bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interleukin-7 receptor α contributes to experimental autoimmune encephalomyelitis (171.42)
Authors: Jopek Ashbaugh Jessica , Brambilla Roberta , Karmally Shaffiat , Cabello Cecilia , Malek Thomas , Bethea John 
Published: January 2023

Abstract
Multiple sclerosis (MS) is a neurodegenerative disease characterized by inflammation, demyelination, and axonal damage. Recently, a mutation in the interleukin-7 receptor alpha (IL7Rα) locus has been identified as a risk factor for MS. IL7Rα has well-documented roles in lymphocyte development, function, and homeostasis, but its involvement in disease settings is largely understudied. Here we show that IL7Rα defective mice (IL7RTgIL7R-/-) display a less severe form of experimental autoimmune encephalomyelitis (EAE), a model for MS. Compared to wild type (WT), IL7RTgIL7R-/- exhibit reduced levels of paralysis, myelin damage, and inflammation. Furthermore, diseased WT treated with neutralizing anti-IL7Rα show significant recovery in EAE clinical scores and reduced lymphocyte infiltration into the CNS. A series of chimeric mice were then generated by bone marrow (BM) transplantation to identify IL7Rα+ cellular compartments contributing to EAE. Rag-/- mice engrafted with IL7RTgIL7R-/- or WT BM display equivalent disease severity, suggesting that IL7Rα on non-hematopoietic cells contributes to EAE. Lymphodeplete IL7R-/- mice reconstituted with WT or IL7RTgIL7R-/- BM showed dramatic reductions in EAE only with IL7RTgIL7R-/- engraftment and not WT, suggesting that IL7Rα signaling on lymphocytes contributes to disease. Taken together, IL7Rα signaling blockade in multiple cell types is necessary for marked reductions in EAE, and should be considered as a new therapeutic target for MS.
Immunization method influences EAE relapse rate in SJL mice (171.6)
Authors: Marusic Suzana , Olson Katrina , Delp Timothy , Tobin Casey , Lindbergh David 
Published: January 2023

Abstract
We have discovered that administration of pertussis toxin as an adjuvant during induction of experimental autoimmune encephalomyelitis (EAE) in SJL mice results in a more severe first EAE wave, but fewer, milder and later relapses than if pertussis toxin is not used. This finding is inconsistent with the widely-accepted epitope spreading hypothesis, which predicts more severe relapses resulting from more severe tissue damage in the first wave. EAE in SJL mice immunized with PLP139-151/CFA is the mouse model which most closely resembles human remitting/relapsing multiple sclerosis. EAE develops in 90-100% of immunized mice 10-15 days after immunization. The first wave of EAE lasts several days and most mice recover from it. After a disease-free period from one day to several months, most mice relapse. 50-75% of mice develop a relapse during the first 6 weeks after immunization. It is not clear why relapses develop. It is widely accepted that relapses result from epitope spreading - new immune responses to epitopes of self antigens other than the PLP139-151. It is believed that tissue damage from the initial immune response allows “presentation” of new epitopes to auto-reactive T cells. Our findings appear to conflict with this hypothesis. Potential mechanisms of relapse suppression by pertussis toxin will be discussed.
U1-snRNP activates the NLRP3 inflammasome in human monocytes (171.7)
Authors: Shin Min Sun , Kang Youna , Lee Naeun , Kang Ki Soo , Lazova Rossitza , Kang Insoo 
Published: January 2023

Abstract
The NLRP3 (NOD-like receptor family, pyrin domain containing 3) inflammasome is a caspase-1-containing cytosolic protein complex that is essential for processing and secretion of IL-1β. The U1-small nuclear ribonucleoprotein (U1-snRNP) which includes U1-small nuclear RNA (U1-snRNA) is a highly conserved intranuclear molecular complex involved in splicing pre-mRNA. Antibodies against this self nuclear molecule are characteristically found in autoimmune diseases like systemic lupus erythematosus (SLE), suggesting a potential role of U1-snRNP in autoimmunity. Although endogenous DNA and microbial nucleic acids are known to activate the inflammasomes, it is unknown whether endogenous RNA-containing U1-snRNP could activate this molecular complex. Here we show that U1-snRNP activates the NLRP3 inflammasome in CD14+ human monocytes dependently of anti-U1-snRNP antibodies, leading to IL-1β production. Reactive oxygen species (ROS) and K+ efflux were responsible for this activation. Knocking down the NLRP3 or inhibiting caspase-1 or TLR 7/8 pathway decreased IL-1β production from monocytes treated with U1-snRNP in the presence of anti-U1-snRNP antibodies. Plus, the expression of caspase-1 and IL-1β by CD14+ cells was found in cutaneous lupus tissue. Our findings indicate that endogenous RNA-containing U1-snRNP could be a signal that activates the NLRP3 inflammasome in autoimmune diseases like SLE where anti-U1-snRNP antibodies are present.
Slamf8 is a negative regulator of Nox2 activity and antigen presentation by macrophages and dendritic cells. (172.16)
Authors: Wang Guoxing , Abadía-Molina Ana , Berger Scott , Romero Xavier , Liao Gongxian , O’Keeffe Michael , Detre Cynthia , Terhorst Cox 
Published: January 2023

