bluuebunny/crossref_metadata_2025_split huggingface dataset:
IL–17 receptor signaling regulates Citrobacter rodentium growth
Authors: Matsunaga Yasuka , Wanek Alanna , Flemington Cathy , Song Kejing , Iwanaga Naoki , Clark Trevon , Bitoun Jacob P. , Good Misty , Kolls Jay K. 
Published: January 2023

Abstract
The type 17 cytokine receptors are thought to play critical roles in mucosal immunity. We have shown that intestinal epithelial expression of IL–17 receptor control the development of microbiota in the terminal ileum and conditional deletion of these receptors results in overgrowth of segmented filamentous bacteria. To study the roles of these receptors in response to an attaching and effacing pathogen we challenged intestinal specific Il17ra mice and Il17rc mice with Citrobacter rodentium (C. rodentium). Conditional deletion of Il17ra and l17rc Iresulted in increased bacterial growth in the colon as well as enhanced dissemination to the liver suggesting that intestinal epithelial IL–17 receptors expression is required for control of this infection. This was supported by unbiased RNAseq analysis of the colon that showed diminished expression of Pigr, Tnfsf13 and Nox1 in the absence of Il17ra. IgA has crucial role in mucosal immunity to protect from pathogenic bacteria. PIGR binds dimeric IgA and translocation into lumen, while TNFSF13 activates induce differentiation to plasma cells following–crass switch. C. rodentium specific IgA in stool and C. rodentium specific IgA producing cells in lamina propria were reduced in Il17ra mice. These results suggested IL-17 receptor signaling regulates transcytosis of C. rodentium specific IgA as well as secretion of bacteria specific IgA. On the other hands Nox1 can produce apical hydrogen peroxide. Nox1 null mice were more sensitive for C. rodentium infection. Furthermore Nox1 was expressed by IL–17A stimulation in colonic organoid. Taken together, IL–17 receptor signaling control to produce C. rodentium specific IgA through PIGR and TNFSF13 as well as hydrogen peroxide through NOX1.
2B4 controls gut immune homeostasis by promoting IL-1β expression in Ly6Chigh monocytes that trigger IL-22/IL-18-mediated epithelial regeneration
Authors: Kim Tae-Jin , Kim Jeongmin , Park Bonggoo , Park Gayoung , Lim Seon Ah , Lee Kyung-mi 
Published: January 2023

Abstract
Impaired signaling, downstream of 2B4, is associated with colitis in human patients with XLP ; however, the precise mechanism by which 2B4 maintains gut integrity remains unknown. In dextran sodium sulfate (DSS)-fed reciprocal chimera mice, massive tissue destruction was observed due to lack of 2B4 in hematopoietic compartments, in particular Ly6ChighCD11b+ monocyte subsets within the lamina propria leukocytes. Not only did the number of Ly6ChighCD11b+ monocytes get significantly reduced, their intrinsic capacity to produce IL-1β during DSS stimulation was also drastically impaired in 2B4−/− mice. These defects led to an impaired IL-22 secretion in ILCs and IL-18 production in gut epithelial cells in the 2B4−/− mice. Furthermore, severe inflammatory phenotypes seen in 2B4−/− mice could only be rescued by adoptive transfer of Ly6ChighCD11b+ monocytes, but not with BMDC or NK cells. Therefore, 2B4 functions as an important receptor in inflammatory monocytes in response to commensal microbiota during acute colonic inflammation.
Ingestion of subtoxic doses of cadmium induces persistent dysbiosis and enhances susceptibility to DSS-induced colitis long after exposure
Authors: Kim Eunsoo , Cormet-Boyaka Estelle , Boyaka Prosper N 
Published: January 2023

