bluuebunny/crossref_metadata_2025_split huggingface dataset:
A possible mechanism for maintenance of the deleterious allele of human CASAPSE-12 (110.17)
Authors: Hermel Evan , Klapstein Kevin 
Published: January 2023

Abstract
In humans, a functional CASPASE-12 (CASP12) gene has been identified only in persons of African and Southern Indian heritage. CASP12 has been suggested to play a regulatory role in response to bacterial pathogens and in promoting and increased susceptibility to sepsis by down-regulating the production of inflammatory cytokines such as interleukin-1 (IL1). The existence of a gene whose effect is deleterious, and which has been the subject of extensive negative selection in the rest of the human population, implies the simultaneous presence of some selective benefit for persons having CASP12. Given the importance of inflammatory immune responses in controlling the initial stages of infection, and the role that CASP12 plays in down-regulating inflammation, we hypothesize that pathogens which exploit the inflammatory response are restrained by an active CASP12 gene product. A number of candidate pathogens can be ruled out on the basis that IL1 is required for their clearance, while others may select for CASP12 by how they utilize the IL1 response as a part of their pathogenesis.
TGF-RbII signifies the molecular pathway for CD11c+DC-mediated osteoclastogenesis & bone loss in vivo (110.23)
Authors: Liu Yen-Chun Grace , Wang Yan-Shong , Teng Andy Yen-Tung 
Published: January 2023

Abstract
Bone loss is associated with osteoclasts (OC). We reported the development of OC from CD11c+dendritc cells (DDOC) via RANKL & Aggregatibacter actinomycetemcomitans (Aa) stimuli [J.Immunol/JBMR]. We aimed to study: i) proliferation, frequency & osteoclastogenic potential of DDOC in-vivo; ii) identify regulators of DDOC-development. CFU & limiting-dilution-analyses showed that CD11c+DDOC did not manifest detectable proliferation with an estimated OCp frequency 3+0.06% based on TRAP+multinucleated-OC. To assess their physiological relevance, CFSE-CD11c+DC were transferred onto NOD/SCID calvarias with Aa+IFA. By q-IHC, higher numbers of CFSE+CD11c+TRAP+OC were detected, in association with more bone-erosion in mice receiving DC, suggesting that CD11c+DC become TRAP+functional-OC under inflammation in-vivo. Moreover, the number of CD11c+TRAP+ multinucleated-OC was highly correlated with bone-loss on sub-chondral bone of collagen-induced arthritic joints in DBA-mice & Aa-induced periodontitis. Micro-arrays, RT-PCR & flow-cytometry were employed to identify regulator(s) in DDOC-development, demonstrating a (+)-correlation with TGF-RbII expression. Neutralization of TGF-b abolished DDOC development, based on TRAP & resorptive-pit assays in-vitro/in-vivo. These data support that: i) CD11c+DC subset(s) can act as OCp during inflammation; ii) TGF-RbII is essential for DDOC-development, an integral mechanism underlying inflammation-induced osteoclastogenesis at osteo-immune interface.
Cholinergic regulation of atrial natriuretic peptide in spleen during sepsis (110.4)
Authors: Huston Jared , Fritz Jason , Gersch Robert 
Published: January 2023

