bluuebunny/crossref_metadata_2025_split huggingface dataset:
Activation of the Stimulator of Interferon Gene Protein is Involved in the Etiopathogenesis of Sjogren’s Syndrome
Authors: Papinska Joanna Aleksandra , Bagavant Harini , Gmyrek Grzegorz B. , Sroka Magdalena , Tummala Saigiridhar , Fitzgerald Kate A. , Deshmukh Umesh S. 
Published: January 2023

Abstract
Activation of innate immune responses and excessive production of type I Interferons (IFNs) plays a critical role in the pathogenesis of Sjögren’s syndrome (SS), a chronic autoimmune disorder affecting the exocrine salivary glands (SG). Recognition of nucleic acids by cytosolic nucleic acid sensors is a major trigger for type I IFN production. Several cytosolic DNA sensors interact downstream with the stimulator of interferon gene (STING) protein and induce type I IFNs. Although STING has been implicated in several interferonopathies, its role in SS is not known.
To investigate whether STING activation is involved in the etiopathogenesis of SS, in this study, female C57BL/6 mice were injected with a STING agonist, dimethylxanthenone-4-acetic acid (DMXAA) and mice were followed for the development of SS. Systemic DMXAA treatment rapidly induced the expression of Ifnb1, Il6, and Tnfa in the SG, and these cytokines were also elevated in circulation. In contrast, increased Ifng gene expression was only detected in the SGs. The type I innate lymphoid cells present within the SG were the major source of IFNγ, and their numbers increased significantly within 3 days of DMXAA treatment. STING expression in SG was mainly observed in the ductal and interstitial cells. In primary SG cells, DMXAA activated STING, which caused phosphorylation of TBK1 and IRF3, and induced IFN-β production. The DMXAA-treated mice developed autoantibodies, sialoadenitis, and SG hypofunction.
Our study demonstrates that activation of STING pathway holds the potential to initiate SS. Thus, apart from viral infections, conditions that cause cellular perturbations and accumulation of host DNA within the cytosol should also be considered as possible triggers for SS.
Effect of combustible tobacco product preparations on neutrophil-like cells
Authors: Arimilli Subhashini , Cutno D’Quan Ke’shawn Lamar , Prasad G.L. 
Published: January 2023

Abstract
Chronic exposure to cigarette smoking causes inflammation and immune suppression, which are known to contribute to smoking-related diseases and increased susceptibility of smokers to microbial infections. Neutrophils play an essential role in innate immune responses to protect against microbial infections. However, there is limited information on how smoking impacts innate immunity, particularly neutrophil functions. The use of neutrophils in research is limited due to their short lived nature. Therefore, alternate sources for neutrophil-like cells have been sought. Treatment with DMSO, results in differentiation of the HL60 cells to neutrophil-like cells, which provides an alternate model for assessment of certain neutrophil functions. In this study, we have differentiated HL60 cells with DMSO to neutrophil-like cell phenotype. The differentiated cells were characterized by the expression of CD11b and phagocytosis, and assessed the effects of exposure to different tobacco products. We assessed the effect of combustible cigarette whole smoke conditioned medium (WS-CM) and smokeless tobacco (ST) extracts, prepared from reference tobacco products, on the neutrophil-like cells on cell migration and phagocytic function. A dose-dependent decrease in the migration and phagocytosis was observed on treatment with WS-CM, but not with ST extracts. These findings suggest that neutrophil-like cells can be utilized to assess the effects of combustible and non-combustible tobacco products. Further, these results show that combustible and non-combustible tobacco products differentially impact neutrophil functions in this model.
Lysophosphatidic acid strongly protects acute liver injury caused by acetaminophen in an experimental animal model
Authors: Bae Geon Ho , Lee Sung Kyun , Kim Hyung Sik , Lee Mingyu , Lee Ha Young , Bae Yoe-Sik 
Published: January 2023

