bluuebunny/crossref_metadata_2025_split huggingface dataset:
Microbiota modify inflammatory arthritis through mucosal inflammation and autoantibody generation
Authors: Kuhn Kristi , Jubair Widian K. , Hendrickson Jason D. , Adhikari Sumitra , Ir Diana , Robertson Charles E , Frank Daniel N , Banda Nirmal K. 
Published: January 2023

Abstract
Mucosal dysbiosis occurs in patients with rheumatoid arthritis (RA), but its role in disease pathophysiology has not been well defined. Using the collagen-induced arthritis (CIA) murine model, we investigated the importance of microbiota in developing inflammatory arthritis. Dysbiosis in CIA occurred in two phases, at 14 days and 35 days after the initial immunization of bovine type II collagen (CII) in complete Freund’s adjuvant. In parallel, mucosal barrier impairment was observed with an initial insult observed at day 14 that stabilized through day 21 but worsened by day 35. Mucsoal inflammation also was observed as determined by colon histology and elevation of tissue cytokines IL-17A and IL-22. Depletion of microbiota through administration of broad-spectrum antibiotics resulted in decreased disease severity and mucosal inflammation. Unexpectedly, we observed that microbial depletion during the late, effector phase of CIA, resulted in more profound suppression of disease. Both disease severity and serum anti-CII autoantibodies correlated with microbial load, further supporting the role of microbiota driving the disease process. Finally, we confirmed that in CIA, the presence of an intact microbiota associated with the presence of RA-relevant anti-citrullinated protein antibodies, possibly through dysbiosis-stimulated activation of the host’s peptidyl arginine deiminase 4 enzyme. Clearly additional studies are needed to solidify the role of the microbiota in driving CIA, but our data together with those of others’ supports a model in which intestinal dysbiosis triggers mucosal immune responses that stimulate T and B cell activities that lead to inflammatory arthritis.
Role of the innate immune response in the progression of Alzheimer’s disease
Authors: Fulop Tamas , Le Page Aurélie Y , Frost Eric H , Dupuis Gilles 
Published: January 2023

Abstract
Alzheimer’s disease (AD) is a progressive irreversible neurological brain disorder. Inflammation and immune alterations have been linked to AD, suggesting that the peripheral immune system plays a role during the asymptomatic period of AD. NK cells and neutrophils (PMN) participate in innate immune surveillance against intracellular pathogens and malignancy but their role in AD remains controversial. We have investigated changes in peripheral NK cell and PMN phenotypes and functions in amnestic mild cognitive impairment (aMCI, n = 10), patients with mild AD (mAD, n = 11), and healthy elderly controls (n = 10). Patients selected according to NINCDS-ADRDA criteria were classified using neuropsychological assessment tests. Phenotype analysis revealed differences in expression of CD16 (increased in mAD), NKG2A (decreased in aMCI), and TLR2 and TLR9 (both decreased in mAD) for NK and CD14 (increased in MCI). Functional assays revealed that NK cell killing activity and degranulation (CD107 expression) were unchanged in the three groups. In contrast, expression of the CD95 receptor was increased in aMCI and mAD. Granzyme B expression and cytokine production (TNFα, IFNγ) were increased in aMCI but not in mAD. Similarly, PMN phagocytosis and free radical production were differentially modulated in MCI and mAD patients. Our data suggest that the number of alterations observed in peripheral NK cells and neutrophils in aMCI represent an activation state compared to mAD patients and that may reflect an active immune response against a still to be defined aggression.
The miR-122 released by hepatocytes during liver disease binds to TLR7 to promote lung dysfunction
Authors: Liang Hongwei , Liu Yuan , Zen Ke 
Published: January 2023

Abstract
The association between lung dysfunction and hepatic disease has been recognized for more than 100 years. More and more studies have revealed lung dysfunction may occur as a result of hepatic disease from any cause. However, the underlying mechanism remains incompletely understood. Here we report that liver-released miR-122 under hepatic disease plays a key role in eliciting lung inflammation and tissue damage via activating alveolar macrophage inflammatory responses. High serum level of miR-122 is widely detected in mice with liver injury caused by ConA, DEN or HCC and in hepatitis and liver cancer patients. A considerable amount of circulating miR-122 was transferred to alveolar macrophages, in which it stimulates inflammatory responses via activating toll-like receptor-7 (TLR7) signaling by serving as a ligand of TLR7. Adoptive transfer experiments show that depleting serum miR-122 significantly attenuates liver injury-induced lung inflammation and tissue damage. Activation of alveolar macrophages by miR-122 can be abolished by mutating the sequence binding to TLR7 or deleting TLR7 in macrophages. Together, our finding reveals an unconventional role of liver miR-122 in stimulating lung immune injury via activating alveolar macrophage TLR7 signaling.
IL-17RA and not IL-17RE is required for IL-17C-mediated psoriasiform inflammation
Authors: Sigurdardottir Sigrun Laufey , Fritz Yi , Klenotic Philip A , Zhang Xiufen , Diaconu Doina , Zhang Li , Ward Nicole L 
Published: January 2023