Abstract
Slamf8 (CD353) is a novel cell surface receptor that is expressed upon activation of resident peritoneal macrophages by interferon-gamma or bacteria. In studying innate immune responses of Slamf8-/- macrophages and dendritic cells, we found a very high activity of the Nox2 enzyme, not only in response to E.coli or S.aureus, but also to phorbol myristate acetate. Thus, Slamf8 acts as a negative regulator of Nox2 activity, which was confirmed by a reduction of the enzyme activity after transfection of the receptor into Slamf8-deficient primary or RAW 264.7 macrophages. The elevated Nox2 activity in Slamf8-/- macrophages partially reverted lowering of the pH in E.coli or S.aureus phagosomes. Consequently, in Slamf8-/- macrophages and dendritic cells MHC Class II antigen presentation to CD4 T+ cells is dramatically increased compared to wt cells. Taken together, the data show that upon response to inflammation-associated stimuli the inducible receptor Slamf8 negatively regulates antigen presentation.
Cys106 Oxidation of High Mobility Group Box 1 (HMGB1) Promotes Self-Oligomerization and Cytokine Release (172.22)
Authors: Kwak Man Sup , Jie Wu , Youn Ju Ho , Kwon Min Kyung , Shin Jeon-Soo 
Published: January 2023

Abstract
Oxidative stress can induce covalent disulfide bonds to form between protein-protein thiol groups. HMGB1, a DNA chaperon and damage associated molecular pattern molecule, is integral to oxidative stress. As a redox-sensitive protein, HMGB1 contains three cysteines: Cys23, Cys45, and Cys106. In this study, we focused on the oxidative oligomerization and pro-inflammatory cytokine induction by Cys106. HMGB1 oligomerization is positively modulated by copper and hydrogen peroxide. Mutagenesis of the Cys106 residue within HMGB1 blocks the formation of such oligomers. Addition of copper and hydrogen peroxide in HEK293T cell enhanced the oxidative self-oligomerization of HMGB1, while inhibiting it for mutant HMGB1 C106A. Furthermore, we used a bimolecular fluorescence complementation assay to directly visualize the Cys106 oxidation-induced HMGB1 oligomerization in live cells under oxidative stress conditions. And we were able to reproduce the oligomerization effect of HMGB1 using FRET analysis. Interestingly, the oligomerized-HMGB1 binds to TLR4/MD2 complex with higher affinity than monomer HMGB1. Oligomerized HMGB1 transferred nuclear factor-κB signaling at significant levels using HEK293/TLR4 cells, and the cytokine production by oligomerized-HMGB1 is now under investigation. In conclusion, the oligomerized-HMGB1 most likely plays a regulatory role in the secretion of pro-inflammatory cytokines under physiological conditions.
The Radioprotective 105/MD-1 Complex Contributes to Diet-induced Obesity and Adipose Tissue Inflammation (172.23)
Authors: Watanabe Yasuharu , Nagai Yoshinori , Nakamura Tomoya , Akira Shizuo , Miyake Kensuke , Takatsu Kiyoshi 
Published: January 2023

