bluuebunny/crossref_metadata_2025_split huggingface dataset:
MMPs/TIMPs imbalances in the peripheral blood and cerebrospinal fluid are associated with the pathogenesis of HIV-1-associated neurocognitive disorders
Authors: Xing Yanyan , Shepherd Nicole , Lan Jie , Li Wei , Gupta Samir , Zhang Shanxiang , Dong Jun , Yu Qigui 
Published: January 2023

Abstract
HIV-1-associated neurocognitive disorders (HAND) continue to be a major concern in the infected population, despite the widespread use of antiretroviral therapy. Growing evidence suggests that an imbalance between matrix metalloproteinases (MMPs) and endogenous tissue inhibitors of MMPs (TIMPs) contributes to the pathogenesis of HAND. In our present study, we examined MMPs/TIMPs protein levels and MMPs enzymatic activities in both plasma and cerebrospinal fluid (CSF) samples from HIV-1 patients and HIV-1-negative controls. We found that imbalances between MMPs and TIMPs occurred in both the plasma and CSF of HIV-1 patients, especially those with neurocognitive disorders. In the plasma, the protein levels of MMP-2, TIMP-1, and TIMP-2, but not MMP-9, were increased in all HIV-1 patients when compared with HIV-1-negative controls. The enzymatic activity of both MMP-2 and MMP-9 was increased in all HIV-1 patients. Particularly, the ratio of MMP-2/TIMP-2 was significantly increased in HAND patients, not in patients without neurocognitive disorders. In the CSF, MMP-2 activity was increased, but the ratio of MMP-2/TIMP-2 was not altered. De novo induction and activation of MMP-9 in the CSF of HAND patients was particularly prominent. The imbalances between MMPs and TIMPs in the blood and CSF were related to the altered profiles of inflammatory cytokines/chemokines and monocyte activation. In addition, HIV-1 plasma directly damaged a blood brain barrier (BBB) model, leading to increased BBB permeability and vigorous transmigration of monocytes. Thus, the increased ratio of MMP-2/TIMP-2 in the peripheral blood and de novo induction and activation of MMP-9 in the CSF are significant in HAND patients and may be biomarkers for HAND.
The role of meningeal lymphatics in viral meningitis
Authors: Herz Jasmin , Lupi Alexander , McGavern Dorian B , Kipnis Jonathan 
Published: January 2023

Abstract
Discovery of the meningeal lymphatic vessels in the brain meninges (coverings of the brain) led to the hypothesis that they carry macromolecules and immune cells from cerebrospinal fluid (CSF) to cervical lymph nodes (cLN). Our new findings suggest that the lymphatic system controls immune responses through guiding antigen-presenting cells, such as dendritic cells (DC) from the meninges to draining lymph nodes. By using surgical and pharmacological methods to interfere with meningeal lymphatic vessels, we found lymphatics to serve as a major conduit by which DC leave the meninges, traffic to cLN and promote the generation of antigen-specific T cells. Inflammation-induced migration of DC is primarily regulated through a CC-chemokine receptor 7 (CCR7) dependent pathway. Co-injection of equal parts of differentially labeled CCR7-deficient and wild-type (WT) DCs into the CSF of the brain did allow translocation of CCR7-competent DC into the T cell zone of the draining lymph nodes but not CCR7−/− DC. Subsequently, antigenic stimulation by CCR7−/− DC did not induce a T cells response in the cLN, whereas WT DC enforced the majority of antigen-specific T cells to proliferate and increase their effective trafficking through integrin expression. To gain insights into how T cell responses are elicited when the meninges are infected with a virus, we currently set out to understand the lymphatics function in a mouse model of virus-induced meningitis. Injection of Lymphocytic choriomeningitis virus into the CSF induces rapid, uniform and fatal inflammation that is dependent on the generation of viral specific CD8+ T cells and potentially the exit of migratory DC through meningeal lymphatic vessels.
TET2 and 3 proteins control iNKT cell lineage specification and TCR mediated expansion
Authors: Tsagaratou Ageliki , Avalos Edahi Gonzalez , Rautio Sini , Browne James Scott , Togher Susan , Pastor William , Rothenberg Ellen V. , Lahdesmaki Harri , Rao Anjana 
Published: January 2023