Abstract
IL-17C is highly expressed in psoriasis skin and is thought to promote inflammation by binding IL-17RA and IL-17RE. Keratinocyte-overexpressing IL-17C (IL-17C+) mice develop a psoriasiform skin phenotype. To investigate IL-17C-mediated inflammation, IL-17C+ mice were mated with IL-17RE-deficient (KO) mice and skin examined. IL-17C+IL-17REKO mice had similar acanthosis and T cell numbers as IL-17C+ mice (n=8/grp; P&gt;0.1), as did IL-17C+ mice transplanted with bone marrow from CD4-IL-17RE vs. WT mice (n=6–9; P&gt;0.1). These results suggest that IL-17C signaling is IL-17RE independent. Next, IL-17C+IL-17REKO mice were treated with anti-IL-17RA antibodies and a 54% reduction in acanthosis was observed (n=3; P=0.006), suggesting that IL-17C-IL-17RA signaling is critical for skin inflammation. In KC-Tie2 psoriasis mice, skin IL-17A and IL-17C increase ~15-fold (P&lt;0.05) and anti-IL-17A and anti-IL-17RA antibody treatment improves acanthosis and decreases CD4+ T cells (P&lt;0.05 vs. IgG, n=5–11/grp), with anti-IL-17RA having greater efficacy than anti-IL-17A (P=0.02). This suggests that both IL-17C and IL-17A signaling through IL-17RA are critical. Indeed, genetic deletion of IL-17C from KC-Tie2 mice led to a 67% and 58% decrease in acanthosis and CD4+ T cells, respectively (n=8/grp; P&lt;0.001 vs. KC-Tie2 mice). Finally, IL-17A modulation in IL-17C+ mice using anti-IL-17A antibodies, transplanting IL-17AKO bone marrow or introducing intradermal IL-17A, each had no effect on IL-17C+ skin inflammation. Our results demonstrate that IL-17C-mediated skin inflammation occurs in an IL-17RE independent, IL-17RA dependent manner and that a tiered balance between IL-17C-IL-17A-IL-17RA signaling may dictate levels of inflammation.
Innate activation of Th17 cells triggers IL-26 release
Authors: Weiss David Isaac , Dang Angeline Tilly , Montoya Dennis , Wu Aiping , Gilliet Michel , Pellegrini Matteo , Modlin Robert L 
Published: January 2023

Abstract
IL-26 is a Th17 cell cytokine with both pro-inflammatory effects and direct antimicrobial activity. We investigated the role of IL-26 in the host response to infection by studying leprosy as a model, finding that IL-26 had direct antimicrobial activity against Mycobacterium leprae. IL-26 mRNA and protein expression was greater in skin lesions from patients with self-limited versus progressive infection, although IL-17 was weakly expressed. To determine the mechanism for IL-26 induction, we examined the kinetics of IL-26 secretion by PBMCs exposed to Mycobacterium leprae sonicate, which revealed induction at 3 hours suggesting activation of the innate response. IL-26 was secreted from PBMCs in response to a variety of pattern recognition receptor (PRR) ligands, correlating with IL-1β release. In PBMCs, IL-1β stimulated IL-26 secretion and blocking IL-1β with either antibodies or depletion of CD14+ cells after PRR ligand stimulation lead to reduction in IL-26 secretion. IL-1β also stimulated IL-26 secretion by both CD4+ and CD8+ T cells, and within the CD4+ compartment IL-26 secretion was limited to memory T cells. Only CD4+ memory Th17 cells, not Th1 or Th2, produced IL-26 in response to IL-1β, and expressed higher amounts of surface IL-1R1. Memory CD4+ T cells stimulated with IL-1β or αCD3/αCD28 secreted IL-26, but only cells stimulated with αCD3/αCD28 secreted IL-17 and IFN-γ. These studies suggest that Th17 cells play a role in the innate immune response by selectively secreting the antibacterial and pro-inflammatory cytokine IL-26 in response to IL-1β.
Maternal microbiota educates neonatal IgA response
Authors: Mu Qinghui , Zhang Husen , Kirby Jay , Luo Xin M 
Published: January 2023

