bluuebunny/crossref_metadata_2025_split huggingface dataset:
Elevated Prostaglandin E2 Post-Bone Marrow Transplant Mediates Interleukin-1β Related-Lung Injury
Authors: Moore Bethany B , Martinez-Colon Giovanny J. , Taylor Quincy M , Wilke Carol A , Podsiad Amy 
Published: January 2023

Abstract
Hematopoietic stem cell transplantation (HSCT) treats hematological and inherited disorders. Unfortunately, patients that undergo HSCT become susceptible to infections by a wide array of opportunistic pathogens. The bacterial pathogen Pseudomonas aeruginosa can have life threatening effects in HSCT patients. In the lung, P. aeruginosa triggers the secretion of Interleukin-1β (IL-1β) by alveolar macrophages (AMs) and induces features of lung injury while inhibition of IL-1β or its receptor signaling has been shown to improve outcomes. In the present study, we used a mouse model of bone marrow transplantation (BMT) and found that high levels of prostaglandin E2 (PGE2) secreted by AMs post-BMT exacerbate IL-1β-mediated pulmonary injury post-P. aeruginosa instillation. We determined that the intracellular signaling pathway by which PGE2 induces IL-1β involves EP2/EP4 signaling with subsequent cAMP increase, PKA/Epac, and CREB transcription factor activation. Immature IL-1β can then be processed via either canonical or non-canonical inflammasomes (caspase-1 and caspase 8). Furthermore, PGE2 can induce IL-1β release despite the ability of PGE2 to limit autophagy, a pathway known to regulate inflammasome accumulation and bacterial killing. Interestingly, PGE2 inhibition in BMT mice decreases bacterial load, lung injury, and IL-1β in the lung. These findings can inform new therapeutic strategies that can improve outcome of HSCT patients with pulmonary complications due to P. aeruginosa, and possibly other pathogens.
Specific role of IL-1β in instigating skin inflammation in Sharpin-deficient mice
Authors: Sharma Bhesh Raj , Gurung Prajwal , Kanneganti Thirumala-Devi 
Published: January 2023

Abstract
Genetically inherited autoinflammatory skin disorders are characterized by spontaneous skin inflammation. Mutations in the members of linear ubiquitin chain assembly complex (LUBAC) are associated with spontaneous skin inflammation. Mice, deficient in SHARPIN (Sharpincpdm mice), a member of LUBAC, develop severe dermatitis associated with systemic autoinflammation. Previous studies have demonstrated that NLRP3 inflammasome provoke skin inflammation in Sharpin-deficient mice. However, whether IL-1α or IL-1β instigates disease and, if skin inflammation precedes systemic autoinflammation is not known. Here, we have performed thorough cellular analysis of pre-diseased and diseased Sharpin-deficient mice and demonstrated that systemic inflammation precedes skin inflammation. Furthermore, we demonstrate a specific role for IL-1β, but not IL-1α in instigating disease in Sharpincpdm mice. Our results altogether demonstrate distinct roles of SHARPIN in initiating systemic autoinflammation and skin dermatitis. Furthermore, skin inflammation in Sharpincpdm mice is specifically mediated by IL-1β, highlighting the importance of specific targeted therapies in IL-1 signaling blockade.
Characterizations of mucosal associated invariant T cells in alcoholic liver disease
Authors: Sa Moa , Kim Sojeong , Kim Won , Park Su-Hyung 
Published: January 2023