Abstract
Accumulating evidence suggest that innate immunity is associated with obesity-induced chronic inflammation and metabolic disorders. For example, the TLR4/MD-2 complex recognizes free fatty acids (FAAs) derived from adipose tissue and promotes adipose tissue inflammation and insulin resistance. The RP105/MD-1 complex is a homolog of the TLR4/MD-2 complex. However, the roles of RP105/MD-1 complex in adipose tissue inflammation have remained elusive. We now report that the RP105/MD-1 complex contributes to high-fat diet (HFD)-induced obesity, adipose tissue inflammation, and insulin resistance independent of TLR4 signaling. RP105 mRNA expression is dramatically increased by HFD in stromal vascular fraction of epididymal white adipose tissue (eWAT) in wild-type (WT) mice. In human, RP105 mRNA expression is also increased in the visceral adipose tissue of obese subjects. The RP105/MD-1 complex is expressed by most adipose tissue macrophages (ATMs). HFD increases RP105/MD-1 expression on the M1 ATMs in eWAT. Increased RP105 and MD-1 mRNA expression in macrophages is induced by co-culture with 3T3L-1 adipocytes. RP105 KO and MD-1 KO mice have less HFD-induced adipose tissue inflammation, hepatic steatosis and insulin resistance compared to these in WT and TLR4 KO mice. Finally, the saturated FAAs palmitic and stearic acids activate TLR4/MD-2 but not RP105/MD-1. Thus, the RP105/MD-1 complex is a major mediator of adipose tissue inflammation independent of TLR4 signaling.
Interaction of High Mobility Group Box-1 (HMGB1) with α-synuclein and its aggregation (172.28)
Authors: Ko Eun Ae , Min Hyun Jin , Shin Jeon-Soo 
Published: January 2023

Abstract
HMGB1, also known as amphoterin, is an abundant non-histone nuclear protein and is involved in neurite outgrowth and neuronal migration in CNS. The accumulation of misfolded proteins and neuronal loss are common features in many neurodegenerative diseases. The aggregation of α-synuclein is implicated as a pathologic hallmark of Parkinson’s disease. In this study, we demonstrated that HMGB1, which was translocated to the cytoplasm by the treatment of lysosomal protease inhibitor of MG-132, was co-localized with α-synuclein in SH-SY5Y neuroblastoma cells. HMGB1 showed much more binding to α-synuclein E46K mutant, which is the site of one of familial mutations that accelerate oligomerization, suggesting that HMGB1 could enhance the aggregation of α-synuclein mutant. The binding of HMGB1 and α-synuclein isolated from brain tissue that is originated from Parkinson’s disease patient is under investigation.
Glutathione reductase facilitates host defense by sustaining phagocytic oxidative burst and promoting the development of neutrophil extracellular traps (172.3)
Authors: Liu Yusen , Yan Jing , Meng Xiaomei , Wancket Lyn , Lintner Katherine , Nelin Leif , Chen Bernadette , Francis Kevin , Smith Charles , Rogers Lynette 
Published: January 2023

Abstract
Glutathione reductase (Gsr) catalyzes the reduction of glutathione disulfide to glutathione. Since Gsr has been implicated in the oxidative burst in human PMN, we hypothesized that Gsr-null mice would exhibit marked defects during the immune response against bacterial challenge. We report here that Gsr-null mice exhibited enhanced susceptibility to E. coli challenge, indicated by dramatically increased bacterial burden, cytokine storm, striking histological abnormalities, and substantially elevated mortality. Examination of the bactericidal functions of the neutrophils from Gsr-null mice in vitro revealed impaired phagocytosis and defective bacterial killing activities. Although Gsr catalyzes the regeneration of glutathione, a major cellular antioxidant, Gsr-null neutrophils paradoxically produced far less reactive oxygen species both ex vivo and in vivo. Unlike wildtype neutrophils that exhibited a sustained oxidative burst upon activation, Gsr-null neutrophils displayed a very transient oxidative burst associated with compromised hexose monophosphate shunt. Likewise, Gsr-null neutrophils also exhibited an attenuated oxidative burst upon encountering E. coli. Moreover, Gsr-null neutrophils displayed a marked impairment in the formation of neutrophil extracellular traps, a bactericidal mechanism which operates after neutrophil death. Thus, Gsr-mediated redox regulation is crucial for bacterial clearance during host defense against massive bacterial challenge.
The bone marrow neutrophil reserve is regulated by serpinB1 and cathepsin G through a cell autonomous and caspase-independent death pathway (172.32)
Authors: Benarafa Charaf , Baumann Mathias 
Published: January 2023

Abstract
The bone marrow (BM) neutrophil reserve is a large pool of mature neutrophils that can be rapidly mobilized to the circulation and recruited to tissues in response to danger signals. We have previously shown that serpinB1-/- mature neutrophils have a survival defect that leads to a considerable reduction of the BM reserve and failure to clear bacterial infection. SerpinB1 is one of the best inhibitors of neutrophil serine proteases including elastase (NE) and cathepsin G (CG). Here, BM chimera showed that serpinB1 deficiency in hematopoietic cells was necessary and sufficient to reproduce the bone marrow neutropenia of serpinB1-/- mice. We found that CG, but not NE, was responsible for the BM neutropenia of serpinB1-/- mice. Mice deficient in both CG and serpinB1 had a normal neutrophil reserve, whereas NE-deficiency did not rescue the BM defect of serpinB1-/- mice. Neutrophil survival was increased by pan-caspase inhibitor Q-VD-OPh in both wild-type and serpinB1-/- neutrophils in vitro compared to untreated cells. However, survival was significantly lower in serpinB1-/- neutrophils (35%) vs. wild type (80%) after 72hr. This survival defect in vitro was rescued by CG deficiency. Furthermore, neither transgenic over expression of anti-apoptotic factor BCL-2 nor G-CSF treatment of serpinB1-/- mice rescued CG-mediated neutrophil death. We conclude that CG and serpinB1 regulate neutrophil survival through a proteolytic process distinct from classical apoptotic pathways.
Cross-talk of Nod1 and Nod2 signaling pathways with IFNγ (172.33)
Authors: Duerr Claudia , Fritz Jörg 
Published: January 2023