Abstract
Introduction: Cardiac atrial natriuretic peptide (ANP) regulates blood volume and pressure. ANP is also produced in spleen and reduces pro-inflammatory cytokine production in macrophages. The cholinergic anti-inflammatory pathway targets spleen to inhibit pro-inflammatory cytokines and organ damage in sepsis. We hypothesized that cholinergic regulation of systemic inflammation requires modulation of splenic ANP. Methods: Male 8-12 wk old BALB/c mice received LPS (15 mg/kg, i.p.), and were euthanized after 60 m. Nicotine (2 mg/kg, i.p.) or vehicle was given 1-2 h before LPS. TNF and ANP were measured using ELISA. Other mice received cecal ligation and puncture +/-splenectomy, and were euthanized at 24 h. One-way ANOVA or the Student’s t test was used to compare experimental groups. P-values &lt; 0.05 are significant. Results: Nicotine significantly reduces systemic and splenic TNF. Nicotine significantly reduces systemic ANP and significantly increases splenic ANP. Nicotine fails to regulate TNF or ANP after splenectomy. Splenectomy significantly reduces systemic TNF and ANP (p &lt; 0.07). Splenectomy significantly improves survival and decreases ANP after CLP. Conclusions: Cholinergic stimulation requires spleen to modulate systemic pro-inflammatory cytokines and ANP. Cholinergic stimulation increases splenic ANP and decreases systemic ANP. The cholinergic anti-inflammatory pathway may regulate systemic inflammation by limiting ANP release and enhancing splenic ANP signaling.
Scytonemin inhibits lipopolysaccharide-induced production of nitric oxide, tumor necrosis factor-α and interleukin-1β by blocking NF-κB/Rel signaling in macrophages (112.13)
Authors: Kang Jong Soon , Cho Sun Ah , Han Sang-Bae , Lee Kiho , Kim Hwan Mook 
Published: January 2023

Abstract
Scytonemin, an ultraviolet sunscreen pigment isolated from the extracellular sheath of cyanobacteria, has been reported to exert anti-inflammatory effect. In this study, we examined the effect of scytonemin on lipopolysaccharide (LPS)-induced production of inflammatory mediators, including nitric oxide (NO), tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), in macrophages and investigated the molecular mechanisms responsible for its effects. Scytonemin significantly inhibited NO production and inducible nitric oxide (iNOS) mRNA expression in LPS-stimulated macrophages. The secretion and mRNA expression of TNF-α and IL-1β were also suppressed by scytonemin treatment in RAW 264.7 cells. Further study demonstrated that scytonemin attenuated LPS-induced NF-κB/Rel activation in RAW 264.7 cells. In addition, scytonemin suppressed phorbol ester-induced skin inflammation in BALB/c mice. These results suggest that scytonemin inhibits the expression of inflammatory mediators, at least in part, by blocking NF-κB/Rel activity and might be a potential therapeutic agent for the treatment of inflammatory diseases.
The role of PKCθ in T cell motility (112.22)
Authors: Cannon Judy , Brown Ivy , Sperling Anne 
Published: January 2023

Abstract
T cell trafficking is critical to immune responses as naïve T cells constantly recirculate into and out of lymph nodes to survey for cognate antigen presented on dendritic cells. While many cell surface receptors including selectins, chemokine receptors, and integrins have been demonstrated to be crucial for T cell motility, less is known about the intracellular mediators of T cell motility. We recently found that PKCθ localizes to the T cell uropod, suggesting a previously unknown role for PKCθ in regulating T cell migration. Consistent with this hypothesis, we now show PKCθ-deficient T cells do not migrate as well as wild type T cells in response to the chemokine CCL21, showing that PKCθ plays a role downstream of the chemokine CCR7. We further show that PKCθ affects the localization of proteins to the uropod, suggesting that one mechanism by which PKCθ affects T cell migration is by regulating the T cell uropod. These data reveal a novel role for PKCθ in regulating T cell migration and suggests that PKCθ signals downstream of CCR7 to regulate T cell motility.
Podoplanin is involved in Th17 cell polarization (113.17)
Authors: Zhang Hong 
Published: January 2023