Abstract
TET proteins are 2-oxoglutarate- and Fe(II) dependent dioxygenases that catalyze the hydroxylation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and further oxidation products (5-formylcytosine and 5-carboxylcytosine) in DNA. They can act as mediators of “active” (replication-independent) DNA demethylation, achieved through excision of 5fC and 5caC by thymine DNA glycosylase (TDG) followed by replacement with an unmethylated cytosine by base excision repair. They are also novel epigenetic marks that are recognized specifically by readers.
The role of TET proteins in developing thymocytes remains elusive. In the present study, we show that simultaneous deletion of TET2 and TET3 in mice (DKO) results in aberrant development of invariant NKT cells that are skewed towards the NKT17 lineage. We also found upregulation of proliferation controlling genes as well as genes that are normally expressed in precursor cells. This results in an unprecedented expansion of iNKT cells, leading to lethality. The expansion is driven by antigen recognition, since the disease is effectively transmitted to fully immunocompetent recipient mice only if they express CD1d, a non-classical MHC protein that presents lipid antigens to iNKT cells. Molecular analysis revealed that TET2 and TET3 drive iNKT lineage specific DNA demethylation and control gene expression via DNA demethylation and/or chromatin accessibility of key lineage specifying factors such as RORgt, Tbet and ThPOK.
Collectively, TET2 and TET3 are fundamental regulators that seal iNKT lineage fate, ensure proper development and maturation and safeguard aberrant TCR mediated expansion.
Defining group 2 innate lymphoid cell tissue niches
Authors: Molofsky Ari B 
Published: January 2023

Abstract
Group 2 innate lymphoid cells (ILC2) are tissue resident cells that are key instigators of type 2 allergic immune responses. ILC2 can promote beneficial type 2 immunity in the context of helminth infection, but are also key contributors to the allergic pathology associated with asthma and atopic dermatitis. ILC2 are developmentally deposited in tissues where they locally proliferate, and recent work suggests their contribution to physiologic tissue responses during tissue development and tissue remodeling. Our group’s prior work indicates adipose tissue ILC2s are key coordinators of a mixed regulatory/type 2 immune response which promotes adipose tissue function and is protective in models of obesity and type 2 diabetes. However, the cells and signals that regulate ILC2 in tissues are only beginning to be explored. In adipose tissue and elsewhere, the IL-1 family cytokine IL-33 is a dominant positive regulator of ILC2 function. As such, we have pursued the regulation and cellular sources of IL-33 that are proximal to tissue-resident ILC2. Using high-resolution imaging and genetic approaches, our studies suggest ILC2 are maintained in specific micro-anatomic tissue niches that are defined by specific non-hematopoietic IL-33 expressing cells. By defining these ILC2 niches, we hope to better understand the cells and signals that regulate ILC2 so that we may ultimately exert control over both beneficial and pathologic type 2 immune responses.
Beta-2 adrenergic receptor signaling prevents hyperinflammation through early release of IL-10
Authors: Agac Didem , Estrada Leonardo , Farrar David 
Published: January 2023

