bluuebunny/crossref_metadata_2025_split huggingface dataset:
An IL-23/STAT4 axis regulates classical dendritic cell expansion and function in CNS autoimmunity
Authors: Alakhras Nada Salem , Kaplan Mark H 
Published: August 2023

Abstract
Signal transducer and activator of transcription 4 (STAT4) is a critical regulator of inflammation in autoimmunity by acting as a messenger for pro-inflammatory cytokines including IL-12 and IL-23. In experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, germ-line deletion of STAT4 in mice results in resistance to the development of paralysis. Here, we examined STAT4 cell-specific requirements in EAE. Using conditional Stat4 mutant mice, we found that mice lacking Stat4 in CD4+ T cells and CD11c+ cells are resistant to EAE, while Lyz2+ cells are susceptible to EAE demonstrating cell type requirement for STAT4 in EAE. STAT4 is expressed and activated in CD11c+ classical dendritic cells (cDCs) in the CNS at the peak of EAE. Stat4fl/flCD11cCre(Stat4ΔCD11c) mice exhibit a significant decrease of cDC expansion in the CNS, and this correlates with diminished numbers of T cells in the CNS and decreased inflammatory cytokine production. Adoptive transfer of wild-type DCs into Stat4ΔCD11c rescues the development of EAE. In contrast, transferring Il23r−/−DCs to Stat4ΔCD11c did not rescue EAE development. Transferred Il23r−/−DCs were retained in the lymph nodes suggesting that IL-23-STAT4 signaling in cDCs promotes their expansion in the CNS during neuroinflammation. CITE-seq analysis of CNS DCs from control and Stat4ΔCD11c mice identified STAT4-dependent genes in cDCs in EAE. Collectively, our results demonstrate that STAT4 in cDCs is required for their expansion in the CNS, the development of pro-inflammatory T cells, and the clinical symptoms of EAE. Thus, our study reveals previously unrecognized functions of STAT4 in cDCs that could identify novel therapeutic approaches for CNS autoimmunity.
Compartmentalized antigen presentation and inflammasome activation between epithelial cells and macrophages orchestrates gut immunity
Authors: Malik Ankit , Sharma Deepika , McGrath Shaina , Aguirre-Gamboa Raúl , Jabri Bana 
Published: August 2023

Abstract
All nucleated cells express MHCI and IFN-gR. It is suggested that structural cells express MHCI to prevent NK-cell mediated cytotoxicity and allow deletion by CD8+ T cells upon intracellular perturbations, but a cell-specific function of antigen presentation via MHCI has not been explored. We show here that upon sensing IFN-g, colonic epithelial cells productively present pathogen and self-derived antigens to the cognate intra-epithelial T cells, which are critically located at the epithelial barrier. Antigen presentation by the epithelial cells confers ATPase expression in the cognate intra-epithelial T cells which limits the accumulation of extracellular ATP and consequent activation of the NLRP3 inflammasome in tissue macrophages. In contrast, antigen presentation by the tissue macrophages alongside inflammasome-associated IL-1a and IL-1b production promotes a pathogenic transformation of CD4+ T cells into GM-CSF-producing T cells in vivo, which underlies colitis and colorectal cancer. Supporting the relevance of these findings in humans, we show that the IBD-associated IFN-gR SNP leads to defective IFN-g signaling. Furthermore, decreased expression of IFN-gR or ATPase and increased expression of GM-CSF are associated with IBD that is resistant to the standard therapies, and reduced survival with colorectal cancer. Taken together, our study has unraveled a critical checkpoint requiring IFN-g sensing and antigen presentation by epithelial cells that control the development of pathogenic CD4+ T cell responses in vivo.
Supported by the US National Institutes of Health (DK067180) to B.J, the University of Chicago’s Center for Interdisciplinary Study of Inflammatory Intestinal Disorders (C-IID) Pilot & Feasibility Award (NIDDK P30 DK042086) to A.M. and D.S, Crohn’s and Colitis Foundation Career Development Award #964209 to A.M. and G.I. Research Foundation Associates Board Award to A.M. and D.S.
Epigenetic mechanisms of epithelial – immune interactions that shape immune surveillance in the intestinal epithelium
Authors: Garipcan Aybuke , Eskiocak Onur , Subhash Santhilal , Ozler Kadir , Yueh Brian , Chung Charlie , Ergin Ilgin , Gautier Nelson , Habel Jill , Rubino Rachel , Van der Velden Adrianus W M , Beyaz Semir 
Published: August 2023