Abstract
Podoplanin is a mucin-type transmembrane glycoprotein containing extensive O-glycosylation in extracellular domain and two phosphorylation sites in a short cytoplasmic tail. It is expressed in kidney glomerular epithelial cells, lymphatic endothelium and subcapsular epithelial cells in murine thymus. Recently, podoplanin was found on F4/80 positive peritoneal macrophages, indicating that podoplanin is involved in immune response. However, the physiologic function of podoplanin is still unknown. To study whether podoplanin is involved in adaptive immunity, we measured its expression on lymphocyts. The data showed that podoplanin was not detectable on freshly isolated T and B lymphocytes from peripheral blood, spleen and thymus, its expression is also non-inducible after stimulation with PMA, Concanavalin A or LPS. Surprisingly, we found that the podoplanin expression on CD4+ cells was dramatically increased after 3 days culture with Th17 polarization medium compose of immobilized CD3/CD28, IL-6, IL-4, TGFb, IFN-r and IL-23, which showed more than 60% cells were podoplanin positive. However, its expression is not able to be induced on Th1 and Th2 polarized cells. By detecting IL-17 production, we interestingly found that the IL-17+ cells can be divided into podplaninhigh and podoplaninlow populations. The significance of the differential expression on Th17 cells needs to be further investigated.
Lung and blood Th1 and Th17 responses against mycobacterial antigens in patients with pulmonary sarcoidosis. (114.9)
Authors: Ostadkarampour Mahyar , Eklund Anders , Moller David , Grunewald Johan , Wahlström Jan 
Published: January 2023

Abstract
Sarcoidosis is an inflammatory disorder characterized by granulomas most commonly affecting the lungs. The presence of mycobacterial antigens, and recently a specific protein, M. tuberculosis catalase-peroxidase (mKatG), in sarcoidosis tissue has been reported. Th1 cell responses against mKatG have been observed in sarcoidosis lung and peripheral blood cells. IL-17 and IFNγ were evaluated by ELISPOT after stimulation of bronchoalveolar lavage (BAL) fluid and peripheral blood cells with mKatG and M. tuberculosis PPD proteins. Two groups of sarcoidosis patients were compared: HLA-DR3 positive (good prognosis) versus HLA-DR3 negative (bad prognosis). We also did dual-color Fluorospot assay and immunohistochemistry for further characterization. Both mKatG and PPD stimulation of BAL cells resulted in higher frequencies of cells producing IFNγ compared to IL-17. We did not detect any significant difference between BAL and blood regarding IL-17 secretion after stimulation with mKatG, while significantly more BAL cells produced IFNγ in comparison to blood after stimulation with mKatG (p&lt;0.05). Preliminary data do not indicate any difference between patient subgroups regarding IL-17 production. The existence of IL-17+ cells in the granulomas also supports the role of IL-17 in sarcoidosis. The observed Th17 responses against mycobacterial antigens could contribute to the inflammation in sarcoidosis, although they generally occur at lower frequencies than corresponding Th1 responses.
IL17A switches from a pathogenic to a protective function in experimental autoimmune myocarditis in the absence of IFNγ. (115.14)
Authors: Barin Jobert , Baldeviano G. , Talor Monica , Zheng Dongfeng , Cihakova Daniela , Rose Noel 
Published: January 2023

Abstract
Deviation to autoaggressive Th17 responses has been reported to account for the protective effect of IFNγ in certain animal models of autoimmune disease. Building on our previous findings that IL17 signaling was critical for the progression of experimental autoimmune myocarditis (EAM) to dilative heart failure, we sought to address the question of whether IL17 mediated the severe form of EAM observed in IFNγ-deficient mice. To our surprise, we found that IFNγ-/-IL17A-/- double-knockout (DKO) mice had greater mortality compared to IFNγ-/- mice, starting at day 14 and reaching 50% by day 21 of EAM. DKO hearts were severely infiltrated, indicating acute inflammatory heart failure as the mode of death in these mice. We have found evidence of aberrant eosinophilic Th2-deviated infiltration in DKO mice, implicating eosinophils in mediating the enhanced morbidity. Production of IL5 by CD4+ cells was increased in DKO hearts, as well as cardiac production of CCL11/eotaxin. Heart-infiltrating DKO CD4+ cells showed evidence of Th2 deviation. These data point to a novel collaboration between IFNγ and IL17A in controlling eosinophil recruitment by autoaggressive Th2 cells. Moreover, they indicate that myocarditis is not restricted to a single CD4+ subset - but instead reflects redundancy among Th1, Th2, and Th17 populations to elicit qualititative and quantitative variations in disease phenotype and progression.
Novel roles of gp96 and CNPY3 complexes in the biogenesis of Toll-like receptor 9 (116.10)
Authors: Liu Bei , Hong Feng , Wu Shuang , Li Zihai 
Published: January 2023

