bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ku70 is a novel cytosolic DNA sensor that induces a Type-III rather than Type-I IFN via activation of IRF-1 and IRF-7. (116.11)
Authors: Imamichi Tomozumi , Zhang Xing , Zhou Ming , Lempicki Richard , Baseler Michael , Veenstra Timothy , Young Howard , Lane H. Clifford 
Published: January 2023

Abstract
Recent studies have demonstrated that foreign cytoplasmic DNA is detected by cytosolic DNA sensors (DAI, AIM-2, LRRFIP1, RNA polymerase III, or IFI16) that induce Type-I IFN or IL-1β. We have previously found that HEK293 cell transfected with DNA induces a Type-III IFN (IFN-λ1) rather than Type-I IFN. In this study, utilizing a pull down assay followed by mass spectrometry, we identified the DNA sensor protein that specifically induces IFN-λ1. Changes in expression level of gene and protein were evaluated by real time RT-PCR and Western blot. Transfection of not only plasmid DNA but also PCR amplified DNA and bacteria DNA induced IFN-λ1 activation in cell lines, primary macrophages and dendritic cells. DNA virus (HSV-2) infection also induced IFN-λ1 production. The pull down assay using DNA-beads resulted in that DNA-binding proteins in cytosole were Ku70 and Ku80, a DNA repair protein, as playing potentially important role. Knockdown of Ku70, but not Ku80, by siRNA led to 90% and 70% reduction in the DNA- and the virus-mediated IFN-λ1 induction, respectively. Over expression of Ku70 induced activation of the IFN-λ1 promoter. DNA binding assay using NFκB-, ISRE- or PRDI-beads with nuclear extract from DNA transfected cells indicated that the DNA-mediated IFN-λ1 induction was associated with the activation of IRF-1 and IRF-7 rather than IRF-3 and NFκB. Taken together; these data demonstrated that Ku70 exerts a novel cytosolic DNA sensor that specifically activates IFN-λ1.
AID mediates innate immunity to endogenous retroelements (116.12)
Authors: Metzner Mirjam , Jäck Hans-Martin , Wabl Matthias 
Published: January 2023

Abstract
A member of the APOBEC protein family, activation-induced cytidine deaminase (AID) is a B-cell-specific mutator that deaminates cytosine to uracil in DNA. AID mediates somatic hypermutation and class switch recombination of immunoglobulin genes—processes important for the generation of high-affinity antibodies and changes in antibody effector functions, respectively. Recent data, including our own, suggest that AID may not only function in adaptive, but also in innate immunity. AID may inhibit retroelements—a function that is well established for APOBEC3 proteins. If unrestricted, endogenous retroelements accumulate in the cytoplasm and insert their DNA into the host genome, with the potential to cause disease ranging from cancer to autoimmunity. We found that AID inhibits the retrotransposition of LINE-1 (L1) retroelements in vitro. In activated B cells, AID forms cytoplasmic high molecular mass complexes with L1 mRNA and decreases the protein level of open reading frame 1 (ORF1) of L1 elements. We propose that AID protects B cells from the adverse effects of retroelements, such as insertional mutagenesis.
The zinc transporter SLC39A8 is a novel negative feedback regulator of the NF-κB pathway and innate immune activation (116.33)
Authors: Liu Mingjie , Bao Shengying , Gálvez-Peralta Marina , Pyle Charlie , Rudawsky Andrew , Nebert Daniel , Wewers Mark , Knoell Daren 
Published: January 2023