Abstract
Innervation of the lymphoid tissues by catecholaminergic nerve endings allow the sympathetic nervous system to communicate with immune cells through the release of norepinephrine (NE). NE signals through adrenergic receptors, which are widely expressed by immune cells. We have identified a novel pathway where NE can suppress pro-inflammatory cytokine secretion from bone marrow-derived macrophages in response to multiple TLR agonists. This pathway operates through the beta2-adrenergic receptor (ADRB2), and the suppressive effect of NE depends on the early induction of the anti-inflammatory cytokine IL-10. We assessed the in vivo role of this pathway using a LPS endotoxemia model and found that ADRB2 knockout (KO) animals rapidly succumbed to a sub-lethal LPS challenge. This sensitivity is correlated with elevated serum levels of TNFα and suppressed IL-10 in ADRB2 KO animals. The lethality in the ADRB2 KO animals was rescued by administering exogenous IL-10. Additionally, the ADRB2-specific agonist salmeterol rescued wild-type animals from a lethal LPS challenge, which was reversed by neutralizing anti-IL-10 antibody. These observations suggest that ADRB2 signaling is critical for controlling inflammation through the rapid induction of IL-10. Through transcriptome analysis, the NR4A nuclear orphan family members were induced by NE, and the presence of several putative NR4A binding sites within the IL-10 promoter suggests that these factors may directly regulate IL-10 expression in response to ADRB2 signaling. Further studies will directly test the control of IL-10 expression by NR4A factors. Understanding this pathway will provide new insights into how the nervous and immune systems communicate through ADRB2 signaling.
Primary cilia regulate accumulation of innate and adaptive immune cells following injury
Authors: Zimmerman Kurt A , Song Cheng , Yoder Bradley K 
Published: January 2023

Abstract
Primary cilia are small microtubule based appendages found on the cell surface of almost every cell type. Mutations in proteins localized to the primary cilia or proteins required for ciliary assembly lead to polycystic kidney and liver disease with fluid filled cysts and fibrosis in both organs. Recent studies have found that tissues in which cilia function on epithelial cells is disrupted have an altered response to injury; however, the signaling pathways, cytokines, and cell types involved remain poorly defined although some studies suggest that macrophages are important. We hypothesize that cells containing a dysfunctional primary cilium are unable to elicit or resolve a normal injury response and produce cytokines that recruit immune cells thereby promoting cystic disease. Our data show that cilia mutant mice have an abnormal accumulation of neutrophils, bone marrow derived monocytes, tissue resident macrophages, and T cells in the kidney and liver following injury. In addition, qRT-PCR analysis of epithelial cells containing dysfunctional primary cilia shows increased mRNA levels of cytokines important for immune cell recruitment and activation including MCP-1, CSF-1, CXCL-1, and CX3CL- 1. Genetic reduction of monocytes (CCR2−/− mice) or a specific subset of tissue resident macrophages (CD11c+) in the kidney of cilia mutant mice did not affect cyst formation. However, our preliminary studies indicate that pharmacological inhibition of tissue resident macrophages (CSF1R inhibitor) or genetic ablation of adaptive immune cells (Rag1−/− mice) reduces the severity of cyst formation in cilia mutant mice. Targeting certain immune populations may prove of therapeutic benefit for polycystic kidney and liver disease patients.
Alpha-7 nicotinic acetylcholine receptor agonist GTS-21 influences the inflammatory response in an animal model of heart failure
Authors: Kha Mindy , Chow Sheryl , Cameron D. Joshua , O’Barr Stephen A 
Published: January 2023