Abstract
TLR9 is an endolysosomal sensor for DNA, which plays important roles in sensing both self DNA and microbial DNA. Tight regulation of TLR9 biology is important to ensure proper anti-microbe response and yet avoid self-destructive response against self DNA. We have observed that TLR9 is crucially dependent on gp96 (also known as grp94 and HSP90b1) and CNPY3 (also known as PRAT4A), two ubiquitous endoplasmic reticulum chaperones for folding and transport to the endolysosomes. However, the detailed roles of gp96 and CNPY3 in TLR9 biogenesis remain poorly understood. In this study, we found that TLR9 forms a multimolecular complex with gp96 and CNPY3, and the binding of TLR9 to either molecule requires the presence of the other, suggesting that CNPY3 is a co-chaperone for gp96 in folding TLR9. We also examined the roles of other canopy family members in TLR9 folding. CNPY4 (also called PRAT4B) shares 38% amino acid sequence identity to CNPY3 and it has 6 conserved cysteine residues in the mature protein. However, genetic knockdown of CNPY4 only decreased TLR4 signaling, but did not affect TLR9 signaling. Finally, since gp96 also participates in general protein homeostasis and in the ER unfolded protein response (UPR), we hypothesize that gp96 and CNPY3 are the critical link between UPR and TLR responsiveness to protein-toxic stress. Ongoing experiments are carried out to determine if protein-toxic stress and inflammation converge on gp96 and CNPY.
CREB is an essential transcription factor for prostaglandin E2 induced IL-23p19 (116.18)
Authors: Kocieda Virginia , Adhikary Sabina , Emig Fran , Ganea Doina 
Published: January 2023

Abstract
We reported previously that PGE2 promotes IL-23p19 expression in dendritic cells (DC) treated with LPS. The effect is mediated through EP4 through the induction of cAMP. This study is focused on the signaling pathways involved in PGE1OH (an EP4 agonist)-induced p19 expression. EP4 activates adenylate cyclase and increases intracellular cAMP which leads to activation of PKA and EPAC. We found that adenylate cyclase, cAMP, and EPAC play a role in IL-23p19 induction. Using chemical inhibitors of PKA, PI3K, MAPK, and GSK3, we did not see a decrease in IL-23p19 expression. Previous studies reported the involvement of NFkB/c-Rel, ATF-2, SMAD-3 and AP-1 in p19 expression. Since two CRE-binding sites have been identified in the p19 promoter, we focused on CREB as a potential transcription factor activated by PGE1OH. Luciferase experiments including vectors containing mutated CRE sites and expressing dominant negative versions of CREB demonstrated the essential role CREB plays in IL-23p19 expression. In a transcription factor assay we found increased CREB binding activity in nuclear extracts from cells treated with PGE1OH. In addition, a ChIP assay confirmed CREB binding to the p19-promoter in the presence of PGE1OH. Overall, we identified CREB as a new transcription factor required for PGE1OH induction of IL-23p19 expression.
Complement Factor MASP-2 is activated after acute myocardial ischemia in human (116.28)
Authors: Zhang Ming , Hou Yunfang , Cavusoglu Erdal , Lee Daniel , Steffensen Rudi , Yang Liming , Jensenius Jens , Marmur Jonathan , Schwaeble Wilhelm , Ko Wilson , Shevde Ketan 
Published: January 2023