Abstract
Maternal microbiota plays a key role in governing the establishment of neonatal gut microbiota. However, whether and how maternal microbiota from breast milk would affect the development of neonatal immune response remains unclear. Here we report that de novo synthesis of neonatal IgA in pre-weaning Rag1-sufficient mouse pups could be super-induced by the milk of Rag1−/− nursing moms. 16S rRNA sequencing analysis showed that the gut microbiota from the upper intestine of Rag1-sufficient pups were distinct depending on the genotypes of their nursing moms, with those nursed by Rag1−/− moms exhibiting a higher bacterial diversity than those nursed by Rag1-sufficient moms. Interestingly, when Rag1−/− moms were co-housed (littermates) with Rag1-sufficient moms, or treated with antibiotics, the pups that they nursed no longer exhibited the heightened IgA synthesis. Further studies revealed that the number of type 3 innate lymphoid cells (ILC3s) in the pups’ intestine was significantly increased when the pups were nursed by Rag1−/− moms. In addition, the super-induction of neonatal IgA was abrogated when pups were treated with an aryl hydrocarbon receptor antagonist that is known to reduce the number and function of ILC3s. These results suggest that the maternal microbiota may educate neonatal IgA response through an ILC3-dependent mechanism.
Complement drives neurodegeneration in Gaucher disease
Authors: Pandey Manoj K , Magnusen Daniel N , Magnusen Albert F , McKay Mary , Caballero Madison , Rani Reena , Setchell Kenneth D , Zhang Wujuan , Grabowski Gregory A , Köhl Jörg 
Published: January 2023

Abstract
GBA1 mutations result in excess storage of glucosylceramide (GC) and the induction of Gaucher disease (GD). GD is frequently associated with elevated levels of pro-inflammatory cytokines and the development of brain inflammation. The mechanisms underlying GC-driven brain inflammation in GD are ill-defined. Recently, we described immune complexes of GC-specific IgG autoantibodies in experimental and clinical GD, which induced massive complement activation and C5a generation. Further, we found that C5a-mediated activation of its cognate C5a receptor 1 (C5aR1) tips the balance between GC formation and degradation, thereby fueling excess GC accumulation and inflammation in visceral tissues in experimental and clinical GD.
Previously, the C5a/C5aR1 axis was found to regulate the blood brain barrier integrity in systemic lupus and promote neurodegeneration in Alzheimer’s disease. Here, we determined the production of C5a in the brain of Gba1 D409V/knockout (9V/null) GD-prone mice. C5a production in the brain of 9V/null mice was markedly elevated, when compared to WT control mice. Also, 9V/null mice suffered from massive accumulation of GC in the brain and loss of neurons. To assess the relevance of C5a/C5aR1 axis activation for brain inflammation in GD, we targeted glucocerebrosidase (GCase) with conduritol B epoxide (CBE) in WT and C5aR1−/− mice. Strikingly, CBE-injected WT mice died within 30 days. In contrast, all C5aR1−/− mice survived the 60 days observation window, were protected from CBE-induced accumulation of GC in the brain, showed a marked reduction of microglial cell activation and only a minor loss of neurons. Our data suggest that the C5a/C5aR1 axis is a critical driver of neurodegeneration in experimental GD.
Control of type I interferon responses by the AIM2 inflammasome
Authors: Banerjee Ishita , Vanaja Sivapriya Kailasan , Fitzgerald Kate A. , Rathinam Vijay 
Published: January 2023

Abstract
The immune system considers the presence of DNA in the cytosol as a sign of potential pathogen invasion and mounts inflammatory responses. Cytosolic DNA can be sensed by cyclic GMP-AMP synthase (c-GAS) leading to the production of type I Interferons (IFN). It can also be recognized by the PYHIN DNA sensor absent in melanoma (AIM2) resulting in the activation of inflammasome responses i.e. production of pro-inflammatory cytokines IL-1β and IL-18 as well as pyroptosis. Our results show that AIM2 inflammasome activation limits the production of type I IFNs in immune cells such as macrophages and dendritic cells. Further analysis showed that the recognition of cytosolic DNA and the assembly of inflammasome complex appear to be required for AIM2 regulation of IFN-β. Biochemical evidence showed an augmented phosphorylation of the transcription factor IRF-3 resulting in increased IFN-β production in AIM2-deficient macrophages. These findings may have implications in the treatment of autoimmune disorders such as systemic lupus erythematosus (SLE) associated with unregulated type I IFN signaling.
(Supported by NIH R01AI119015 and Charles Hood Child Health Research Award)
An arrayed genome-wide RNAi screen for the discovery of novel inflammasome regulators
Authors: Rabinovich-Ernst Orna , Sun Jing , LIN BIN , Fraser Iain D 
Published: January 2023