Abstract
The effect of lysophosphatidic acid (LPA) against experimental acetaminophen (APAP)-induced acute liver injury was investigated. LPA administration elicited strongly protective effects against APAP-challenged acute liver injury, showing attenuated liver damage, liver cell death, and AST and ALT levels. APAP overdose-induced mortality was also significantly attenuated by LPA administration. On the mechanism involved in LPA-induced protection against acute liver injury, LPA not only markedly increased the glutathione level but also strongly blocked the APAP challenge-elicited phosphorylation of JNK, ERK, and GSK3β, which are involved in the pathogenesis of acute liver injury. Moreover, LPA decreased the production of TNF-α and IL-1β in an experimental liver injury animal model. Mouse primary hepatocytes express LPA1,3–6, and injection of the LPA receptor antagonist KI16425 (an LPA1,3-selective inhibitor) or H2L 5765834 (an LPA1,3,5-selective inhibitor) did not reverse the LPA-induced protective effects against acute liver injury. In conclusion, our findings indicate that LPA can block the pathogenesis of APAP-induced acute liver injury by increasing the glutathione level but decreasing inflammatory cytokines in an LPA1,3,5-independent manner. Therefore, we suggest that LPA can be considered as a possible therapeutic agent for drug-induced liver injury.
Suppression of CD8+ T cell and Neutrophil Function Distinguishes Ruxolitinib Treatment from IFNγ Neutralization in Hemophagocytic Lymphohistiocytosis
Authors: Albeituni Sabrin H. , Verbist Katherine , Tedrick Paige , Tillman Heather , Nichols Kim 
Published: January 2023

Abstract
HLH is an often-fatal cytokine storm syndrome characterized by an ineffective yet overactive immune response. CD8+ T cells and IFNγ are thought to be the primary effectors driving disease; however, outcomes for HLH patients remain suboptimal despite therapies that target T cells or IFNγ. As many of the cytokines amplified in HLH signal through the JAK-STAT pathway, we examined the therapeutic potential of the JAK1/2 inhibitor ruxolitinib in HLH. For mechanistic insight, we also compared its effects to IFNγ neutralization (αIFNγ). Using complimentary murine models (LCMV-infected perforin-deficient mice to model “primary” or inherited HLH and administration of CpG+αIL10R to model “secondary” non-inherited HLH), we found that HLH-associated cytopenias were ameliorated by either agent, but cellular inflammation was improved only by ruxolitinib. Consistently, ruxolitinib was also superior to αIFNγ in reducing the number and size of hepatic inflammatory foci and decreasing the numbers and cytokine-producing capacity of tissue-infiltrating CD8+ T cells and neutrophils. Surprisingly, ruxolitinib-induced reductions in pro-inflammatory cytokine levels and enhancements in survival were sustained despite discontinuation of the drug. However, such was not the case following discontinuation of αIFNγ. Fatality in these latter animals was reversed upon the simultaneous depletion of neutrophils. Together, these data reveal that the hematological parameters of HLH are IFNγ-dependent, while tissue immunopathology results from the activity of numerous cytokines that drive expansion and activation of CD8+ T cells and neutrophils. These data further support the incorporation of ruxolitinib into future HLH clinical trials.
Exogenous Lipocalin2 facilitates the upregulation of thermogenic and beige/browning markers in murine white adipocytes
Authors: Meyers Keya R. , Lopez Maria , samuels janaiya , Rayalam Srujana , Shashidharamurthy Rangaiah 
Published: January 2023