Abstract
The liver is a critical immunological site for chronic alcohol consumption as it filters various antigens activating both innate and adaptive responses. The pathogenesis of alcoholic liver disease (ALD) in human is not clear in terms of the specific role of immune cell population. Mucosal associated invariant T (MAIT) cells are found to be abundant in the mucosal organs, especially within the liver organ in which the cells comprise up to 50 % of T cells. Here, we show that the percentage of circulating MAIT cells is severely reduced in ALD patients (p=0.0028), including patients with steatohepatitis (ASH, n=20), steatohepatitis with cirrhosis (ASHAC, n=15) and cirrhosis (AC, n=12), compared to age-matched healthy donors (HD, n=8). Moreover, compared to non-liver disease group, MAIT cells are depleted among liver infiltrating lymphocytes in ASH (p=0.0276) and ASHAC (p=0.0049) patients, whereas that of AC group is recovered. Although the percentage of MAIT cells is decreased, the cells display increased expression level of activation markers. Pro-inflammatory cytokines such as IL-17A and MIP-1 beta are up-regulated in ASH and ASHAC patients by PMA/Ionomycin stimulation. In addition, Perforin and Granzyme B, which are cytotoxic markers in granule, are significantly increased in both peripheral blood and liver of ASHAC group. Taken together, our results suggest that activated MAIT cell population in the liver may contribute to the pathogenesis of ALD.
The xenobiotic transporter Mdr1 permits T cell adaptation to mucosa-associated bile acids in the ileum
Authors: Sundrud Mark S , Cao Wei , Kayama Hisako , Chen Mei Lan , Delmas Amber , Sun Amy , Kim Sang Yong , McKevitt Kelly , Rangarajan Erumbi S. , Beck Amanda P. , Oikonomopoulos Angelos , Lacey Precious N. , Martinez Gustavo J , Izard Tina , Lorenz Robin G , Rodriguez-Palacios Alex , Cominelli Fabio , Abreu Maria T , Hommes Daniel W. , Koralov Sergei B , Takeda Kiyoshi 
Published: January 2023

Abstract
Intestinal CD4+ T helper (TH) cells are subject to extensive regulation by microbiota. By contrast, it is not known whether or how TH cells interface with other, host-derived intestinal metabolites. Here we show that bile acids directly regulate mucosal TH cell function in the distal small intestine (i.e., ileum) via the xenobiotic transporter, Mdr1. Using both Mdr1-dependent dye efflux and a novel CRISPR-generated Mdr1 reporter mouse, we show that wild type RORγt+IL-17A+ (Th17) and RORγt-IFNγ+ (Th1) cells upregulate Mdr1 expression upon migration into the ileum. By contrast, germline ablation or shRNAmir-mediated knockdown of Mdr1 in Th17 and Th1 cells results in local dysfunction in the ileum, and these cells transfer Crohn’s disease-like ileitis in Rag1−/− hosts. Mdr1 enforces Th17 and Th1 cell survival and limits pro-inflammatory cytokine (TNFα, IFNγ) expression in the presence of conjugated bile acids (CBAs), which are actively reabsorbed through the ileal mucosa as a function of enterohepatic bile acid circulation. Accordingly, genetic or pharmacologic blockade of ileal CBA reabsorption restores Mdr1-deficient Th17 and Th1 cell homeostasis in ilea of transferred Rag1−/− hosts and rescues ileitis. In addition, MDR1 loss-of-function is evident in both ileitis-prone (SAMP1/YitFc) mice, and a subset of ileal Crohn’s disease patients. These data indicate that coordinated, local and druggable interactions between mucosal TH cells and mucosa-associated bile acids in the ileum contribute to intestinal immune homeostasis.
Contraction of intestinal effector T cells by retinoic acid-induced purinergic receptor P2X7
Authors: Hashimoto-Hill Seika , Friesen Leon , Kim Myunghoo , Kim Chang H 
Published: January 2023

Abstract
Vitamin A is a key regulator of immunity and immune tolerance. Here we report that the vitamin A metabolite retinoic acid regulates the population size of intestinal effector T cells by inducing purinergic receptor P2X7 expression. RA induces P2X7 expression by direct binding to an intragenic enhancer of the P2rx7 gene in CD4+T cells, rendering them highly susceptible to apoptosis triggered by P2X7 activation in response to extracellular ATP and NAD. Utilizing P2X7-null mice, we found that this tolerogenic mechanism is critical for reining in the expansion of Th1 and Th17 effector T cell populations in the intestine where the concentrations of extracellular ATP/NAD and retinoic acid are high. We demonstrated that P2X7 activation can ameliorate colitis by inducing the apoptosis of inflammatory effector T cells. We conclude that the RA-P2X7 axis is a novel immune homeostatic mechanism by which the size of potentially inflammatory effector T cell populations is tightly controlled to prevent inflammatory diseases.
Short chain fatty acids differentially regulate differentiation and function of Th1 and Th17 cells in the intestines
Authors: Chen Liang , Sun Mingming , Wu Wei , Chen Feidi , Huang Xiangsheng , Xiao Yi , Yao Suxia , Cong Yingzi 
Published: January 2023