Abstract
Zinc is an essential micronutrient required for proper immune function. We previously reported that zinc deficiency increases inflammation and mortality in response to polymicrobial sepsis. Here we report that a specific zinc transporter, SLC39A8 (ZIP8), is a transcriptional target of NF-κB and functions as a negative regulator of NF-κB. Initially we observed that TNFα or LPS inducesSLC39A8 expression in human monocytes, macrophages and lung epithelial cells, leading to an increase in intracellular zinc. We then identified a functional NF-κB binding site in the promoter region that triggers ZIP8 expression. Silencing of ZIP8 expression significantly decreased intracellular accumulation of zinc and increased the inflammatory response, as determined by increased cytokine production and phosphorylation of IκBα, P65, ERK and Akt. We further revealed that zinc directly inhibits IKKβ in a ZIP8-dependent manner. In mice, endotoxin or cecal ligation and puncture resulted in increased ZIP8 expression and zinc uptake in circulating monocytes and lung tissue, contributing to hypozincemia. Consistent with these observations, mouse embryonic fibroblasts obtained from Slc39a8 hypomorphic mice were more responsive to TNFα and IL-1β compared to wild-type cells, confirming the function of ZIP8 as a negative regulator of NF-κB and innate immune activation. Taken together, our findings identify a novel inducible inhibitory feedback pathway for NF-κB and the pro-inflammatory response.
PKR is an essential regulator of HMGB1 release (116.38)
Authors: Lu Ben , Yang Huan , Chavan Sangeeta , Tracey Kevin 
Published: January 2023

Abstract
High-mobility group box 1 (HMGB1), a leader-less proinflammatory cytokine, is a necessary and sufficient mediator of inflammation during sterile and infectious injury. However, the mechanism of HMGB1 release by activated immune cells is largely unknown. Here we demonstrate that macrophages stimulated with Type 1 interferon release HMGB1 in a dose- and time- dependent manner. Consistently, inhibition of JAK-STAT pathway attenuated Type 1 interferon-induced HMGB1 release. Analysis of downstream effectors demonstrated that Interferon-inducible double-stranded RNA activated protein kinase R (PKR) is essential for Type 1 interferon mediated HMGB1 release. Inhibition of PKR activity by using specific inhibitor reduced Type 1 interferon-induced HMGB1 release in a dose dependent manner. Inhibition of PKR activity also blocked LPS- and Poly I:C- induced HMGB1 release from macrophages. Using immunohistochemical analysis, we have identified two important steps in HMGB1 release by activated macrophages. The first step is mediated by activation of JAK-STAT pathway by Type 1 interferon that culminates into translocation of HMGB1 from nucleus to cytoplasm. This is followed by PKR activation that in turn regulates HMGB1 release by macrophages. Our studies indicate that PKR is an essential regulator of HMGB1 release induced by multiple stimuli, such as Type 1 interferon, LPS and Poly I:C.
IL-34 produced by human synovial fibroblast in rheumatoid arthritis supports osteoclastogenesis (117.17)
Authors: Chang Eun-Ju , Kang Soon-Sook , Jeang Yeon-Ho , Kim Yong-Gil , Lee Chang Keun , Yoon Seung-Yong , Hwang Seung-Joon 
Published: January 2023

Abstract
Interleukin-34 (IL-34) has a similar function with M-CSF via M-CSF receptor, c-fms, which also involves in RANKL-osteoclastogenesis. In this study, we found that IL-34 was up-regulated in the synovial fluid of RA patients with diagnostic positive rheumatoid factors. IL-34 production was much higher in the synovial fibroblast of RA patients than in that of OA patients and which was enhanced by TNFa stimulation. The expression of IL-34 mRNA and protein in synovial fibroblasts of RA patient after TNFa stimulation were determined using real-time PCR and western blot. Interestingly, TNFa induced IL-34 expression but not M-CSF dependently on NF-kB activity. The conditioned medium of synovial fibroblasts of RA patient cultured with TNFa led to chemotactic migration of human monocytes, and which was blocked by anti-IL-34 antibodies. Moreover, blocking IL-34 activity hindered the RNAKL-induced osteoclastogenesis in same conditioned medium. These results demonstrate that the increase of biologically active IL-34 in the RA synovium induces the chemotactic migration of osteoclast precursor cells and subsequently supports osteoclastogenesis in the inflammed synovium. Together, the differential regulation of IL-34 and M-CSF expression levels by TNFa further implies discrete role of IL-34 in the inflammatory condition involving RA pathogenesis.
RSAD2 is a key requirement for Golgi trafficking of TNF-α in activated microglia (117.26)
Authors: Chung Eun Sook , Chung Hwansuck , Bae Hyunsu 
Published: January 2023