Abstract
Lipocalin2 (Lcn2) belongs to a small molecular weight lipocalin subfamily of secretory proteins that binds to small hydrophobic molecules. Recent studies have shown that Lcn2 is highly upregulated by adipocytes and is categorized as a new adipokine with a role in innate immunity and metabolic disorders, including obesity. However, the exact role Lcn2 plays in the mediation and progression of obesity has yet to be elucidated. Herein, we have investigated the role of exogenous Lcn2 in inducing the browning of white adipocytes in vitro using the 3T3-L1 murine adipocyte cell line. Treatment with exogenous recombinant Lcn2 (rec-Lcn2) resulted in the upregulation of thermogenic and beige/brown markers (UCP1, PGC-1α, PPARγ, PRDM16, ZIC-1 and TBX1) in mature adipocytes. Additionally, rec-Lcn2 increased mitochondrial activity in 3T3-L1 cells. Further, rec-Lcn2 decreased the pre-adipocyte differentiation resulting in the attenuation of adipogenesis as evidenced by reduced lipid content accumulation. These results suggest that Lcn2 is a naturally occurring adipokine, and may serve as an anti-obesity agent by both decreasing adipogenesis in white adipocytes and inducing the transdifferentiation of white to brown-like beige adipocytes. Therefore, Lcn2 could be a potential target to attenuate/prevent obesity.
Glucocorticoids inhibit group 3 innate lymphocyte IL-22 production
Authors: Zenewicz Lauren A. , Seshadri Sudarshan , Pope Rosemary L. 
Published: January 2023

Abstract
Glucocorticoids (GCs) are commonly prescribed to patients with a variety of inflammatory disorders, including inflammatory bowel disease (IBD). IBD is the manifestation of a dysregulated mucosal immune response, usually against commensal bacteria, involving many different immune cells. GCs mediate their immunomodulatory effects through many different mechanisms and target multiple signaling pathways. The GC dexamethasone down-modulates both innate and adaptive immune cell activation. Group 3 innate lymphocytes (ILC3s) have critical roles in mucosal inflammation. ILC3s secrete high levels of the cytokine IL-22, promoting epithelial proliferation, antimicrobial peptides and mucins. The effects of dexamethasone on T cell function are well described, however, it is not known if dexamethasone modulates the critical function of ILC3s or if dexamethasone regulates the cytokine IL-22. In this study, we examined the effects of dexamethasone on IL-22 production by ILC3s. We found that dexamethasone suppressed IL-23-mediated IL-22 production in homeostatic and activated human and mouse ILC3s. Dexamethasone did not modulate the IL-23 canonical signaling pathway of JAK2/STAT3, but did suppress phosphorylation of IkBa, an important regulator in NF-kB activation. These findings implicate NF-kB as a regulator of IL-22 production in ILC3s and have likely repercussions on GC treatment of IBD patients.
Selective electrical stimulation of vagus nerve induces specific cytokine response.
Authors: Datta-Chaudhuri Timir , Tsaava Tea , Addorissio Meghan , Bouton Chad , Tracey Kevin J. , Chavan Sangeeta S. 
Published: January 2023

Abstract
Neuro-immune communication and neural circuits regulating immunity have been therapeutically explored in preclinical models and successfully in recent human clinical trials. Implantable bioelectronic devices that stimulate the inflammatory reflex are effective in suppressing cytokine production during endoxtoxemia and other models of infection and injury. Whether vagus nerve stimulation can enhance cytokines was previously unknown. Here we analyzed serum cytokine levels in response to electrical stimulation of the vagus nerve using different pulse parameters. The cervical vagus nerve was isolated in adult male Balb/C mice and subjected to asymmetric charge-balanced stimulation using bipolar cuff electrodes. Animals were stimulated for 4 min using the following parameters: frequency 30–200 Hz, amplitude 50–750 μA, pulse width 50–250 μs. After 2 hrs, blood was collected and serum levels of TNFα, IL-6, IL-10, IL-12, and KC/GRO determined. Serum cytokine levels changed significantly (p&lt;0.0001–0.05) and exhibited tuning curve properties when subjected to varying electrical pulse parameters, suggesting selective recruitment of efferent or afferent fibers that regulate specific cytokine production. Further insight into the nature of the neural circuits was ascertained through unilateral and bilateral vagotomies, distal and proximal to the stimulation location. Together, these studies demonstrate that systemic cytokine levels can be modulated by selectively stimulating the vagus nerve using specific combinations of frequency, amplitude, and pulse width. This study was funded in part by DARPA (HR0011-15-2-0016) and NIH (1R35GM118182-01).
IL-2 enhances IFNγ signals in subpopulations of T and B lymphocytes from treatment naive relapsing remitting multiple sclerosis (RRMS) patients.
Authors: Pope Brandon J. , Sharma Vishal , Boland Molly , Meador William , Bridges S. Louis , Raman Chander 
Published: January 2023