Abstract
The mechanisms by which gut microbiota regulate host immune responses are still not completely understood. Short chain fatty acids (SCFA), mainly acetate (C2), propionate (C3), and butyrate (C4), the metabolites produced solely by gut microbiota, have been shown to promote development of Treg cells, and possibly other T cell subsets, in the intestines. However, the mechanisms involved remain unclear. In this report, we investigated how SCFA regulate development and function of microbiota antigen-specific T cells. We treated CBir1 transgenic T cells, specific for an immunodominant microbiota antigen CBir1 flagellin, with SCFA under various T cell polarization conditions to determine how they regulate T cell differentiation, and transferred those T cells into RAG−/− mice to determine their function in induction of colitis. Our results demonstrated that C2, C3 and C4 all promoted T cell production of IFN-γ and IL-10 when cultured under neutral and Th1 conditions. Under Th17 conditions C2, C3 promoted, while C4 inhibited, T cell IL-17 production at early stage of cell divisions. However, all three SCFA promoted T cell IL-10 production. Mechanistically, SCFA activation of mTOR pathway but not inhibition of HDAC or binding GPR43 mediated their effects on Th1 and Th17 cells. Functionally, transfer of C2- and C4-treated Th1 and Th17 cells induced less severe colitis in RAG−/− mice compared to untreated T cells, probably through induction of IL-10 by those T cells. Collectively, our study indicated that SCFA differentially regulate T cells differentiation and function in the intestines, which could contribute the maintenance of intestinal homeostasis.
IL-33 regulates the IgA-microbiota axis to restrain IL-1α dependent colitis and tumorigenesis
Authors: Malik Ankit , Sharma Deepika , Zhu Qifan , Karki Rajendra , Guy Clifford , Vogel Peter , Kanneganti Thirumala-Devi 
Published: January 2023

Abstract
Inflammatory bowel diseases (IBD) affect over 5 million individuals in the industrialized world, with an increasing incidence rate worldwide. IBD also predisposes affected individuals to development of colorectal cancer, which is a leading cause of cancer-related deaths in adults. Mutations in genes encoding molecules in the IL-33 signaling pathway are associated with colitis and colitis-associated cancer (CAC), but how IL-33 modulates gut homeostasis is unclear. Here, we show that Il33-deficient mice are highly susceptible to colitis and CAC. IL-33 promotes IgA production in the intestine, which is important for maintaining gut microbial homeostasis. Consequently, Il33-deficient mice develop a dysbiotic microbiota characterized by increased level of mucolytic and colitogenic bacteria. In response to DSS administration, this microbial landscape promotes the release of IL-1α, which acts as a critical driver of colitis and CAC. Consequently, reconstitution of symbiotic microbiota or IL-1α ablation markedly ameliorates colitis susceptibility in Il33−/− animals. Our results demonstrate that IL-33 promotes IgA production to maintain gut microbial homoeostasis, and restrain IL-1α dependent colitis and CAC. This study therefore highlights modulation of IL-33, IgA, IL-1α and the microbiota as potential therapeutic targets in the treatment of IBD and CAC.
Effect of TGF-β on Antigen-specific CD8+ T cell Response in Colitis
Authors: Demel Erika L , Mishra Shruti , Liu Yong , Liu Xun , Ma Chaoyu , Dube Peter , Zhang Nu 
Published: January 2023

Abstract
Inflammatory Bowel Disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract primarily including Crohn’s Disease (CD) and Ulcerative Colitis (UC). IBD affects 1.6 million Americans, and the worldwide incidence of IBD is growing in areas where the disease was previously infrequent. Currently, genetics, intestinal microbiota, environment, and dysregulation of the intestinal immune response are thought to be responsible for the development of IBD. Increased understanding of the immune response in IBD can be used to develop and improve treatments for patients. Much work has been done on the role of CD4+ T helper cells in IBD. The role of CD8+ T cells has been less heavily investigated despite noted differences in CD8+ T cells between UC and CD patients and healthy subjects.
In order to follow antigen-specific CD8+ T cell response during IBD, we developed a mouse strain in which the expression of model antigen Ova was specifically induced in the large intestine epithelium upon tamoxifen treatment (i.e. CDX2-cre/ERT2 Rosa26-Ova mice). By examining adoptively transferred OT-1 T cells, large intestine-specific CD8+ T cell response was determined during DSS induced colitis. Interestingly, the response of control OT-1 T cells was largely restricted to the large intestine while TGF-β unresponsive OT-1 T cells underwent dramatic expansion at both gut-associated and systemic sites. The functional consequence of TGF-β-controlled expansion of CD8+ T cells in colitis is currently under investigation.
Targeted delivery of microbial metabolite, urolithin A protects from chemically (DSS or TNBS) induced colitis in pre-clinical models
Authors: Singh Rajbir , Hegde Bindu , Von Baby Becca , Sadeep C , Kotla Niranjan , Chandrasekar Bhargavi , Marepally Srujan , Bodduluri Haribabu , Vemula Praveen K , Jala Venkatakrishna R 
Published: January 2023