Abstract
The importance of Nod1- and Nod2-mediated PGN-recognition for the elicitation of antimicrobial immunity has been highlighted by observations demonstrating that animals deficient in Nod1 and Nod2 are more susceptible to several bacterial infections. Moreover, we recently revealed that Nod1-/- and Nod2-/- animals exert altered microbe-specific T cells producing IFNγ. However, sole Nod1 and Nod2 stimulation fails to elicit the Ag-specific type 1 immune response suggesting that PGN recognition by Nod1 and Nod2 acts in concert with (an)other signal(s) for the priming of protective immunity. Since IFNγ provides an innate mechanism of resistance to many intracellular pathogens, we hypothesize that the synergistic activity of Nod1 and Nod2 with IFNγ exerts critical antimicrobial activity through the enhanced priming of CXCR3+ Ag-specific CD4+ and CD8+T cells. Following our hypothesis we acquired preliminary data demonstrating that stimulation of murine and human macrophages and DC by a combination of IFNγ and Nod1- or Nod2 agonists, induces the synergistic release of the chemokines RANTES, MIG and IP-10, known to chemoattract Th1 and NK cells as well as the upregulation of co-stimulatory molecules such as MHC class II, CD40 CD80 and CD86. These finding demonstrate that the synergistic stimulation of IFNγ with Nod1- or Nod2-agonists leads to the potent induction of CXCR3 and CCL5 ligating chemokines and the subsequent polarization of protective antimicrobial type 1 immunity in vivo.
Use of novel small molecule inhibitors to investigate the role of endogenous RIP2 kinase activity in modulating NOD2/RIP2-dependent cytokine signaling (172.4)
Authors: Desai Biva , Haile Pamela , Casillas Linda , Gough Peter , Bertin John , Votta Bart 
Published: January 2023

Abstract
RIP2 is a Ser/Thr protein kinase, which undergoes autophosphorylation and activates NF-κB and MAPKs following stimulation of the upstream NOD1/NOD2 receptors resulting in proinflammatory cytokine production. Previous studies using transient overexpression systems have suggested that RIP2 kinase activity mediates NOD1/2-dependent signaling by regulating cellular RIP2 protein levels. To interrogate whether this is also the case for endogenous RIP2 kinase, we used novel, potent and highly-selective small-molecule RIP2 kinase inhibitors to study MDP-stimulated signaling in both primary human monocytes and human colonic epithelial (HCT116) cells. We demonstrated that inhibition of RIP2 kinase activity blocks proinflammatory cytokine production in monocytes in the absence of detectable changes in total RIP2 protein levels. Using TNFα-primed HCT116 cells, we confirmed these observations and demonstrated a direct correlation between the inhibition of endogenous RIP2 kinase activity (measured as a decrease in pS176-RIPK2 levels) and a reduction in proinflammatory cytokine signaling in response to MDP-stimulation. Our data confirm the importance of endogenous RIP2 kinase activity in modulating proinflammatory cytokine release from both human monocytes and intestinal epithelial cells in response to bacterial ligands. Furthermore, our results suggest that RIP2 kinase inhibition may represent a novel therapeutic strategy for the treatment of intestinal inflammation.
Regulation of Innate Immune Responses by Receptor Interacting Protein Kinases (172.43)
Authors: Chan Francis , McQuade Thomas , Moquin David 
Published: January 2023