Abstract
Immune surveillance of the intestinal epithelium is regulated by the reciprocal interactions between intestinal epithelial cells, immune system and microbiome. This highly specialized compartment maintains the tolerance against dietary products and commensal bacteria while protecting the epithelium against pathogens, cancer risk and tissue damage. While recent studies identified epigenetic mechanisms that orchestrate the self-renewal and differentiation of intestinal epithelial cells (IECs), little is known about the mechanisms that govern epithelial – immune interactions and how they influence immune surveillance and tissue regeneration. Here we dissect epithelial-intrinsic epigenetic features including transcription factors and co-activators that govern immune surveillance of intestinal epithelium using genetically engineered mouse models and autologous human patient-derived organoid – immune co-cultures. Ablation of epigenetic regulators that associate with immune interaction gene modules specifically in IECs dampens intraepithelial lymphocyte-mediated immune surveillance. We identified precise epigenetic mechanisms of epithelial – immune interactions including promoter and enhancer regulation by transcription factors and co-activators both in mice and humans. Finally, disruption of the epigenetic regulators that maintain epithelial – immune interactions lead to impaired responses in clinically-relevant mouse models of infection, tissue regeneration and cancer. These results establish a strong foundation towards understanding the epigenetic mechanisms that govern multi-cellular interactions within the barrier tissues in physiology or disease states.
Supported by grants from Mathers Foundation, STARR Cancer Consortium (I13-0052), The Mark Foundation for Cancer Research (20-028-EDV), NIH (P30CA045508-33), CZI Ancestry Network for the Human Cell Atlas
Lipid sensing by gut CD1d calibrates peripheral serotonin release
Authors: Wu Chuan , Luo Jialie , Chen Zuojia , Castellano David , Han Wenyan , Lu Wei , Li Jian , Kim Girak 
Published: August 2023

Abstract
The crosstalk between the immune and the neuroendocrine system is critical for intestinal homeostasis and gut-brain communications. However, it remains unclear how immune cells participate in gut sensation of hormones release in response to environmental cues, such as self and microbial lipids. We show here that lipid-mediated engagement of invariant natural killer T (iNKT) cells with enterochromaffin (EC) cells, a subset of intestinal epithelial cells, promotes peripheral serotonin (5-HT) release via a CD1d-dependent manner, regulating gut motility and hemostasis. CD1d ligation on EC cells transduces a reverse signal and restrains potassium conductance, leading to calcium influx and 5-HT secretion. Together, we show that by coupling with iNKT cells, gut chemosensory cells perceive lipid antigens via CD1d to calibrate 5-HT release, modulating intestinal and systemic physiology.
Leaky gut mechanisms in giardiasis
Authors: Angelova Vanessa V , Li Erqiu , Fiedler Brooke , Wexelblatt Haley , Kosile Rita Taye , Darmadi Matthew , Miskovsky Eleanor , Singer Steven M 
Published: August 2023

Abstract
Giardia duodenalis is a common intestinal pathogen transmitted via consumption of contaminated water. In addition to causing intestinal distress symptoms, Giardia infection is one of the top 5 infectious causes of growth stunting in children under two. Growth faltering is a complex pathology facilitated by changes in the intestinal barrier and enzymatic deficiencies. While infection is widely associated with barrier damage in vitro, in animal models, and in patient studies, the mechanisms behind this process are not well understood. Since PAR2 has a prominent role in increased intestinal permeability in Celiac disease, we are focusing on the involvement of the protease activated receptor 2 (PAR2) in giardiasis-facilitated intestinal defects. We are using human intestinal cell lines, murine intestinal organoids, and a mouse infection model to address the role of PAR2. Co-culture of Giardia and Caco2 cells results in altered tight junction morphology as revealed by staining for ZO-1; these changes are reduced by treatment with a PAR2 antagonist. Effects of PAR2 signaling on barrier function are being assessed by measuring transepithelial electrical resistance (TEER) in Caco2 cells and PAR2+/− and PAR2−/− organoids cultured on transwell filters. Additionally, while C57BL/6 mice fed a low-protein diet exhibit reduced weight gain when infected with Giardia, mice lacking PAR2 gain weight normally when infected. These data indicate that PAR2 signaling contributes to intestinal permeability defects and growth faltering. Identifying parasite factors that activate PAR2 will provide novel targets for development of pharmaceuticals and vaccines to improve child growth.
AI166467
Reduced γδ intraepithelial lymphocyte number and motility precede the onset of Crohn’s disease-like ileitis
Authors: Golovchenko Natasha B , Xu Weili , Fong Andrew , Zhang Lanjing , Edelblum Karen 
Published: August 2023