Abstract
Cardiovascular disease, specifically heart failure affects nearly 6 million Americans, and remains to be the number one cause of hospitalization and death globally. Multiple studies have suggested that inflammation plays a pivotal role in the pathogenesis of this disease. There is a novel link between the vagus nerve and the inflammatory responses, where the vagus nerve can limit inflammation via the alpha-7 nicotinic acetylcholine receptor (α7 nAChR) in relation to the “cholinergic anti-inflammatory pathway (CAP)”. Selective pharmacological stimulation of the α7 nAChR may have therapeutic potential for the treatment of inflammatory conditions. We determined the anti-inflammatory potential of 3-(2,4-dimethoxybenzylident)-anabaseine (GTS-21), an α7-selective partial agonist, in an in vivo zebrafish heart failure model. To investigate the possible therapeutic benefit of GTS- 21, we used a chronic exposure system in which animals are pre-treated with GTS-21 for 20 minutes per day for four consecutive days. On day four after a short washout period, heart failure is chemically induced by Oligo-[2-(2- ethoxy)-ethoxyethyl)-guanidinium-chloride] (PGH) and survival is recorded. We show that GTS-21 has a profound anti-inflammatory effect in improving survivability in a concentration dependent manner. Moreover, rtPCR analysis on heart tissue shows that pre-treatment with GTS-21 induces modifications in levels of gene regulatory proteins leading to altered cytokine expression within the myocardium. In all, these data indicate that GTS-21 may be a promising therapeutic as it influences the inflammatory response in heart failure.
PLAG reduces the infection risk via acceleration of bacteria clearance through NF-κB activation in Pseudomonas aeruginosa induced pneumonia model with chemotherapy-induced neutropenia
Authors: Kim Yong-jae , Jeong Jinseon , Yoon Sun Young , Sohn Ki-Young , Kim Heung-Jae , Kim Jae Wha 
Published: January 2023

Abstract
Pseudomonas aeruginosa (P. aeruginosa) is an opportunistic pathogen and can cause an acute and chronic infection disease in immunocompromised condition. P. aeruginosa has a potent pathogen; causes invasion diseases in hospitalized patients and complicates 90% of cystic fibrosis deaths. NF-κB and STAT3 are important signal molecules in inflammatory responses. Recently, research on the interaction between NF-κB and STAT3 in inflammation has been actively conducted. Previously, we reported that PLAG (1-palmityoyl-2-linoleoyl-3-acetyl-rac- glycerol) has an effect on regulation of STAT3 activation in diverse disease model. Therefore, we investigated whether PLAG has an effect on bacteria-infected mice with chemotherapy-induced neutropenia. To establish neutropenic mouse model, we used Cyclophosphamide and doxorubicin (AC regimen). And P. aeruginosa was administrated by intranasal injection in AC regimen induced neutropenic mice and followed by oral administration of PLAG during the experiment. We observed that survival rate of P. aeruginosa infected neutropenic mice is increased and bacteria in BALF is decreased by PLAG at early time. To reveal the function of PLAG on increase of infected bacteria elimination, we checked out neutrophil recruitment and NETosis. We observed that neutrophil recruitment in BALF was not increased significantly, but NETosis occured by P. aeruginosa at early time. And PLAG enhanced NETosis through NF-κB activation via down-regulation of STAT3. Based on these data, we suggest that role of PLAG on bacteria clearance, regulates interaction between NF-κB and STAT3 activation through P. aeruginosa induced pneumonia model with CIN and PLAG could be help immunocompromised patients.
The mitochodnrial E3 ligase MARCH5 resolves RIG-I and MAVS aggregates in innate immunity
Authors: You Young Suk , Kim Jae-Hoon , Lee Jong-Soo , Cho Hyeseong 
Published: January 2023

Abstract
Ubiquitin proteasome system (UPS) on the mitochondrial is one of quality control systems that works as a first line of defense barrier against aggregated or misfolded proteins. In innate immunity formation of the MAVS(Mitochondrial anti-viral signaling protein) oligomers elicits robust type-I interferon induction upon viral infection and however, persistent RIG-I and MAVS complex rather leads to host immunopathology. We recently reported that mitochondria-resident E3 ligase, MARCH5, recognizes the oligomeric form of RIG-I and MAVS complex. MARCH5+/− mice and MARCH5 deficient immune cells exhibited low viral replication and elevated type-I interferon response to viral infection. MARCH5 bound RIG-I and MAVS complex only during viral infection when MAVS forms oligomer. MARCH5 mediates Lys-48-linked poly-ubiquitination chain addition to RIG-I and MAVS oligomer and induces the RIG-I/MAVS monomer. Next, we studies have suggested that a novel function of MARCH5 in inflammation signaling. Together, these data demonstrates that MARCH5 regulates oligomeric RIG-I and MAVS complex.
PTGER4 inhibition in non-obese diabetic mice restores impaired IFNAR signaling, decreases chronic inflammatory signals and inhibits autoimmunity
Authors: Rahman M. Jubayer , Rodrigues Kameron , Liu Yi , Zhao Yongge , Quiel Juan A. , Tarbell Kristin V 
Published: January 2023