Abstract
Multiple sclerosis (MS) is the most common demyelinating disorder where most patients exhibit an undulating relapsing remitting course of disease progression (RRMS). Dysregulated effector and regulatory arms of the adaptive immune system contribute to disease progression and severity. Low dose interleukin 2 (IL-2) therapy is being considered for the treatment of autoimmunity to control adaptive effector responses and promote regulatory T cell (Treg) activity. In RRMS, others have shown that IFNγ responsiveness leads to loss of Treg function. We tested the possibility that IL-2 signals will dampen IFNγ dependent STAT activation in subpopulations of effector and regulatory T and B lymphocytes in a disease specific context. We stimulated PBMC from treatment naive RRMS or as a disease control, RA patients, with IFNγ and/or IL-2. Using a multi-parameter phospho-flow approach we evaluated the activation of STAT1, STAT3, and STAT5 in each subpopulation of T and B cells. The data was analyzed using t-SNE and SPADE visualization tools to interrogate changes in the activation and proportion of cell populations. We found IFNγ stimulation broadly induced greater activation of STAT1 in MS than in RA within multiple lymphocyte populations. IL-2 co-stimulation further increased IFN-γ activation in MS but not in RA cell populations, including in Tregs. Our observations suggest that in MS (1) there are enhanced IFNγ induced effector responses and (2) IL-2 signals synergize with IFNγ induced STAT1 activation. Thus, low dose IL-2 as a therapy for MS is likely to further exacerbate RRMS pathogenesis.
Soluble TIR-8 neutralizes anti-inflammatory effects of IL-37 in Crohn disease patients
Authors: Ahmad Ali , Samarani Suzanne , Abulkhair Ayoub , Jantchou Prevost , Faure Christophe , Deslandres Colette , Amre Devendra 
Published: January 2023

Abstract
Toll-IL-1Receptor (TIR)-8 is an atypical member of the IL-1 receptor family (IL-1RF). Recently, it was shown to act as the second sub-unit of the receptor for IL-37, the first being IL-18Rα chain. IL-37 is a potent anti-inflammatory cytokine belonging to the IL-1 family that exerts anti-inflammatory, immune deviating and metabolic effects. We found that the cytokine concentrations are increased in the circulation of Crohn disease (CD) patients compared with healthy controls. However, the expression of TIR-8 was decreased on the surface of different peripheral blood mononuclear cells in the patients. Furthermore, the concentrations of soluble TIR-8 were also increased in the circulation of the patients. Our results show that metalloproteinase inhibitors prevent shedding of TIR-8 from the cell surface. Soluble TIR-8 inhibits anti-inflammatory effects of IL-37 in human cells. When soluble TIR-8 was added in different concentrations, in the presence and absence of IL-37, to LPS-stimulated THP-1 cells, it inhibited the anti-inflammatory effects of the cytokine on the secretion of TNF-α from these cells. The inhibition was exerted in a dose-dependent manner. Taken together, these results suggest that IL-37 is neutralized in CD patients by TIR-8 shedding, which makes immune cells less responsive to the cytokine. Furthermore, soluble TIR-8 also neutralizes anti-inflammatory effects of the cytokine and contributes towards a pro-inflammatory state in these patients. Measures aimed at restoring anti-inflammatory effects of IL-37 by inhibiting shedding of TIR-8 and/or neutralizing its soluble form may be helpful in attenuating inflammation in CD patients.
More than a decoy receptor? Interleukin 22 Binding Protein (IL-22BP) in bacterial pneumonia
Authors: Trevejo-Nunez Giraldina , Castillo Patricia , Chen Kong , Kolls Jay K. 
Published: January 2023

