels of ST2 expression. ST2+ B1 cells produced significantly higher levels of IL-10 and significantly lower levels of TNF-α and IL-17 as compared to ST2+ B1 cells from NP mice.
In a separate project in our laboratory we demonstrated that prophylactic treatment with probiotic Lactobacillus kefiri prevented LPS-induced PTB in mice. Interestingly, we observed that numbers of splenic and decidual ST2-expressing B1 cells were increased in L. kefiri treated mice that were protected against LPS-induced PTB.
Our data strongly suggest an anti-inflammatory capacity of ST2-expressing B1 cells during gestation, presumably to ensure pregnancy wellbeing and prevent inflammation induced PTB.
Antigen recognition by CD8+ T cells in non-lymphoid tissues initiates a transcriptional program of tissue-resident memory differentiation
Authors: Nolz Jeffrey C , Hobbs Samuel J 
Published: January 2023

Abstract
Tissue-resident memory (TRM) CD8+ T cells permanently reside within non-lymphoid tissues to provide a first-line of defense against invading pathogens. TRM T cells are largely derived from recently activated effector T cells, but the mechanisms that control the extent of TRM differentiation once they are recruited into non-lymphoid tissue microenvironments are largely undefined. To determine how T cell receptor (TCR) engagement promotes TRM formation, we utilized interferon-gamma (IFNγ)-YFP reporter T cells and found that only ~25% of the antigen-specific CD8+ T cells in the skin produced IFNγ during the course of a Vaccinia virus (VacV) infection. Strikingly, expression of IFNγ was strictly antigen-dependent and genome-wide transcriptional profiling revealed that IFNγ+ CD8+ T cells in the VacV-infected skin were becoming tissue-residents, suggesting that local antigen recognition identifies the dominant TRM precursor population. Mechanistically, TCR engagement caused effector CD8+ T cells to express Blimp1 and repress expression of the tissue egress receptor S1PR1 and the transcription factor KLF2, collectively preventing S1P-dependent migration. Interestingly, the S1PR1 antagonist CD69 was not transcriptionally upregulated by TCR stimulation. However, CD69 surface expression was Blimp1 dependent, suggesting that Blimp1-mediated repression of S1PR1 causes increased availability of CD69 protein to remain on the cell surface, a hallmark of TRM differentiation. Thus, antigen recognition by effector CD8+ T cells in non-lymphoid tissues is a critical factor that promotes Blimp1 expression, ultimately causing stable expression of CD69 and retention of TRM CD8+ T cells in the skin following viral infection.
Fli-1 inhibitors reduce the production of inflammatory cytokines in human renal glomerular endothelial cells and ameliorate lupus nephritis in NZB/W F1 mice
Authors: Wang Xuan , Gilkeson Gary S , Zhang Xian 
Published: January 2023

Abstract
Expression of transcription factor Fli-1 impacts lupus nephritis (LN) development in both human patients and murine models of lupus. We studied the effects of camptothecin and topotecan, Fli-1 inhibitors, on LN in NZB/W F1 mice and renal endothelial cells. Human Renal Glomerular Endothelial Cells (HRGEC) were treated with Fli-1 inhibitors, and inflammatory cytokines were measured after stimulation with IFN-α and IFN-γ. NZB/W F1 female mice were treated with camptothecin, topotecan, cyclophosphamide, or vehicle control. Blood and urine were collected, and autoantibodies and proteinuria were monitored.
The expression of Fli-1 in HRGEC, when treated with 0.1 μM or higher concentrations of camptothecin, was significantly reduced. The production of MCP-1 and IP-10, inflammatory cytokines associated with LN development, were significantly lower in the HRGEC treated with camptothecin compared to the HRGEC treated with DMSO at 4 and 24 hours following stimulation with IFN-α and IFN-γ at the concentration of 100 ng/ml. NZB/W F1 mice were treated with camptothecin, topotecan, cyclophosphamide, or PBS control when more than 40% of mice had proteinuria higher than 30 mg/dL. At the age of 37 weeks, 70% of NZB/W F1 mice treated with vehicle had proteinuria higher than 2,000 mg/dL. None of the NZB/W F1 mice treated with camptothecin or topotecan had proteinuria higher than 100 mg/dL. One of the NZB/W F1 mice treated with cyclophosphamide had proteinuria higher than 100 mg/dL. Blood urea nitrogen (BUN) was lower in the sera from NZB/W F1 mice treated with camptothecin, topotecan, or cyclophosphamide compared to that of the mice treated with vehicle. Together, these results indicate that Fli-1 inhibitors are novel therapeutic approaches in treating LN.