Abstract
The Tumor Necrosis Factor (TNF) family of cytokines are crucial regulators of host defense and immunity against pathogens. The Receptor Interacting Protein (RIP) family of serine/threonine kinases play critical roles in the signal transduction pathway of many TNF family receptors. The archetype member of this kinase family, RIPK1, promotes cell survival by activating the latent transcription factor NF-κB. Paradoxically, RIPK1 also promotes apoptosis in the presence of IAP antagonist. When caspases are inhibited, RIPK1 induces programmed necrosis though interacting with another RIP family RIPK3. We found that the switch between cell survival and cell death involves regulation of caspase mediated cleavage, protein ubiquitination and phosphorylation of the RIP kinases. Mice deficient in RIPK3 are highly susceptible to poxvirus infection. In addition, inactivation of the apoptosis mediators Fadd or caspase 8 led to extensive programmed necrosis of lymphocytes that severely impairs antigen-specific lymphocyte expansion. We will discuss the molecular events that regulate RIP kinase dependent necrosis and its role in the immune system.
Lung surfactant protein A attenuates alveolar macrophage classical activation induced by LPS + IFN-γ through binding to IFN-γ and blocking LPS-signaling (172.5)
Authors: Minutti Carlos , García-Fojeda Belén , Casals Cristina 
Published: January 2023

Abstract
There is evidence that lung surfactant protein A (SP-A) plays an important role in modulating inflammation during lung infection. However, it has been reported that SP-A either stimulates or inhibits the inflammatory activity of IFN-γ on alveolar macrophages (aMϕ). The aim of this study was to determine the effect of human SP-A on alveolar macrophages stimulated with IFN-γ in the presence or absence of LPS. To accomplish this, purified rat aMϕ were cultured in the presence or absence of IFN-γ (10 ng/ml), LPS (1 ng/ml), SP-A (5, 12.5, 25 μg/mL), and combinations thereof. We measured iNOS synthesis, TNF-α secretion, as well as STAT-1, ERK, and Akt phosphorylation by rat aMϕ. We found that SP-A inhibited STAT1 phosphorylation activated by IFN-γ. In addition, SP-A diminished LPS-induced ERK and Akt phosphorylation. Finally, SP-A inhibited [LPS+IFN-γ]-induced TNF-α and iNOS production. Therefore, the inhibitory effect of SP-A on [IFN-γ+LPS]-elicited macrophage activation is due to SP-A attenuation of both inflamatory agents. To determine the mechanism by which SP-A abrogates IFN-γ effects, we studied the potential interaction between SP-A and IFN-γ. SP-A specifically bound to IFN-γ, with Kd = 28, 2 ± 8 nM. These data support the biological function of SP-A in host defense, revealing a role of this alveolar protein in limiting classical activation of aMϕ elicited by IFN-γ + LPS.
The cytolytic effects of lamprey variable lymphocyte receptors (172.7)
Authors: Li Qingwei , Wu Fenfang , Chen Liyong , Qiao Xu 
Published: January 2023

Abstract
Lamprey uses variable lymphocyte receptors (VLR), a leucine-rich-repeat (LRR)-based receptors, for antigen recognition instead of the immunoglobulin (Ig)-based receptors used in vertebrates. We report herein the cytolytic effects of antigen stimulated sera in Japanese lamprey (Lampetra japonica) for bacteria and tumor cells. We demonstrated that the antigen-specific VLRB antibodies mediates cytotoxicity, and the humoral immunity based cell lysis involved deposition of VLRB on the surface of target cells with formation of pore-like structures that disrupt cell wall integrity. Our finding provides evidence of role of VLRB in lamprey humoral immunity, and offers new insight into the evolution of adaptive immunity.
Identification of matrix metalloproteinases involved in the activation induced CD16 down-modulation by primary NK cells (172.9)
Authors: Peruzzi Giovanna , Femnou Laurette , Borrego Francisco , Krzewski Konrad , Coligan John 
Published: January 2023

Abstract
CD16 (FcgammaRIIIa), the low affinity receptor for IgG is a potent activating receptor expressed by the majority of human natural killer (NK) cells that functions to mediate antibody-dependent cell-mediated cytotoxicity (ADCC). Since the bound IgG can be exchanged, the target cell recognition through CD16 gives NK cells flexibility in receptor specificity that can be manipulated for therapeutic purposes. ADCC dysfunction has been linked to cancer progression, poor prognosis and chronic infections; thus, understanding how CD16 expression is regulated by NK cells has clinical relevance. It is well established that upon activation NK cells enter into a refractory period in which CD16 expression is dramatically down-modulated, mainly due to the action of matrix metalloproteinases (MMPs). The aim of this project is to identify the MMP(s) responsible for CD16 cell surface down-modulation on activated NK cells and to determine if this down-modulation can be inhibited. Our data indicate that CD16 is down-modulated upon cell activation in primary NK cells, the released CD16 can be detected in the supernatant of the activated cells and a membrane-type MMP is involved in the process of CD16 shedding.