Abstract
We recently demonstrated that dendritic cells (DCs) from autoimmune-prone non-obese diabetic (NOD) mice at prediabetic age (8–10 week) have a diminished IFN-alpha Receptor (IFNAR) response despite increased production of type 1 IFN. This impaired IFN response may result from chronic activation of inflammatory pathways that contribute to dysregulated innate activation. qPCR of innate targets showed that younger NOD mice (3 week old) did not yet display impaired IFNAR signaling, but already had higher IL-1. To understand the interplay between different innate signals, we compared gene expression of 5 key DC populations from prediabetic NOD mice and diabetes-resistant B6.g7 mice. Several inflammatory pathways including IL-1, Eicosanoids, and NFκB were higher in NOD DCs whereas type 1 IFN-response genes, especially those associated with tonic signal, were lower in prediabetic NOD mice. Analysis of potential upstream regulators of these changes identified increased PTGER4 signal and decreased IRF7. PTGER4 binds prostaglandin E2 (PGE2) and mediates specific aspects of both inflammatory and regulatory eicosanoid signaling. Interestingly, NOD mice treated with an inhibitor of PTGER4 displayed increased IFNAR signaling in DCs, but decreased IL-1, Nlrp3 and IFN-gamma production. These changes suggest restoration of cross-talk between key inflammatory mediators, namely that IFN-gamma and IL-1 can inhibit type 1 IFN and vice versa. Furthermore, mice treated with the PTGER4 antagonist display reduced autoimmune pathology, namely an increase in the number and percentage of healthy islets. These findings highlight PTGER4 as a potential target in type 1 diabetes, affecting several inflammatory pathways including IFNAR signaling.
Polymorphisms in FcγRII (CD32) mediate abnormal antibody half-life in NOD SCID mice and reduce antibody-mediated tumour cell deletion.
Authors: Oldham Robert J , Cox Kerry L , Cragg Mark S 
Published: January 2023

Abstract
NOD SCID (NS) mice are commonly used for the assessment of monoclonal antibody (mAb) therapeutics and form the genetic background of NSG mice widely used in human patient derived xenograft models. However, relatively little is known regarding how the NS background effects monoclonal antibody (mAb) pharmacokinetics and how this might influence therapeutic response. To address this we examined mAb half-life and clearance of hCD20 transgenic EμTCL-1 tumours in NS mice following administration of anti-hCD20 hIgG1 mAb and showed mAb half-life to be significantly shorter in NS versus SCID mice, correlating with reduced therapy.
Reduced half-life was also seen with mIgG2a but not mIgG1 or hIgG2 isotypes. Additionally, NS mice lacking CD32 or the FcR γ-chain demonstrated this rapid loss was dependent on the expression of CD32 and not activatory FcγRs. Sequencing confirmed the NOD strains carry the rare ly17.1 variant of CD32. Recombinant ly17.1 displayed increased affinity for hIgG1 compared to the more common ly17.2 variant, providing a potential mechanism for its more rapid removal from serum.
Importantly, the reduced half-life was dependent on the presence of both SCID and NOD mutations. SCID mice lack endogenous IgG and so we reasoned this might accentuate the effects of the NOD CD32 polymorphic variant. Accordingly, reconstitution of NS mice with physiological levels of mIgG restored normal half-life. These findings highlight the importance of examining mAb pharmacokinetics in complex mouse strains and demonstrate that therapeutic studies in mice on the NS background should be performed in the presence of exogenous IgG.
Cell-intrinsic glycogen metabolism supports early glycolytic reprogramming associated with dendritic cell immune responses
Authors: Thwe Phyu M. , Beauchamp Saritha , Reisz Julie A , D’Alessandro Angelo , Amiel Eyal 
Published: January 2023