Abstract
Health officials often focus on the effect of high doses of heavy metal pollutants. However, most people will more likely be exposed to subtoxic doses via contaminated water or food. We addressed the effects exposure to subtoxic doses of heavy metal pollutants could have on the gut immune homeostasis. We report that chronic ingestion of environmentally relevant subtoxic doses of cadmium does not impair the barrier function of the intestine in mice. On the other hand, chronic exposure to subtoxic doses of this heavy metal stimulates the growth of intestinal epithelial cells including Paneth cells, and increased production of antimicrobial peptides by Paneth cells. We also found that subtoxic doses of cadmium induce a dysbiosis of the gut microbiota that persist months after the end of the exposure. Importantly, 12–14 months after exposure to cadmium, the cadmium-exposed mice weighted more and had more fat content than age-matched controls suggesting that these mice have developed a state of chronic inflammation. Cadmium is also known to accumulates in soft tissues with a half-life of 10–20 years. Thus, to investigate the long-term effect of exposure to subtoxic doses of cadmium, control and post-menopausal mice (&gt; 15 months old) previously exposed to cadmium were treated with dextran sodium sulfate (DSS) in drinking water. Post-menopausal mice previously exposed to cadmium developed more severe signs of DSS-induced colitis including weight loss, shortened large intestine. Furthermore, they exhibited enhanced Th17 responses in mucosal tissues. Our results provide new insights the impact of chronic exposure to subtoxic doses of cadmium, and possibly other heavy metals on gut homeostasis and colitis or colon cancer.
ECM1 is an essential factor for the determination of M1 macrophage polarization in inflammatory bowel disease in response to LPS stimulation
Authors: Sun Bing , Zhang Yaguang 
Published: January 2023

Abstract
Inflammatory bowel disease (IBD) comprises chronic relapsing disorders of the gastrointestinal tract characterized pathologically by intestinal inflammation and epithelial injury. Here, we uncover a new function of extracellular matrix protein 1 (ECM1) in promoting the pathogenesis of human and mouse IBD. ECM1 was highly expressed in macrophages, particularly tissue-infiltrated macrophages under inflammatory conditions, and ECM1 expression was significantly induced during IBD progression. The macrophage-specific knockout of ECM1 resulted in increased arginase 1 (ARG1) expression and impaired polarization into the M1 macrophage phenotype following LPS treatment. A mechanistic study showed that ECM1 can regulate M1 macrophage polarization through the GM-CSF/STAT5 signalling pathway. Pathological changes in mice with dextran sodium sulphate-induced IBD were alleviated by the specific knockout of the ECM1 gene in macrophages. Taken together, our findings show that ECM1 has an important function in promoting M1 macrophage polarization, which is critical for controlling inflammation and tissue repair in the intestine.
Role of NFKB signaling in Respiratory Epithelial Cells in Vaccine-Induced T Cell Immunity to Influenza
Authors: Luu Tracy NK , Kingstad-Bakke Brock , Marinaik Chandramaik , Larsen Autumn Rose , Suresh Marulasiddappa R 
Published: January 2023

Abstract
Respiratory epithelial cells (RECs) express Toll-like receptors (TLRs), produce both pro-inflammatory and anti-inflammatory molecules and function as immunological rheostats in the respiratory tract. The role of RECs in T cell responses to mucosal vaccination remains unknown. We have identified a combination adjuvant consisting of acrylic acid polymers in a nanoemulsion (Adjuplex; ADJ) and TLR4 agonist (glucopyranosyl lipid adjuvant; GLA) that elicits potent CD8 and CD4 T cell responses in the respiratory tract. Using mice (NFKB-REC) that conditionally lack NF-KB signaling in the RECs, we addressed the role of NFKB-dependent REC responses in regulating primary T cell responses to influenza virus nucleoprotein (NP), following intranasal vaccination with ADJ, GLA or ADJ+GLA. Surprisingly, we found that loss of REC NFKB signaling did not affect the magnitude of primary or recall antigen-specific T cell responses in the lungs and airways. Further, mucosal imprinting of CD8 T cells, as evidenced by expression of CD103 and CD49a, was minimally affected in NFKB-REC mice. Greater percentages of effector CD8 T cells in NFKB-REC mice expressed KLRG-1, regardless of the adjuvant but effector CD8 T cells in GLA mice showed elevated levels of CX3CR1, CD49a and granzyme B following challenge with influenza A virus. Preliminary evidence suggests that vaccine-induced T cell-dependent protection against influenza virus might be impaired in NFKB-REC mice.
Baby’s First Macrophage: characterizing Hofbauer Cell phenotype through gestation using unsupervised dimensionality reduction
Authors: Swieboda Dominika , Beaver Jacob , Johnson Erica LaShai , Skountzou Ioanna , Chakraborty Rana 
Published: January 2023