Abstract
Acute blockage of coronary artery results in myocardial injury manifested in clinical situations such as myocardial infarction (MI). Following ischemia, inflammation is provoked and may be related to the clinical outcomes. We studied the acute inflammatory response immediately following myocardial ischemia in human. Our results showed that in acute MI patients circulation levels of complement factor MASP-2 were significantly reduced comparing with those of healthy individuals or of coronary artery disease (CAD) patients without acute MI. This reduction was not due to genetic polymorphism of MASP-2 in acute MI patients. We hypothesized that MASP-2 was activated after acute myocardial ischemia, and tested this in cardiac patients undergoing surgically induced transient global heart ischemia. Our results showed that MASP-2 was significantly reduced in coronary circulation after global heart ischemia and was independently correlated with the post-operative increase of the myocardial injury marker, cardiac Troponin I. These data suggested that MASP-2 is activated in human acute heart ischemia and associated with myocardial injury.
alpha7 nicotinic acetylcholine receptor and cAMP response element binding protein are essential for prolonged monocyte deactivation by vagus nerve signaling (116.37)
Authors: Olofsson Lars Peder , Tusche Mike , Reardon Colin , Rosas-Ballina Mauricio , Parrish William , Levine Yaakov , Gregersen Peter , Diamond Betty , Chavan Sangeeta , Mak Tak , Tracey Kevin 
Published: January 2023

Abstract
The inflammatory reflex is a neural circuit that regulates innate immune responses to endotoxin and other stimulating agents. It confers protection against damaging inflammation by inhibiting synthesis and release of TNF and other cytokines. Action potentials transmitted in the vagus nerve stimulate acetylcholine release, a neurotransmitter which inhibits cytokine production by interacting with a7nAChR expressed on macrophages and other cytokine-producing cells. We studied the effects of electrical stimulation of the vagus nerve, and observed that a brief period of neural stimulation resulted in suppression of TNF release that persisted for several days. To deconvolute this effect, we implanted vagus nerve stimulators in ambulatory canines, and found that brief electrical pulses significantly inhibited endotoxin-induced TNF release for up to 9 days. Exposure of isolated monocytes and macrophages to acetylcholine reduced TNF production for 24 h via signal transduction through a7nAChR. a7nAChR interaction with type 6 adenylate cylcase upregulated cAMP levels, and enhanced phosphorylation of CREB. Transfection of monocytes with a dominant negative CREB blocked the prolonged deactivation of monocytes exposed transiently to acetylcholine or a7nAChR agonists. Thus, signals originating as action potentials in the vagus nerve produce an a7nAChR - CREB dependent deactivated phenotype in monocytes, which has significant implications for understanding the regulation of innate immunity.
The Enhanced Sensitivity Cytometric Bead Array, a method for detecting cytokines present in low concentrations. (117.11)
Authors: Luan Fengjun , Rabenstein Jacob , Chau Vicki , Chen Yu , Maher Patricia , Zhang Victor , Sepulveda Homero 
Published: January 2023

Abstract
Bead-based immunoassays enable users to measure multiple proteins in the same sample, significantly increasing the amount of data generated from a single sample. For samples that have significant levels of the cytokines of interest, bead-based immunoassays allow users to get a complete cytokine profile from a single sample in a single experiment. As powerful as bead-based assays are, there are still situations where the levels of cytokines fall below the assay range. Supernatants from un-stimulated cells, samples taken from early time-points in a culture stimulation, and numerous biological samples contain very low levels of some cytokines. Results obtained from these samples, where measurements are taken from below the standard curve range, are often ambiguous, variable, and can be misleading. Advances in technology have enabled the development of more sensitive bead-based immunoassays that can help to more reliably measure samples containing low levels of cytokines. Here, we evaluate the Enhanced Sensitivity (ES) Cytometric Bead Array (CBA) Assays for their use measuring low levels of cytokines in various sample types. Using the ES CBA assays, we were able to detect many cytokines earlier in the response than when using the regular CBA assays. The ES CBA Assays were able to detect cytokines when the regular CBA assays could not. For cytokines that were able to be measured using both the ES and the regular CBA Assays, the results obtained by both assays were comparable.
Alternatively spliced Interleukin-4 protein is naturally produced in asthmatics, and elicits immune inflammation through a STAT6- and STAT3-independent mechanism (117.14)
Authors: Luzina Irina , Lockatell Virginia , Kang Phillip , Bashkatova Yulia , Andreev Sergey , Atamas Sergei 
Published: January 2023