Abstract
Stimulation of dendritic cells (DCs) through toll-like receptors (TLRs) is accompanied by an increased metabolic demand, which provides metabolites and energy required for DC activation. This metabolic requirement is fulfilled by TLR-driven rapid glycolytic burst, and inhibition of glycolysis impairs the survival and effector function of DCs. Previous studies have shown an important role for extracellular glucose uptake via glucose transporter 1 (Glut1) in supporting TLR-driven glycolysis; however, the contributions of intracellular glucose stores to these processes have not been well characterized. While non-immune cells store glucose in the form of glycogen as an intracellular energy reserve, the role of glycogen in DCs has not been identified. We propose here that cell-intrinsic glycogen metabolism in DCs supports the early glycolytic reprogramming essential for TLR-driven activation. Our data indicate that glycogen metabolism supports the activation of DCs, particularly before the upregulation of Glut1. Here, we show that DCs express the rate-limiting enzymes for glycogen metabolism and possess intracellular glycogen stores. Inhibition of glycogen breakdown severely impairs the expression of key maturation-associated molecules as well as the ability of DCs to stimulate T cells. Additionally, our metabolomics data indicate that the glycogen metabolism in DCs generates both glycolytic and TCA cycle intermediates and that glycogen-derived carbons preferentially engage in metabolic pathways distinct from free glucose catabolism. Our work reveals a novel metabolic regulatory pathway by which DCs differentially utilize glycogen and glucose metabolism to support their activation.
Canonical and cross-reactive binding of NK cell inhibitory receptors to HLA-C allotypes is dictated by peptides bound to HLA-C
Authors: Sim Malcolm John Wyness , Malaker Stacy A , Khan Ayesha , Stowell Janet M , Shabanowitz Jeffrey , Peterson Mary E , Rajagopalan Sumati , Hunt Donald F , Altmann Daniel M , Long Eric O , Boyton Rosemary J 
Published: January 2023

Abstract
Human NK cell activity is regulated by killer-cell Ig-like receptors (KIR) that bind HLA class I. Combinations of KIR and HLA genotypes are associated with disease, including susceptibility to viral infection and disorders of pregnancy. KIR2DL1 binds group C2 HLA-C (Lys80), while KIR2DL2/3 bind group C1 HLA-C (Asn80). The goal of this study was to determine how the endogenous HLA-C peptide repertoire influences specific binding of inhibitory KIR to HLA-C allotypes.
HLA-C*05:01 (C2) and HLA-C*08:02 (C1) have identical sequences apart from the key KIR specificity determining residues at 77 and 80. Endogenous peptides were eluted from HLA-C*05:01 and used to test KIR2DL1 and KIR2DL2/3 binding to HLA-C*05:01 and HLA-C*08:02 and subsequent impact on NK cell function. Canonical binding of KIR2DL1 to C2 occurred with the majority of peptides tested, while KIR2DL2/3 binding to C1 occurred with a subset of peptides. Cross-reactive binding of KIR2DL2/3 with C2 was restricted to even fewer peptides. Unexpectedly, two peptides promoted binding of the C2 specific KIR2DL1 to the C1 allotype.
KIR2DL2/3 binding to C1 is more peptide selective than KIR2DL1 binding to C2, providing an explanation for why KIR2DL3–C1 interactions appear weaker than KIR2DL1–C2. Cross-reactive KIR binding is characterized by even higher peptide selectivity. These differences in peptide selectivity may aid the interpretation of human disease associations with KIR and HLA, while peptide sequence-driven KIR binding provides a potential mechanism for pathogen or self-peptide to modulate KIR binding and NK cell activation.