Abstract
Fetal placental macrophages (Hofbauer cells (HCs)) appear at 18 days post-conception and are maintained throughout pregnancy. Despite their identification more than a century ago, there are few studies characterizing the evolution of human HC phenotype through gestation. Using high-dimensional flow cytometry, we measured expression of CD68, CD80, CD86, HLA-DR, CD163, CD206, and CD209 on human HCs ex vivo. This panel includes markers previously validated on term human HCs for immune activation (CD80, CD86) and modulation (DC-SIGN, HLA-DR). To best capture the spectrum of HC diversity across gestation, we employed an unbiased approach to analyze processed datasets from HCs isolated from placentae 12–17 weeks gestational age (n=5), 17–24 weeks gestational age (n=7) and at term (n=5) using t-distributed stochastic neighbor embedding analysis (tSNE). HC populations were more diverse early in pregnancy and at term, compared to the second trimester; this is anticipated given the changing microenvironment following initial placental anchoring to eventual parturition. Marker expression heatmaps were generated to assess gestation-dependent changes in HC phenotype; HCs expressing activation markers were most frequent in early gestation, and reduced by term. HCs bearing markers of immune modulation were most frequent at mid-gestation, and least in early gestation. These results demonstrate the power of utilizing computational methods to analyze high-dimensional flow cytometry data collected from an understudied cell type and demonstrate how HCs phenotypically evolve during human pregnancy.
Targeting interferon regulatory factor 5 (IRF5) activation with a peptide inhibitor ameliorates clinical lupus in MRL/lpr mice
Authors: Song Su M , LaPan Margaret , Chopra Samin , Kampta Kyle , Guo Qin , Barnes Betsy J 
Published: January 2023

Abstract
Systemic lupus erythematosus (SLE) is associated with high levels of inflammatory cytokines as well as increased autoantibodies. Accumulating evidence show that loss and/or inhibition of the transcription factor interferon regulatory factor 5 (Irf5) ameliorates disease severity. Previously, we characterized a peptide inhibitor targeting Irf5 activation in the NZB/W F1 murine model of lupus and showed therapeutic protection when treated before disease onset. Here, we expanded our study to include a clinical treatment arm in the MRL/lpr lupus model after disease onset. 8 week-old MRL/lpr female mice were IP-injected with PBS or inhibitor at a dose of 100ug/mouse/injection on D0, D1, D4, D7 and D14. Proteinuria was monitored weekly; serum auto-antibodies were measured by ANA-HEp-2; anti-dsDNA IgG by ELISA, and kidney pathology was assessed. Blood was collected weekly to examine Irf5 expression and activation in immune cell subsets by imaging flow cytometry. At 8 weeks-old and before treatment, MRL/lpr mice were positive for anti-nuclear antibodies (ANA). At week 17, IgG and IgM staining on HEp-2 cells showed stronger fluorescence intensity in the control group (p=0.0053 for IgG; p&lt;0.0001 for IgM). Serum anti-dsDNA IgG levels were also higher in the control group (782179 ± 337490 U/mL, n=7) as compared to treated (385947 ± 156487 U/mL, n=9). By week 17, 2 out of 9 mice in the control group had died, while all mice in the treated group survived. Proteinuria and body weights remained similar between groups. Data indicate that direct inhibition of murine Irf5 in multiple lupus models (NZB/W F1 and MRL/lpr) ameliorates disease severity. The inhibitor was also well-tolerated supporting the therapeutic utility of IRF5 inhibitors in the clinic.
Immune-phenotyping IRF5 genetic risk and in vivo targeting of Irf5 hyper-activation in mouse models of lupus
Authors: Barnes Betsy J , Song Su , Li Dan , Matta Bharati , De Saurav 
Published: January 2023

Abstract
Genetic variations within interferon regulatory factor 5 (IRF5) associate with risk of systemic lupus erythematosus (SLE) and mice lacking Irf5 are protected from lupus onset and severity. Exactly how IRF5 functions in the context of SLE disease progression remains unclear. We sought to determine how IRF5 genetic risk contributes to SLE disease onset and severity, and whether targeting IRF5 with select inhibitors would alleviate disease severity and mortality. Studies were performed in blood from genotyped healthy donors, SLE patients and mouse models of murine lupus. In NZB/W F1 lupus mice, we found that Irf5 is already hyper-activated before clinical onset in a cell type-specific manner. In healthy donors carrying IRF5 genetic risk, we detected IRF5 hyper-activation in the myeloid compartment that drives a pre-symptomatic SLE immune-phenotype. In SLE patients, IRF5 hyper-activation correlates with SLEDAI and dsDNA titers. To test whether IRF5 hyper-activation is a targetable function, we developed novel inhibitors that are cell permeable, non-toxic and selectively bind to the inactive IRF5 monomer. Treatment of NZB/W F1 and MRL/lpr mice with inhibitor attenuated lupus pathology by reducing serum ANA and dsDNA titers. In NZB/W F1 mice, we detected significant reductions in the number of circulating plasma cells and age- or autoimmune-associated B cells (ABCs), which alleviated kidney pathology and improved overall survival. In ex vivo human studies, the inhibitor blocked SLE serum-induced IRF5 activation in healthy immune cells and reversed basal IRF5 hyper-activation in SLE immune cells. This study provides the first in vivo pre-clinical support for treating SLE patients with an IRF5 inhibitor.
Cell therapy targeting follicular T cells as an innovative approach for treating autoimmune disease
Authors: Rangel Kelly M , Reighard Seth D , Ochayon David E , Krishnamurthy Durga , Shao Wen-Hai , Waggoner Stephen N 
Published: January 2023