Abstract
Antiviral protein RSAD2 (radical S-adenosyl methionine domain-containing protein 2), also known as viperin, has been recognized as a highly inducible ER (endoplasmic reticulum) protein in response to a wide range of viruses and microbial products such as LPS and double-stranded RNA. However, the functions of RSAD2 other than its antiviral activity have remained unexplored. The present studies showed that RSAD2 mRNA and protein expression was highly induced by LPS treatment in both primary microglia and BV2 cells. To investigate the function of RSAD2 in activated microglia, BV2 cells were depleted RSAD2 by using a short hairpin RNA (shRNA) plasmid. TNF-α and IL-6 production in RSAD2 depleted cells was remarkably reduced after stimulation with LPS. However, mRNA expression of TNF-α and IL-6 did not reveal significant differences between RSAD2-shRNA transfected cells and cont-shRNA transfected cells after stimulation with LPS. The intracellular distribution and trafficking of TNF-α was demonstrated by immunofluorescence staining. Non-transfected control cells showed strong intracellular staining of TNF-α in a perinuclear Golgi complex after LPS treatment. However, depletion of RSAD2 inhibited the Golgi trafficking of TNF-α. These results suggest that RSAD2 play an important role in microglia activation, especially regulation of Golgi trafficking of secretary molecules such as TNF-α.
NLRP3 inflammasome regulates obesity induced systemic inflammation and insulin signaling (117.4)
Authors: Vandanmagsar Bolormaa , Youm Yun-Hee , Ravussin Anthony , Galgani Jose , Stadler Krisztian , Mynatt Randall , Ravussin Eric , Stephens Jacqueline , Dixit Vishwa 
Published: January 2023

Abstract
Activation of adipose tissue macrophages and T cells within fat depots is coupled with the development of obesity-induced proinflammatory state and insulin resistance. The release of IL-1β and IL-18 from macrophages is dependent on autocatalytic activation of procaspase-1 into active 20-kDa caspase-1. However, an upstream initiating event for obesity-induced immune cell activation in adipose tissue is not established. We found that Nlrp3 inflammasome, member of the Nod-like receptor (NLR) family of innate immune cell sensors is activated by obesity-associated lipotoxic factors. The obesity-induced macrophage activation and IL-1b production was lowered in absence of Nlrp3 signaling. Furthermore, elimination of Nlrp3 in obese mice reduced IL-18 and adipose tissue Interferon-g expression and improved insulin signaling. However, blocking the obesity-induced Nlrp3 inflamma¬some function in mice did not affect Treg cell homeostasis in adipose tissue but specifically reduced the numbers of effector memory cells and increased the naive CD4+ and CD8+ T cell populations in adipose tissue. Notably, weight loss associated improvement in type 2 diabetes in obese patients was associated with reduced NLRP3 expression and inflammation in adipose tissue. Our data establishes that Nlrp3 inflamamsome participates in origin of inflammation in obesity and development of insulin-resistance.
IL-4 suppresses prostaglandins production in human follicular dendritic cells by repressing COX-2 through JAK1-STAT6 (147.1)
Authors: Choe Jongseon , Cho Whajung 
Published: January 2023