Abstract
A natural splice variant of IL-4 mRNA omits exon 2. It is unknown whether a corresponding protein, IL-4δ2, is also naturally produced. We have developed an mAb against IL-4δ2 with no cross-reactivity against IL-4. Freshly purified T cells from 8 patients with mild or moderate asthma and from 4 healthy controls were tested after up to 96 h activation with PMA/ionomycin. Levels of IL-4 and IL-4δ2 mRNAs were measured by RT-Q-PCR, and secretion of IL-4 and IL-4δ2 proteins was measured by ELISA. All cells expressed IL-4 and IL-4δ2 mRNAs; stimulation caused a 5-12 fold increase in IL-4 mRNA, and a 20-70 fold increase in IL-4δ2 mRNA at 12-24 h of activation. T cells from controls secreted IL-4 but not IL-4δ2 protein, whereas T cells from asthmatics produced both IL-4 and IL-4δ2 proteins in comparable amounts. Levels of IL-4 protein peaked at 24-48 h of activation, whereas IL-4δ2 protein peaked at 72 h. Adenoviral gene delivery of either mouse IL-4 or mouse IL-4δ2 to mouse lungs in vivo induced immune inflammation with accumulation of T and B cells in both cases. Delivery of IL-4 but not IL-4δ2 induced pulmonary eosinophilia, suggesting that IL-4 does and IL-4δ2 does not engage STAT6 signaling. Experiments in primary human T cell cultures revealed that, indeed, IL-4 but not IL-4δ2 induces phosphorylation of STAT6 or STAT3 in a time- and dose-dependent fashion. Thus, IL-4δ2 is naturally secreted as a protein; it is biologically active in vivo without engaging STAT6 or STAT3 signaling.
Antipsychotics affect DC differentiation and maturation with a skewed T-cell polarization (117.20)
Authors: Moins-Teisserenc Hélène , Aoki Masayuki , Hamdani Nora , Charron Dominique , Leboyer Marion , Tamouza Ryad 
Published: January 2023

Abstract
Schizophrenia is a complex disorder encompassing positive, negative symptoms and cognitive deficits. The immune system is implicated in the multifactorial pathogenesis of the disease through a cytokine network dysregulation leading to inflammation. Dendritic cells play a critical role in both innate and adaptive immune responses and generation of Th1 and Th2 cells. We hypothesized that some anti-psychotics could regulate DCs, resetting the equilibrium between the Th1 and Th2 pathways in addition to their anti-dopaminergic effect. The immunomodulatory activity of atypical antipsychotics on monocyte-derived dendritic cells (MoDCs) from donors and patients was examined by studying cell subsets, cytokine production and T-cell polarization. In vitro addition of antipsychotics delayed differentiation of CD14+ cells to CD1a+ DCs but increased expression of costimulatory molecules. MoDC+antipsychotics exhibited markedly different cytokine profiles after 2 days of maturation with a 12 fold reduction of IL-12p40 and high levels of IFN-a transcripts. Functional assays showed naïve T-cell polarization toward the Th2 phenotype. These data were supported by the ex vivo profile of Th2 lymphocyte polarization induced by MoDCs from schizophrenic patients after antipsychotic therapy. Our data provide new insights in the pathogenesis of schizophrenia and the beneficial role of antipsychotics, suggesting that the influence of these drugs on the cytokine network contribute to clinical efficacy.