Abstract
Systemic lupus erythematosus (SLE) is a debilitating and incurable autoimmune disease characterized by the uncontrolled production of autoantibodies and inflammatory damage to multiple organ systems. Dysregulated follicular helper T cell (TFH) responses are a cardinal feature and putative driver of disease in both mice and humans, where these cells contribute to unrestrained inflammation and autoantibody production by B cells. There is currently no safe and effective way to selectively eliminate TFH as a means to therapeutically alleviate diseases caused by these cells. Although cell surface biomarkers that are unique (lineage-specific targets) to TFH remain undefined, these cells express markedly more programmed cell death protein 1 (PD-1) than other immune cells. We recently engineered a novel programmed death-ligand 1 (PD-L1)-based chimeric antigen receptor (CAR) that when expressed on human natural killer (NK) cells, facilitated discriminate targeting of PD-1high follicular T cells while sparing other PD-1-expressing lymphocytes. The inherent specificity of this approach lies in the lower affinity interactions between PD-L1 and PD-1 compared to that likely achieved with a PD-1-specific single-chain variable fragment-based CAR. Here, we develop a mouse T cell version of the PD-L1 CAR platform to show that selective depletion of PD-1high T cells is safe and effective at undermining harmful autoreactive T and B cell responses in mouse models of SLE-like disease. We believe this affinity-based CAR approach for PD-1high target cell elimination represents a novel clinical tool for treatment of TFH-driven diseases like SLE.
Prevention of Type 1 Diabetes via a lipid Nanoparticle-Based Oral Immunotherapy that Targets Selective Lymphoid Tissues
Authors: ZHANG YICHUAN , Wang Jialu , Calderon-Colon Xiomara , Tiburzi Olivia , Lozano Marcos Iglesias , Patrone Julia B. , Raimondi Giorgio 
Published: January 2023

Abstract
Type 1 diabetes (T1D) is an untreatable autoimmune disease caused by the destruction of pancreatic beta cells by autoreactive T cells. Antigen presenting cells (APCs) malfunctions and aberrant accumulation of type 1 interferons contribute to T1D, and the inhibition of inflammatory cytokines signaling via JAK inhibitors like Tofacitinib (Tofa) has shown promise in the prevention of the disease. However, maintenance of a therapeutic concentration of these drugs is challenging and their prolonged use leads to significant side effects. Our objective was to design a controlled and localized delivery of Tofa via biocompatible lipid nanoparticles, Nanostructured Lipid Carrier (NLC), and assess if, via this strategy, a short-term administration would impact T1D development.
We identified a formulation of NLC that had negligible toxicity, could be readily taken up by multiple immune cells, and had a favorable Tofa encapsulation efficiency. Live animal imaging confirmed these particles have the unique property of accumulating in lymphoid tissues, particularly in spleen, pancreatic and mesenteric lymph nodes when administrated via oral gavage. Ex-vivo, Tofa-NLC rapidly delivered Tofa to mouse APCs preventing their maturation and the release of inflammatory cytokines. Importantly, short-term administration of Tofa-NLC via oral gavage at early (3-week-old) or late (10-week-old) stage in disease prone NOD mice promoted a significant delay of T1D onset. Cell profiling and in vivo challenges indicated that this therapeutic effect is likely due to localized inhibition of APCs maturation and promotion of anergy in diabetogenic T cells. These results highlight the versatility of this lipid nanoparticle-based drug delivery strategy.
Saliva plebeia ameliorates articular carttilage degration of osteoarthritis induced rats
Authors: Lee Sung Hyen , Lee Eun-Byeol , Choi Ji-Hye , Ku Sae-Kwang , Choi Beom-Rak , Kim Jung-Bong , Jang Hwan-Hee , Hwang Kyung-Ah , Park Shin-Young 
Published: January 2023