Abstract
In a recent report, we demonstrated that IL-4 inhibits prostaglandins (PGs) production in follicular dendritic cell (FDC)-like cells, HK. To understand the inhibitory mechanisms of IL-4, its effects on the biosynthesis of enzymes in charge of PG production were assessed in this study. Although IL-4 did not affect COX-1 expression, it specifically inhibited LPS-induced COX-2 biosynthesis at the mRNA and protein levels. Protein expression of mPGES-1, a downstream enzyme of COX-2, was also markedly diminished by IL-4 but not by IL-10, maximizing the inhibitory activity. Next, we attempted to identify the early signaling molecules that led to this inhibition of COX-2 expression. Although IL-4 induced tyrosine phosphorylation of JAK1 and TYK2, RNA interference experiments revealed that only JAK1 was responsible for the IL-4-stimulated STAT6 phosphorylation. Knocking down JAK1 and STAT6 ablated the inhibitory effect of IL-4 on COX-2 expression and significantly reduced production of PGE2 and prostacyclin. These results stress the essential roles of JAK1 and STAT6 in the early signaling pathway of IL-4 leading to suppression of COX-2 expression and repression of PG production by HK cells. Our results suggest that T cells via IL-4 play a regulatory role in PG generation in FDC. IL-4 therapeutics may be applied to immune disorders where normal and ectopic expression of germinal center reactions needs to be regulated.
Monocytic myeloid-derived suppressor cells isolated from mice with colitis actively suppress CD4+ T cell functions in vitro. (147.11)
Authors: Kurmaeva Elvira , Berney Seth , Ostanin Dmitry 
Published: January 2023

Abstract
The inflammatory bowel diseases (IBD) are accompanied by extensive myelopoiesis and infiltration of myeloid cells into colonic lamina propria. Surprisingly, little is known about the contribution of these cells to the disease pathogenesis. In a mouse CD45RBhigh T cell transfer model we have identified a population of monocytic MDSC. When isolated from spleens and colons of colitic mice MDSC potently suppressed proliferation of ovalbumin (OVA)-specific CD4+ T cells (&gt;95% inhibition at 1:1 ratio). Interestingly, suppression was also observed in an antigen-non-specific manner with in vitro stimulated WT CD4+ T cells. It was partially reversed by fixation of MDSCs and addition of nitric oxide synthase inhibitor L-NMMA. Correlating with the suppression we saw decreased levels of T cell-derived cytokines (GM-CSF, IFN-γ, IL-2, and IL-17), but increased levels of IL-10 in the cell culture supernatant. We did not observe enhanced T cell apoptosis associated with suppression. On the contrary, T cells cultured with MDSCs showed increased viability when compared to culturing of T cells alone. Taken together, our data indicate that myelopoiesis associated with chronic inflammation results in the increased release into the circulation and recruitment of anti-inflammatory monocytic MDSCs to the inflamed tissue. Better understanding of the mechanisms behind expansion of anti-inflammatory MDSC in chronic inflammatory diseases may prove beneficial for future therapies.
CD99 regulates CD1A expression during dendritic cells differentiation (147.14)
Authors: Bernard Ghislaine , Sghaier Mouna , Mahiddine Karim , Bzioueche Hanene , Mallavialle Aude , Bernard Alain 
Published: January 2023

Abstract
Dendritic cells (DCs) are professional antigen-presenting cells (APCs) that play a dominant role in the regulation of immune responses. CD1a has a unique expression pattern among Ag-presenting molecules, expressed specifically on cortical thymocytes and APCs. We have previously established that CD99, a 32kd transmembrane molecule expressed as two isoforms, could regulate classical MHC class I expression. We found that CD99LF triggers phosphorylation of p38 mitogen-activated protein kinase (MAPK) and two activating transcription factor (ATF)/CREB family members, CREB-1 and ATF-2 to inhibit CD1a expression in DC derived from monocytes CD14+. We also showed that this regulation is counteracted in the presence of CD99 short form (CD99SF).To confirm our results, we used CD99 deficient Jurkat cells and CD99pos transfected cells, CD99 silencing experiments and inhibitors/activators of cell-signaling pathways. Accumulating data have shown that the microenvironment of dendritic cells modulates subtype differentiation and CD1a expression, but the mechanisms by which exogenous factors confer these effects are poorly understood. This study strongly suggests a role for CD99 in regulation of differentiation of DCs subtype. In conclusion, we propose that cAMP is a novel pathway exploited by CD99 to regulate CD1a expression.
Role of host lipid metabolism and tissue macrophages in psoriasis (147.30)
Authors: Wharton David , Gharavi Nima , Navab Mohamad , Lee Sangderk , Berliner Judith , Fogelman Alan , Modlin Robert 
Published: January 2023