Abstract
Epidemiological data suggests that consumption of diets rich in phytochemicals are protective in inflammatory bowel diseases (IBDs). However, the beneficial effects are not uniform among individuals and attributed to variations in gut microbiota, and altered capacity to generate certain metabolites. Urolithin A (UroA) (3,8-dihydroxybenzo[c]chromen-6-one) is a microbial metabolite, derived from ellagic acid and ellagitannins, major poly phenolic components in berries and pomegranates. Here, we examined therapeutic applications of UroA and mechanisms of action in IBDs. Our studies suggested that UroA significantly reduced LPS induced inflammatory mediators (e.g., IL-6, TNF-alpha and IL-12) as well as ROS production in mouse bone marrow-derived macrophages (BMDMs), dendritic and THP1 cells. Most importantly, UroA also reduced LPS induced systemic inflammation in mouse models. Next, we examined therapeutic applications of UroA in dextran sodium sulphate (DSS)-induced, 2,4,6-Trinitrobenzenesulfonic acid (TNBS)-induced colitis models. Treatment with UroA significantly reduced both acute and chronic DSS-induced colitis as well as TNBS induced colitis in mouse models. Most importantly, delivery of UroA utilizing inflammation targeting oral nano-particles (single treatment regimen) effectively mitigated the colitis in both models. In summary, these results highlight even presence of single microbial metabolite at right location at right time will have significant beneficial effects to protect from adverse inflammatory activities.
Canonical Wnt Signaling in CD11c+ antigen presenting cells controls inflammation-associated colon carcinogenesis and commensal homeostasis
Authors: Swafford Daniel J , Shanmugam Arulkumaran , Ranganathan Punithavathi , Manicassamy Santhakumar 
Published: January 2023

Abstract
The intestine contains high levels of the Wnt family of ligands, and the Wnt-signaling pathway is essential for intestinal homeostasis. Thus, aberrant Wnt/β-catenin-signaling may result in inflammatory bowel disease (IBD) and IBD-associated colon carcinogenesis. Although past studies have focused on this signaling pathway’s role in intestinal stem cell proliferation and epithelial cell maintenance, its role in shaping mucosal immune responses and commensal homeostasis in the gut remains unknown. In the present study, using a mouse model of colitis-associated colorectal cancer, we demonstrated that canonical Wnt-signaling in intestinal CD11c+ antigen presenting cells (APCs) controls intestinal inflammation and suppresses inflammation-driven colon carcinogenesis by imparting an anti-inflammatory phenotype. Genetic deletion of Wnt co-receptors, low-density lipoprotein receptor-related protein 5 and 6 (LRP5/6), in CD11c+ APCs in mice (LRP5/6ΔAPC mice) caused enhanced intestinal inflammation with increased tumor numbers in the colon due to increased production of pro-inflammatory cytokines and decreased expression of immune regulatory factors resulting from commensal dysbiosis. Mechanistically, loss of LRP5/6-mediated signaling in intestinal APCs resulted in enhanced effector T cell differentiation and decreased regulatory T cell differentiation. Furthermore, our study demonstrates that in LRP5/6ΔAPC mice conditional activation of β-catenin in intestinal APCs or in vivo blockade of IL-6 results in reduced intestinal inflammation with decreased colon tumor burden. These results reveal a mechanism by which intestinal APCs control gut inflammation and commensal homeostasis via canonical Wnt signaling.
The effects of obesity on the efficacy of immunotherapy.
Authors: Dudzinski Stephanie O , Beckermann Kathryn E , Rathmell Jeffrey C , Giorgio Todd D 
Published: January 2023