Abstract
Bacterial lipopolysaccharide (LPS) is a prominent PAMP implicated as the primary causative agent of septic shock in a wide range of bacterial infections. LPS is known to activate two receptors: the plasma membrane receptor, TLR4, and the cytosolic receptor, Caspase 11. We have conducted a genome-wide siRNA screen to identify novel gene products involved in the non-canonical inflammasome response to cytosolic LPS. A ‘prime-trigger’ assay was established in which macrophages were primed with Pam3CSK4, triggered by transfection of the active component of LPS, Lipid A, and IL-1α secretion measured by a screening-optimized HTRF assay, and pyroptosis was evaluated using an LDH assay. The screen was designed to identify and distinguish regulators at multiple stages of the non-canonical inflammasome activation process, from TLR priming, to cytosolic LPS detection, pyroptosis and IL-1α release. Initial analysis of the primary screen data identified a high canonical pathway hit rate in both the TLR priming step and the response to cytosolic LPS, with Irak4, Irak2, Casp4, Gsdmd and Gsdmc among the strongest gene hits. Among the genes not previously linked to regulation of the non-canonical inflammasome, we observed an enrichment for mitochondrial proteins. In order to further validate this finding, we have created a CRISPR/Cas9 knock-out macrophage cell line and knock-out mouse for one of the mitochondrial screen hits, confirming the effect of this novel hit on IL-1α release in response to cytosolic LPS. Our results suggest a critical role for mitochondria in regulation of the non-canonical inflammasome response.
This work was generously supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases.
Abrogation of IL-13Rα2 ameliorates acute inflammatory bowel disease
Authors: Karmele Erik P , Vannella Kevin M , Kasaian Marion T , Urban Joseph F , Wynn Thomas A 
Published: January 2023

Abstract
Anti-TNFα agents are commonly used for treatment of patients with inflammatory bowel disease (IBD), yet up to 40% of patients are non-responders for unknown reasons. IL13RA2 mRNA was more abundant in mucosal biopsy samples of patients with active IBD who are non-responders compared to responders, serving as a potential predictive marker for non-responsiveness. IL-13Rα2 is a high affinity decoy receptor for IL-13, a cytokine with both anti-inflammatory and wound healing functions. In this study, we hypothesized that TNFα and IL-17 produced during the initiation of IBD induces IL-13Rα2 production that neutralizes the endogenous anti-inflammatory activity of IL-13. Using an acute dextran sodium sulfate (DSS) model of mouse colitis, we show that DSS increases the production of both systemic and colonic IL-13Rα2 compared to naive controls. DSS-induced colitis was less severe in Il13ra2−/− mice compared to wild type controls as no shortening in the length of the colon was observed. Histological analysis of the distal colon revealed less goblet cell depletion, inflammatory cell infiltration, and submucosal inflammation in DSS-administered Il13ra2−/− mice compared to DSS-administered wild type mice. However, when Il13ra2−/− mice were infected with the nematode Heligmosomoides polygyrus bakeri, the increased IL-13 activity led to significant morbidity during DSS-colitis. Together, these findings suggest that the absence of IL-13Rα2 enhances endogenous IL-13 bioactivity, which protects mice from acute IBD. Yet, results from the nematode infection model suggest this protective activity must be carefully regulated. Collectively, these results suggest that IL-13Rα2 functions as a key regulator of IBD pathogenesis.
Cigarette smoke attenuated colon inflammation through the induction of regulatory T cells in ulcerative colitis model
Authors: Kitabatake Masahiro , Tomoda Koichi , Kubo Kaoru , Ito Toshihiro 
Published: January 2023

Abstract

Background
Ulcerative colitis (UC) is a chronic inflammatory disease induced by dysregulation of immune response in intestinal mucosa. Several cohort studies have shown that cigarette smoke (CS) is the protective factor for UC, but the underlying mechanisms are not fully elucidated. Here, we evaluated the influence of CS in the experimental UC model.