Abstract
Epidemiologic studies and clinical co-morbidity suggests a link between psoriasis and atherosclerosis. These conditions share common inflammatory mediators, including macrophage (Mp) signaling and the presence of oxidized low-density lipoprotein (LDL). We examined the role of lipid metabolism and tissue Mp in psoriasis. Using immunohistochemistry on psoriatic tissue, we identified a subpopulation of CD209+/CD163+ dermal Mp which have phagocytic properties and are capable of engulfing oxidized lipids. Next, using gene-expression arrays, we examined the effect of oxidized lipids on Mp signaling. Treatment of THP-1 Mp with a component of minimally oxidized LDL induced the expression of interleukins-1, -6, -15, -17, -23, cathelicidin and vascular endothelial growth factor, all of which play a role is psoriasis. Lastly, we examined the properties of high-density lipoprotein (HDL) in serum from psoriatic patients. In healthy patients, HDL is capable of reverse cholesterol transport and has potent anti-inflammatory properties. In patients with systemic inflammatory disease, including atherosclerosis, HDL loses these properties and becomes dysfunctional. Using a well-established model of monocyte chemotaxis as well as an in-vitro model of IL-23 production, both as markers of inflammation, we demonstrated that HDL from psoriatic patients was dysfunctional and had pro-inflammatory properties. Taken together, these data provide a role for tissue Mp and host lipid metabolism in psoriasis
Therapeutic modulation of experimental autoimmune encephalomyelitis by gamma secretase inhibition (148.15)
Authors: Cummings Matthew , Villegas Alicia , Karandikar Nitin , Eagar Todd 
Published: January 2023

Abstract
Intramembranous proteolysis by the γ-secretase complex is a key regulator of transmembrane protein turnover and intracellular signaling. Small molecule inhibitors of γ-secretase (γSI) have previously been shown to suppress Th1 differentiation and reduce the severity of EAE, presumably by affecting Notch1 signaling. In order to understand the mechanisms through which γSI affect T effector responses we examined helper T cell polarization and function in vitro and in EAE. In vitro γSI treatment reduced T cell production of the Th1 cytokine IFNγ. We found γSI do not change activation but have effects on proliferation. Additionally, expression of the Th1 transcription factor Tbet was also diminished in γSI treated T cells. Looking upstream of Tbet expression, we found that γSI modulated STAT1 phosphorylation induced by exposing the cells to IFNγ. These results suggest that γSI might work at preventing Th1 differentiation but do not address the affects γSI may have on fully differentiated Th1 cells. We found that treatment with a γSI reduced the severity of EAE induced by adoptive transfer of myelin-specific TCR-transgenic T cells. Antigen recall experiments demonstrated that there was a dramatic decrease in the production of IFNγ by T cells ex vivo. These results demonstrate that γSI act not just to diminish differentiation of myelin-specific T cells into autoimmune Th1 effectors but impair the ability of established Th1 cells to cause damage to the CNS.
Aire mediates peptide epitope-specific thymic deletion of self reactive T cells to prevent autoimmune uveitis (148.3)
Authors: Taniguchi Ruth , Devoss Jason , Moon James , Jenkins Marc , Anderson Mark 
Published: January 2023