Abstract
IL-22 is secreted by lymphoid cells such as Th17 cells and ILC3s. The IL-22 receptor is composed of IL-22Ra1 and IL-10Rbeta. In the lung, the IL-22R localizes in the upper airway epithelial cells. We previously reported that IL-22 contains pneumococcal lung infection due to hepatic activation of C3 and improved cellular phagocytosis. IL-22 also binds to a natural antagonist, known as IL-22BP or IL-22Ra2. In vitro, IL-22BP binds to IL-22 with high affinity, competing with IL-22R and neutralizing IL-22 activity. Studies have shown that IL-22BP controls tumor development in the colon, regulates inflammation in autoimmune encephalitis and promotes bacterial uptake in Peyer’s patches. However, it is unclear whether these multifaceted effects associated with IL-22BP are due solely to IL-22 binding and neutralization, given discrepant phenotypes in IL-22−/− versus IL-22BP−/− mice. Furthermore, surprisingly little is known about IL-22BP in the lung. We therefore interrogated the role of IL-22BP in a mouse model of bacterial pneumonia. In naïve lungs, we saw that IL-22BP is mostly expressed in alveolar and airway epithelial cells. IL-22BP−/− mice were less susceptible than controls to Streptococcus pneumoniae infection. This resistance was not due to differences in cellular recruitment, neutrophil phagocytosis or chemokine expression. RNA-Seq analyses of total lung tissue that compared infected IL-22BP−/− cohorts versus wild type revealed differential expression of several genes in the mitochondrial oxidative phosphorylation pathway. These data were strikingly different from prior findings made in IL-22−/−mice, leading us to speculate that IL-22BP may regulate mitochondria metabolism and have functions beyond the IL-22 system.
Defective Microglia-Neuronal Communication during Demyelinating Disease Correlates with Altered Neurogenesis
Authors: Cardona Astrid E. , Church Kaira , Mendiola Andrew , Cardona Sandra M. , Vanegas Difernando , Garcia Charles , Luera Dezzarae , Lira Sergio A. , Kokovay Erzsebet , Lin Chi-Hsing Annie 
Published: January 2023

Abstract
Inflammatory demyelination is a hallmark of the pathology of multiple sclerosis (MS) and microglia are considered responsible for exacerbating myelin loss. The link between inflammation and neural stem cell (NSC) development, key events during the remyelination process, is being increasingly recognized. However, the mechanisms that connect microglia, myelination and inflammatory-mediated oxidative damage are unclear. Fractalkine (FKN), a neuronal derived chemokine, and its unique receptor, CX3CR1, expressed by microglia, are highly abundant in the healthy brain, and our laboratory has reported severe CNS demyelination and neuronal damage in EAE-induced CX3CR1-KO mice. Our hypothesis is that CX3CR1-defective signaling promotes inflammatory-mediated damage to neuron and myelin-forming cells. We found that expression of the adhesive defective human variant hCX3CR1-M280 caused enhanced disease severity, increased demyelination and exacerbated neuronal loss, mirroring the findings we observed in CX3CR1KO mice. Also, enhanced demyelination was observed after 4 wk of cuprizone treatment. Densities of NG2+ glia were comparable between WT and CX3CR1KO mice, but a significant reduction in DCX+ cells in the subgranular zone of the hippocampus was observed. In addition, lipocalin-2 an acute phase protein, linked to resolution of inflammation by reducing iron-induced toxicity, was found upregulated in cuprizone-induced demyelinated lesions of WT but not CX3CR1KO or hCX3CR1M280 mice. Thus, the FKN/CX3CR1 signaling pathway in microglia plays an under-appreciated role in MS, perhaps via anti-inflammatory processes that enhance neurogenesis through regulation of oxidative damage.
IL7R regulates fetal tissue resident macrophage development
Authors: Leung Gabriel , McCann Taylor , Forsberg Camilla , Beaudin Anna 
Published: January 2023