Abstract
Crohn’s disease (CD) is a relapsing, remitting disease resulting in chronic intestinal inflammation. Recent studies of resected ileal tissue from CD patients reported a loss of intraepithelial lymphocytes expressing the γδ T cell receptor (γδ IELs). γδ IELs continuously survey the epithelial barrier and protect against experimental colitis; however, the role of γδ IELs in the initiation of ileitis is unknown. To this end, we profiled the IEL compartment in TNFΔARE/+ mice, which develop chronic CD-like ileitis at 8 wks old, prior to and during ileitis onset (4–10 wks). We observed a 2.5-fold reduction in the frequency of ileal γδ IELs in 5-wk-old TNFΔARE/+ mice compared to TNF+/+ (WT) littermates (p&lt;0.001). Using intravital microscopy, we observed reduced γδ IEL surveillance behavior (10.6 vs 6.4 mm/min track speed mean, p&lt;0.0001) in TNFΔARE/+ mice compared to WT at 6 wks. Analysis of cleared ileal tissue from 6-wk-old WT and TNFΔARE/+ mice revealed a reduction in the number of γδ IELs in villus tips in TNFΔARE/+ mice relative to WT, thereby increasing the proportion of γδ IELs found in the crypt region. Based on several reported links between γδ IELs and Paneth cells (PC), we quantified PCs by lysozyme immunostaining in ileal tissue. We found an increased proportion of morphologically abnormal PCs in 6-wk-old TNFΔARE/+ mice, reflecting PC dysfunction consistent with CD pathology. These findings are supported by a reduction in ileal Lyz1 expression in TNFΔARE/+ mice compared to WT prior to ileitis onset (p=0.02). Together, these studies demonstrate that γδ IELs exhibit impaired surveillance behavior and altered distribution along the crypt/villus axis prior to ileitis onset, which coincides with PC dysfunction in CD-like ileitis.
COCR23PRF017 NJCCR Predoctoral Fellowship
Golovchenko (PI)
June 1, 2022 – May 31, 2024
γδ IEL surveillance behavior in the onset of chronic ileitis
Maternal immune regulation of lactogenesis
Authors: Corral Dan , Chi Liang , Gine Eduard , Yong Daniel , Nie Jia , Sun Lilian , Bhandoola Avinash , Bosselut Remy , Jabri Bana , Belkaid Yasmine 
Published: August 2023

Abstract
Breastfeeding has long been associated with health benefits for the infant. Breast milk is composed of essential nutrients and bioactive molecules shaping the growth, and the immune development of the offspring. An optimal development of the mammary gland (MG) during pregnancy is critical to maintaining the beneficial effects of lactation. Nevertheless, how the lactation process is regulated by the immune system remains largely unexplored. Our data reveal that the commitment of mammary epithelial cells into milk-secreting cells is associated with the accumulation of T-bet+ lymphoid cells, preferentially localized at the proximity and inside the mammary epithelium. Among mammary T-bet+ cells, we characterized an unconventional T cell population exhibiting common features with gut CD8αα+ intra-epithelial lymphocytes and deriving from the same thymic progenitor. Such process is associated with thymus involution during pregnancy and specific enrichment in thymic precursor that preferentially migrates into the MG during pregnancy. These cells promote milk production and expression of β-casein, one of the main milk protein, resulting in an increase in newborn weight. This work uncovers a previously unappreciated contribution for the adaptive immune system in mammary gland development and lactation. Decoding the immune regulation of the MG will allow to understand the profound transformation of this compartment as a primary nutritional source for the offspring and may allow to understand how dysregulation of this process could affect the long-term development of newborns.
This work was supported in part by intramural funds of NIAID, NIH.
Butyrate silences MUC5AC expression in airway epithelial cells by mediating histone deacetylation at its transcription start site
Authors: Jo Sang Hee , Bae Ikhyeon , Sim Myeong Seong , Kim Hye Jeong , Kim Chun , Chung Il Yup 
Published: August 2023