Abstract
Aire is a transcription factor required for the expression of many tissue specific antigens in the thymus. In the absence of functional Aire protein, human patients and mice develop multi-organ autoimmune disease, including autoimmune uveitis, due to a defect in negative selection. The development of spontaneous uveitis in the Aire KO mouse model is dependent on the eye antigen, interphotoreceptor retinoid-binding antigen (IRBP), which has Aire-regulated expression the thymus. To study the mechanism by which Aire prevents IRBP-dependent autoimmune uveitis, two tetramer reagents were generated to measure the frequency and phenotype of IRBP specific CD4+ T cells in the polyclonal repertoire of WT and Aire KO mice. Analysis of the polyclonal T cell repertoire of WT and Aire KO mice showed that T cells specific for both IRBP tetramers proliferated in Aire KO mice when they developed uveitis. However, tetramer staining of thymocytes showed that only one of the two tetramer binding populations were deleted via an Aire-dependent mechanism. These studies demonstrate that two types of IRBP-specific T cells participate in spontaneous autoimmune uveitis in Aire KO mice, those that are deleted in an Aire-dependent manner and those that are not deleted by Aire.
Interleukin-17 exacerbates tumor necrosis Factor-α induced apoptotic cell death of oligodendrocytes (148.8)
Authors: Paintlia Manjeet , Paintlia Ajaib , Singh Avtar , Singh Inderjit 
Published: January 2023

Abstract
Pro-inflammatory cytokine-induced cell death of oligodendrocytes (OLs) is associated with axonal loss in neurodegenerative disorders including multiple sclerosis (MS) and that contributes to clinical exacerbation in affected individuals. Accumulating evidence suggest that both Th1 phenotype cytokine including tumor necrosis factor (TNF)-α and Th17 phenotype cytokine, interleukin (IL)-17 participate equally in MS pathogenesis. Here, we investigated the effect of IL-17 on OLs survival in the presence/absence of TNF-α in vitro. Our findings suggest that OL survival was not affected by IL-17 alone, but it exacerbated the TNF-α-induced OL apoptosis in a dose dependent fashion. Synergistic effect of these cytokines was ascribed to an inhibition of cell survival mechanisms, co-localization of Bid/Bax proteins in the mitochondrial membrane and caspase 8 activation mediated release of apoptosis inducing factor from mitochondria in OLs. In addition, cytokine treatment disturbed the mitochondrial membrane potential in OLs with corresponding increase in the generation of reactive oxygen species, which were attenuated by N-acetyl cysteine. Collectively, these data provide initial evidence that IL-17 exacerbates TNF-α-induced apoptotic cell death of OLs that antioxidant-based therapies have potential to limit CNS demyelination in MS or other related demyelinating disorders.
Functional expression of CCR9 by lung cancer (149.16)
Authors: Singh Rajesh , Grizzle William , Lillard Jr. James , Singh Shailesh 
Published: January 2023

Abstract
Lung cancer is the leading cause of cancer-related deaths worldwide in both men and women. Metastasis is responsible for many of the lung cancer-related deaths; therefore, a better understanding of the metastatic processes and therapies to prevent the spread and growth of these tumors is greatly needed. The specific mechanisms that promote metastases have not been fully elucidated. Multiple chemokine receptors are involved in the multi-step process of metastasis and growth of cancer cells. For the first time, we show that non-small cell lung carcinoma (NSCLC) tissue express high levels of CCR9, which is the receptor for CCL25. It addition, serum levels of CCL25 which is natural ligand for CCR9 was significantly elevated in lung cancer patents compared to normal healthy donor. CCR9 was also highly expressed by NSCLC cell lines. To this end, CCR9 mRNA and protein levels were higher than similar levels expressed by small cell lung carcinoma (SCLC) cell lines. Functional CCR9 expression was demonstrated by CCL25-mediated lung cancer cell migration that was inhibited by anti-CCR9 antibody. The mechanisms underlying these clinically and biologically relevant findings need to be further explored. However, our studies elucidate a novel role for CCL25-CCR9 interactions in lung cancer progression.