Abstract
Tissue-resident macrophages play critical roles in tissue homeostasis and disease. Many populations of tissue-resident macrophages derive from fetal progenitors and self-maintain across the lifespan through in situ proliferation, independent of bone marrow hematopoiesis. However, the developmental mechanisms that specify fetal-derived tissue-resident macrophages are poorly understood. Here, we have identified a novel cytokine regulating tissue-resident macrophage development using an IL7Ra-cre lineage tracing model. Adult tissue resident macrophages in the brain, skin, liver, and lung were extensively labeled by IL7ra-cre, in the absence of IL7ra message or protein expression. To gain insight into developmental expression of IL7ra, we profiled IL7Ra surface expression, mRNA expression, and IL7ra-cre-driven labeling across fetal myeloid development. We observed rapid upregulation of IL7ra surface expression during a limited window of tissue macrophage establishment, and dynamic regulation of IL7ra message and protein levels in monocyte precursors, suggesting that IL7ra regulated the transition from fetal liver monocytes into tissue macrophages. Blockade of the IL7R using a monoclonal antibody decreased cellularity of liver, lung and skin tissue resident macrophages at birth, and increased cellularity of fetal liver monocytes. These data suggest that late in gestation, IL7Ra is upregulated as fetal monocytes exit the fetal liver and differentiate into macrophages, and provides evidence that IL-7R signaling regulates fetal tissue-resident macrophage development. Ongoing work addresses the function of IL-7 signaling in myeloid development, and the function of IL-7R marked macrophages in adult immunity.
Assessing the disease specificity of urinary PF4 for active lupus nephritis
Authors: Gokaraju Sirisha , Haque Anam , Vanarsa Kamala , Soliman Samar , Saxena Ramesh , Mohan Chandra 
Published: January 2023

Abstract

Background
The use of urinary biomarkers is particularly helpful in avoiding invasive procedures such as renal biopsy. We recently observed that urinary Platelet factor 4 (PF4) was elevated in patients with active lupus nephritis compared to patients with inactive lupus or healthy controls. Objective of this study is to assess the specificity of urinary PF4 for lupus nephritis (LN). PF4 is a small cytokine, also known as CXCL-4, known to play a role in inflammation.

Methods
Urinary PF4 level was measured using ELISA in urine samples obtained from 50 chronic kidney disease patient samples comprising of DN (Diabetic Nephropathy) (N = 23), HTN Nephropathy (Hypertensive nephropathy) (N = 6), combination of DN and HTN nephropathy (N = 4), IgA nephropathy (N = 4), FSGS (Focal segmental glomerular sclerosis) (N = 13). As a negative control, urine samples were included from healthy controls, while urine samples from patients with active lupus nephritis were included as a positive control. All results were normalized to urinary creatinine. The urinary PF4 levels in various CKD groups were compared to both negative and positive controls.

Results
Urinary PF4 was significantly elevated (P&lt;0.05) in samples from DN (678±285 pg/mg), FSGS (423±208 pg/mg), and LN (1438±901 pg/mg), compared to healthy controls (11±10 pg/mg). Urine PF4 levels in IgA nephropathy (24±15 pg/mg), HTN nephropathy (38±33), and DN/HTN nephropathy (463±410 pg/mg) were not significantly elevated compared to healthy controls.

Conclusion
PF4, as a urinary biomarker, exhibited significant elevation in patients with DN, FSGS as well as LN when compared to other renal diseases like IgA nephropathy and HTN nephropathy. Hence PF4 may aid in the noninvasive monitoring of DN, FSGS, and LN.