Abstract
Immunotherapy is a revolutionary treatment that harnesses the immune system to fight cancer. However, only a small fraction of patients responds to these treatments. Differences in an individual’s immune system and/or the tumor microenvironment may explain why immunotherapy is effective in only some patients. Obesity is an important cancer risk factor that is known to impair protective immunity, which may impact the effectiveness of immunotherapy. However, the impact of obesity on immunotherapy efficacy has never been investigated. We thus hypothesized that obesity reduces immunotherapy efficacy.
We studied the effects of obesity on the tumor microenvironment using a diet-induced obesity mouse model and immunoresponsive cell line. MC38 colon cancer cells were injected subcutaneously in C57BL/6 mice fed a high-fat or control diet. The tumors were collected three weeks post-injection and processed into single cell suspensions for flow cytometry. Samples were stained for helper T cells, cytotoxic T cells, and for macrophages with CD11b and F4/80, where CD206 and CD86 identified M2 and M1 macrophages, respectively. Initial experiments revealed a higher concentration of cytotoxic T cells in lean mice, which matches studies conducted in different cell lines. We will investigate the role of immune cell and cytokine differences further. In future experiments, we have engineered biocompatible nanoparticles that can modulate immune cells and shift the tumor microenvironment using siRNA, potentially improving immunotherapy efficacy in obesity. These initial studies will lay the foundation for future research and have important translational implications in improving the efficacy of immunotherapy treatment in obese patients.
Commensal dysbiosis alters the tumor microenvironment in luminal breast cancer
Authors: Buchta Claire M , Bostic Raegan R , Kearney John E , Rutkowski Melanie R 
Published: January 2023

Abstract
Many factors, including diet, race, and recurrent use of antibiotics, have been associated with an adverse outcome in breast cancer. These extrinsic factors also significantly impact the composition of commensal microbes. This is relevant, as a recent clinical trial demonstrated that patients with advanced hormone receptor+breast cancer had commensal dysbiosis, or significantly reduced composition of commensal microbes, supporting previous studies demonstrating that commensal microbes influence both the systemic immune environment and breast cancer progression. Dysbiosis was additionally shown to promote liver fibrosis in a mouse model of nonalcoholic fatty liver disease. As collagen deposition in mammary tissue is known to associate with breast cancer aggressiveness and metastasis, we hypothesized that dysbiosis enhances metastatic disease in luminal breast cancer through systemic changes to the immune environment, ultimately altering the extracellular matrix of tumors and mediating metastatic disease. To investigate this, we utilized a transplantable model of luminal HR+breast cancer where tumor fragments are transplanted into recipients with or without established commensal dysbiosis. We demonstrate that although the growth of primary tumors is not affected, commensal dysbiosis increases collagen deposition and macrophage infiltration in transplanted tumor fragments. Systemically, dysbiosis amplifies the production of CCL2, a chemokine associated with macrophage infiltration and metastatic potential. These data suggest that commensal dysbiosis enhances collagen deposition in breast tumors and influences the tumor microenvironment, potentially promoting metastatic disease.
Investigating the molecular mechanism of CRISPR-Cas adaptation of Streptococcus thermophilus
Authors: Louis Edwin Pierre , Wei Yunzhou , Terns Michael P 
Published: January 2023

Abstract
Bacteria are constantly challenged by viral infection. In order to combat potentially lethal viruses, bacteria possess adaptive immune defenses called CRISPR-Cas (Clustered Regularly Interspaced Short Palindromic Repeats-CRISPR-Associated) systems. These systems are RNA-based defense systems that memorize past viral infections to protect prokaryotes like bacteria from future infections. The acquisition of short DNA sequences (spacers) from previously encountered invaders allows bacteria to generate immunity. These systems capture spacers and incorporated them into their CRISPR loci to initialize immunity. Once integrated, spacers are then transcribed and processed into small RNA molecules called crRNAs, which are eventually bound by Cas proteins and form targeting complexes capable of cleaving viral DNA to achieve immunity. Genetic evidence indicates that Cas1, Cas2, Cas9 and Csn2 are each essential for CRISPR adaptation in the Type II-A system of Streptococcus thermophilus. However, the role of each of these proteins in adaptation is not clear. We have systematically constructed single cas gene deletion strains. We aim to detect and analyze low level of adaptation events in these genetic backgrounds, and in turn gain insight into the specific roles of each of these proteins. We also plan to apply biochemical approaches using purified proteins to investigate the molecular mechanistic steps of adaptation.