Methods
UC was induced by dextran sodium sulfate (DSS) during three weeks of CS exposure, and mice were sacrificed at day 7 following UC induction. Colon pathology, lymphocytes recruitment into intestinal mucosa, and gut microbiota were analyzed.

Results
CS exposure suppressed colon inflammation and disease activity in DSS-induced colitis model. CS exposed mice displayed significant reduction of activated CD8+ T cells in colon lamina propria, whereas regulatory T cells (Tregs) were significantly increased. In addition, Ruminococcus, which belongs to Clostridium cluster IV, increased in fecal microbiota of CS exposed mice, suggesting that Tregs are induced by CS exposure through the alteration of microbiota composition.

Conclusions
CS might suppress colon inflammation in UC through the alteration of microbiota composition and immune system including Tregs.
Mechanistic role of eosinophils in the initiation and progression of pancreatitis pathogenesis
Authors: Manohar Murli , Verma Alok K , Venkateshaiah Sathisha Upparahalli , Mishra Anil 
Published: January 2023

Abstract
Several clinical reports indicated that IL-18 and eosinophils are induced in patient with chronic pancreatitis and pancreatic malignancy. However, the etiology and pathogenesis of eosinophilic pancreatitis (EP) is poorly understood and termed as rare disease. Accordingly, we tested the hypothesis that IL-18 and IL-5 synergy may be critical in promoting EP pathogenesis. We performed qPCR, ELISA, western blot, immunofluorescence and immunohistochemical analyses to detect eosinophils, mast cells, collagen, associated cytokines and chemokines in experimental and human pancreatitis. Herein, we show the evidence of tissue eosinophilic microabscesses, mast cells and collagen accumulation in non-malignant and malignant human pancreatitis. Additionally, we observed more prominent collagen accumulation, fibrotic lesions and degranulated eosinophils in malignant pancreatic tissue samples compare to non-malignant pancreatic samples. A similar characteristics such as acinar cells atrophy, increased accumulation of tissue eosinophils, mast cells and induced levels of IL-5, IL-18, Eotaxin-2, TGF-β1, Collagen-1, Collagen-3, fibronectin and α-SMA was observed in cerulein-induced chronic mouse model of pancreatitis. Mechanistically, we show that IL-5 deficiency in mice protect pancreatic pathogenesis including fibrosis in cerulein-induced mouse model of pancreatitis, indicating a critical role of eosinophils in disease pathogenesis. Taken together, our combined clinical and experimental data indicates that eosinophils accumulation and degranulation may be critical in promoting pancreatic fibrosis that may leads to pancreatic malignancy.
Correlation of NK Cell Phenotypic Properties with Individual Differences in Human Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC)
Authors: Hudig Dorothy , Tang Jennifer J-J , Sung Alexander P. , Guglielmo Micheal , Smith-Gagen Julie , Anderson Stephen K. , Bateman Lucinda , Barao Isabel , Redelman Doug D. 
Published: January 2023

Abstract
Antibody-dependent cell-mediated cytotoxicity (ADCC) supports anti-viral protection and monoclonal antibody anti-tumor therapies. We used two assays to compare ADCC of healthy donors: CX@1:1 (the percentage cells killed at a 1:1 ratio of CD16Apositive NK cells to ‘target’ cells that were pre-labeled with saturating antibody); and EC50 (the effective concentration of antibody that supports 50% of maximal ADCC). CX@1:1 measures lytic capacity while the EC50 measures cellular recognition; there was no correlation between the 2 assays though we observed 4.5-fold differences among donors in each assay. We correlated ADCC with 5 cytometric parameters (the median fluorescent intensities [MFIs] of the CD16A IgG Fc-receptor; the %NK cells positive & MFIs of the adhesion molecule CD2; the MFIs of perforin; and the %CD16Apositive of CD56positive NK cells) and with CD16A V&F genotypes that affect FcR affinity. For CX@1:1, the best donor killed 73% of targets while the worst killed 16% and perforin levels correlated weakly (P=0.11). Unexpectedly and inexplicably, the %CD16Apositive cells among NK cells correlated (P&lt;0.05). CD16A and CD2 were dissociated from CX@1:1 as might be expected for the high antibody concentrations. For EC50s, there were no statistical correlations except for the expected difference between V/V &V/F vs. F/F genotypes, though the P=0.11. We conclude that substantial individual differences in ADCC per CD16Apositive NK cell are determined by parameters other than cell surface receptors and perforin. The unanticipated correlation of %CD16Apositive NK cells with CX@1:1 has potential as a surrogate marker for ADCC function.