Abstract
Secreted airway mucins form a mucous gel consisting of MUC5AC and MUC5B and maintain airway homeostasis for appropriate mucociliary clearance and airway defense. There is conceivably a global mechanism to counteract excessive mucin production in response to incessant exposure to external and internal stimuli, which otherwise leads to goblet metaplasia and mucus hyperproduction. Here, we report that butyrate, a short-chain fatty acid (SCFA), strongly suppresses MUC5AC production at as low as sub-to micromolar concentrations in NCI-H292, airway epithelial cells. Butyrate transcriptionally inhibits MUC5AC mRNA and protein that are induced by a variety of stimuli including EGF and LPS. In line, butyrate upregulates FOXA2, which is known to block goblet cell metaplasia. The mode of the inhibition by butyrate appears to be independent of the known receptors of butyrate. In addition, butyrate does not alter the EGFR signaling pathway. Chromatin immunoprecipitation analysis demonstrates that histone H3K27 acetylation level is increased upon stimulation with EGF and returns to baseline in the presence of butyrate. We propose that butyrate, a metabolic product of gut microbiota, plays a central role in maintaining homeostasis of airway mucous gel by counteracting mucin production resulting from repeated provocation of airway epithelium.
National Research Foundation of Korea (NRF) funded by the Korean government (MSIT), NRF-2022R1A2B5B01002127.
TL1A control of eczema and psoriasis
Authors: Cheng Jason Liang , Steele Hope , Breckenridge Joey , Dell Garrison , Ghastine Andrew , Willicut Ashley , Herro Rana 
Published: August 2023

Abstract
Psoriasis is a Th17-induced dermatitis, characterized by epidermal thickening. Psoriasis increases the risk of developing arthritis and cardiovascular-related morbidities, hence the need to stop its progression early. Why the disease is patchy, and what activates the keratinocytes in the psoriatic plaques driving a Th17-type inflammation, remain unknown. Chronic exposure to imiquimod (IMQ) drives psoriasis in mice reminiscent of human disease. We have preliminary data implicating the TNFSF (tumor necrosis factor superfamily) member TL1A (tumor necrosis factor-like cytokine 1A) in psoriasis. Our loss of function studies show that the genetic deletion of TL1A receptor, protects from IMQ-induced psoriasis. Further, TL1A is known to be enriched in the psoriatic lesions and serum of psoriatic patients. These findings suggest that TL1A may play a central role in the development and maintenance of psoriasis. Therefore, targeting TL1A could be beneficial to treat Psoriasis.
Dedicator of cytokinesis 8 (DOCK8) is a negative regulator of skin mast cell function
Authors: Molina Irina Miralda , Samanas Nyssa B , Seo Albert J , Foronda Jake , Deutsch Gail H , Baris Safa , Unal Ekrem , Eken Ahmet , James Richard G , Piliponsky Adrian M 
Published: August 2023

Abstract
Dysregulated expansion and/or activation of mast cells have detrimental consequences in allergic disease. In humans, homozygous or compound heterozygous deletions of DOCK8 cause a combined immunodeficiency characterized by allergic disorders. Based on this evidence, we hypothesized that DOCK8 may be a negative regulator of mast cell function. To address this hypothesis, we used mice with a loss-of-function mutation in Dock8 (primuris, Dock8pri/primice) and conditional mice in which DOCK8 is ablated in connective tissue mast cells (Mcpt5-Cre+; Dock8fl/fl mice). Dock8pri/primice exhibited increased plasma levels of mast cell protease-1 (MCPT1) in homeostatic conditions. Furthermore, Dock8pri/primice and Mcpt5-Cre+; Dock8fl/fl mice experienced a more severe IgE-dependent passive cutaneous anaphylactic reaction (PCA) than control mice. This data suggests that DOCK8 deficiency is linked to increased mast cell activation in homeostatic conditions and upon stimulation by IgE-dependent mechanisms. Fetal skin derived cultured mast cells (FSMCs) generated from Dock8pri/primice released increased amounts of β-hexosaminidase upon IgE-dependent activation. Consistent with this finding, naïve DOCK8-deficient FSMCs exhibited alterations in cytoskeletal dynamics that may facilitate mast cell degranulation.
Finally, we observed an increased number of tryptase positive cells in skin biopsies obtained from three pediatric patients diagnosed with hyper IgE syndrome (HIES) due to DOCK8 mutations, suggesting that DOCK8 immunodeficiency may contribute to skin mast cell expansion in humans.
Our findings provide strong evidence that DOCK8 can contribute to negative regulation of skin mast cell activation and expansion.
R01 AI140626-05
Cell-Intrinsic Effects of TGF-b Signaling in Mast Cell Effector Function that Modulate Allergic Inflammation
Authors: Haque Tamara , Leak Leshawna , Laky Karen , Guererrio Pamela 
Published: August 2023