Abstract
Osteoarthritis (OA) is the most prevalent articular disease in the elderly. The process is characterized by changes in the structure and function of the articulation, mainly due to a degeneration that takes place in the articular cartilage (AC). OA is characterized by destruction of AC and is the most common clinical syndrome of joint pain accompanied by varying degrees of functional limitation and reduced quality of life. This study was conducted to evaluate the effects of Saliva plebeia (SP) on AC degration of osteoarthritis induced rats. Salvia plebeia R.Br is an annual or biennial plant that grows in numerous countries, including Korea, China, and India. It is used as a traditional medicine to treat inflammatory diseases. The active components of SP comprise flavonoids, diterpenoids, and lignin. It is considered that appropriate treatment of SP inhibits surgical-induced OA through anti-inflammatory and AC preserve effects. In the histopathological observation, OA control rats showed marked increases of surface cartilage damages and clone formations, and decreases of chondrocytes and Safranin O stain intensities on the both femur and tibia AC. Significant increases of the Mankin scores were detected in surgical-induced OA control rats as compared with those of normal control rats. However, SP significantly improved surface cartilage damages, Mankin scores, mean femur and tibia AC thicknesses, and inflammatory cell numbers. It is expected that SP may be used as a novel potent therapeutic regime for various OA though detail mechanism studies should be needed in near future.
ST8Sia6 overexpression in beta cells prevents onset of autoimmune diabetes in the murine NOD model
Authors: Choe Justin , Belmonte Paul , Rajcula Matthew , McCue Shaylene , Shapiro Michael J , Shapiro Virginia 
Published: January 2023

Abstract
Cell surface hypersialylation is used by malignant cells as a survival mechanism, leveraging interactions with Siglec receptors to dampen the immune response. In this study, we aimed to harness this mechanism to prevent autoimmune rejection of beta cells in the context of type 1 diabetes. Mice engineered to overexpress the sialyltransferase ST8Sia6 in beta cell (BST) were generated and crossed to the non-obese diabetic (NOD) mouse for 10 generations. The blood glucose of these mice compared to non-overexpressing littermates was assessed twice weekly to determine diabetes incidence, defined as 3 consecutive blood glucose readings above 250 mg/dL. Analysis of female BST mice aged 15 weeks or greater showed no incidence of overt diabetes, while littermates developed diabetes. BST males aged 15 weeks or greater also had no disease incidence, while littermate controls also became diabetic. An insulin tolerance test demonstrated no significant difference between BST mice and littermates, though the BST had significantly higher blood glucose during a glucose challenge, possibly representing insulin hypersecretion by littermate islets in a stressed pre-diabetic state. Histologic analysis of young BST and littermate pancreata showed no differences, with similar levels of insulitis at 8 weeks. Thus, the overexpression of ST8Sia6 has been shown to mitigate autoimmune attack in the NOD model and presents a novel path forward for prevention of islet transplant rejection.
Blockade of the neurokinin-1 receptor in keratinocytes prevents neuroinflammation and decreases innate and adaptive immune responses in the skin
Authors: Bandyopadhyay Mohna , Morelli Adrian E , Erdos Geza , Sumpter Tina L , Tkacheva Olga , Shufesky William , Falo Louis D , Larregina Adriana T 
Published: January 2023

Abstract
Substance P (SP) is a proinflammatory neuropeptide that following Ag entrance in peripheral tissues signals via the neurokinin 1 receptor (NK1R) to initiate innate and support adaptive cellular immune responses. These mechanisms underlie chronic skin inflammatory disorders like contact dermatitis (CD). Here we propose to develop an immunosuppressive method to prevent and treat CD by blocking the effects of SP during skin sensitization with haptens. We utilized microneedle arrays to efficiently deliver the hapten 2,4-dinitrocholorobencene (DNCB) and NK1R antagonists simultaneously to the skin of C57/BL6 mice. This approach, restrained neuroinflammation, increased T regulatory cells and decreased the viability of Th1 and Tc1 biased cells in the draining lymph nodes. Together these effects inhibited local and systemic CD and prevented its relapses. Using the Cre-Lox P system, we demonstrate that specific deletion of the NK1R in keratinocytes but not in leukocytes inhibited the sensitization phase of CD by blocking the release of IL-1β and IL-6. Whereas deletion of the receptor in keratinocytes or in dendritic cells was necessary to abrogate the adaptive cellular immunity. Our data demonstrate the possibility of preventing the development of cellular immunity by engineering the skin microenvironment to restrain the effects of neuroinflammatory peptides accounting for the onset of chronic skin inflammatory diseases.