Abstract
IgE mediated mast cell activation is a key feature of allergic disease, although the mechanisms that govern mast cell homeostasis are not fully understood. The TGFb signaling pathway has been shown to regulate mast cell effector function. Furthermore, variants in the TGFb signaling pathway are associated with allergic diseases; TGFb mediated mast cell regulation is likely involved in the allergy diathesis. Patients with Loeys Dietz Syndrome (LDS), a disorder caused by loss of function variants in TGFBR1 and TGFBR2, are predisposed to develop allergic diseases, thus provide an opportunity to study the role of mast cell TGFb signaling in allergic diseases. Mast cells are activated through the high affinity IgE receptor FcERI causing the release of granules containing mediators that are directly involved in anaphylaxis and other allergic symptoms. IgE mediated activation can be modulated by other co-stimulatory signals such as the type 2 alarmin IL-33. We examined murine mast cells carrying an LDS mutation, or with conditional deletion of Tgfbr1, and found that they degranulated less in response to IgE/antigen, in vivo and in vitro. This phenotype was not tied to changes in the IgE and SCF receptor expression or mast cell tissue distribution in mice and was recapitulated in human LDS mast cells, in vitro. Additionally, LDS mice responded more to IL-33 stimulation. Mechanistically, the LDS anaphylaxis phenotype was linked to IL-33, as the reduction of anaphylaxis in LDS mice was partially restored in IL-33RKO LDS mice. Thus, the TGFb-IL-33R axis likely plays a major role in controlling IgE mediated mast cell functions. Taken together, TGFb signaling upregulates mast cell effector function by disrupting an IL-33/ST2 mediated regulatory pathway.
Intramural NIAID Support
The induction of histamine synthesis from rat bone marrow derived mast cells with rat stem cell factor
Authors: Cho Sung-Weon , Sur Bong Jung , Shin Kyung Sook 
Published: August 2023

Abstract
Mast cells are the main cells to produce histamine regarded as the main factor to induce allergy. To comprehend the allergy by mast cell activation, The mast cells of bone marrow derived mast cells (BMMC) are usually prepared by culturing bone marrow cells including rodent hematopoietic stem cells, in the presence of both IL-3 and stem cell factor (SCF). However, BMMC was reported not to produce the high levels histamine comparable to mature mast cells in host tissue. In this study, rat BMMC (rBMMC) were cultured in 96 well plate to induce diverse conditions in cell numbers per unit culture media, rat IL-3 and rat SCF to find the conditions to synthesize high level histamine. Cells of rat bone marrow cells were cultured in the cell density of 1.1×105/ml (low density, lowD) and 5.5 × 105/ml (high D), rat IL-3 was added to the levels of 10 ng/ml (low 3) or 50 ng/ml (high 3), Rat SCF was adjusted to the levels of 12.5 (lows), 25 (midS) and 50 (highS) ng/ml. Histamine included in 5×104 BMMC were extracted by perchloric acid, n-butanol, and heptane. The levels of histamine were measured by ophthalialdehyde solution and read for fluorometric intensity. The levels at culture day 4 (D 4) were in the range of 12~45 ng. The significant elevation was observed at D 11 in the conditions of lowD high3 (153 ng), however, D 8 in highD high3 (253 ng). The average histamine level was 74 ng in the condition of low Dlow 3, but 112 ng in low Dhigh 3 at D 11. That was 106 ng in high Dlow 3 but 183 ng in high Dhigh 3 at culture D 8. These results indicated that rat IL-3 increased the level of histamine synthesis and shorten the histamine production from undifferentiated hematopoietic stem cells.
The induction of histamine synthesis from rat bone marrow derived mast cells with rat stem cell factor