bluuebunny/crossref_metadata_2025_split huggingface dataset:
Au nanorod-induced NLRP3 inflammasome activation is mediated by ER stress
Authors: Vandebriel Rob , Remy Sylvie , Vermeulen Jolanda , Hurkmans Evelien , Bastus Neus , Pelaz Beatriz , Puntes Victor , Parak Wolfgang , Pennings Jeroen , Nelissen Inge 
Published: January 2023

Abstract
The widespread and increasing use of engineered nanomaterials (ENM) increases the risk of human exposure, generating concern that ENM may provoke adverse health effects. In this respect, their physicochemical characteristics are critical. The immune system may respond to specific ENM properties by inflammatory reactions. Inflammasome activation has drawn significant attention since inflammasomes, especially NLRP3 respond to a wide range of stimuli including nanoparticles, and their activation is associated with various inflammatory diseases, including lung fibrosis, obesity and type-2 diabetes. Endoplasmic reticulum (ER) stress has been reported as one of the mechanisms underlying NLRP3 inflammasome activation.
In this study, PEGylated Au ENM of ≈60 nm, having different shapes (stars, spheres and rods) were extensively characterized, and tested for possible LPS contamination. PMA-activated THP-1 cells were exposed to these ENM, and cell viability and IL-1β production were measured to assess NLRP3 activation. In addition, the exposed cells were subjected to gene expression analysis using microarray analysis to investigate related signalling pathway regulation.
PEGylated Au nanorods (NR), but not nanostars or nanospheres, showed NLRP3 inflammasome activation. Cells deficient in the NLRP3 scaffold or ASC adaptor did not show this effect. Only NR-exposed cells showed down-regulation of ER-associated cholesterol metabolism.
This finding may suggest that ER stress mediates NLRP3 inflammasome activation by Au NR.
Supported by the EU funded project FutureNanoNeeds (Grant agreement N° 604602).
Coronary artery bypass grafting surgery differentially modulates the leucocyte gene expression profile
Authors: Perros Alexis J , Chong Fenny , Engkilde-Pedersen Sanne , Esguerra-Lallen Arlanna , Rooks Kelly , Faddy Helen M , Hewlett Elise , Naidoo Rishendran , Tung John-Paul , Fraser John F , Tesar Peter , Ziegenfuss Marc , Smith Susan , O’Brien Donalee , Flower Robert L , Dean Melinda M 
Published: January 2023

Abstract
Coronary artery bypass grafting (CABG) surgery triggers a systemic inflammatory response activating leucocyte subsets and cytokine secretion. Changes to the patient immune profile post-surgery may contribute to adverse outcomes such as infection. Investigating patient immune modulation at the molecular level may improve our understanding of the underlying mechanisms associated with adverse outcomes post-surgery. This study assessed changes to the leucocyte gene expression profile of CABG patients (n=50) at 5 time-points (admission, intra-operative, ICU, day 3, day 5). RNA was isolated from freshly collected whole blood for cDNA synthesis, pre-amplification and RT-PCR of 48 genes using the TaqMan Gene Expression Array Cards (Applied Biosystems). Gene expression at each time-point was compared to admission (repeated-measures one-way ANOVA with Dunnett’s post-test; P&lt;0.05). Antigen presentation capacity was decreased throughout the post-operative period, evidenced by reduced expression of key regulator genes TAP1, TAP2, HLA-DRA and CD40. CABG surgery increased gene expression of cytokines and chemokines including IL-12A, IL-6 and TNF before decreasing throughout the post-operative period. CABG also modulated the expression of signalling molecules including JAK1, RELA and STAT3, however expression returned towards baseline levels post-surgery. This study demonstrated CABG significantly impaired the patient immune response and key immune pathways at the molecular level. Understanding how CABG alters the patient immune profile assists in elucidating underlying mechanisms of adverse outcomes.
Leukotriene B4 receptors have roles in the development of endotoxic shock
Authors: Park Donghwan , Kwak DongWook , Kim Jae-Hong 
Published: January 2023

Abstract
Sepsis is the most common disease in patients treated in the intensive care units. Endotoxic shock, the most critical form of sepsis, is caused by gram-negative bacterial infection. However, the detailed mechanism of endotoxic shock remains unclear. In the present study, we observed that the productions of leukotriene B4 and 12(S)-hydroxyeicosatetraenoic acid, inflammatory lipid mediators acting on LTB4 receptors BLT1/2, were highly up-regulated in peritoneal lavage fluid and serum of LPS-induced endotoxic shock mouse model. Furthermore, we found that BLT1/2-dependent signaling pathways mediate the expression of IL-17, IL-6, and IL-1β, key cytokines for the development of endotoxic shock, via NF-κB activation in the LPS-induced mouse model. We also found that the inhibition of BLT1/2 significantly attenuates inflammation and tissue damages induced by endotoxic shock, and enhances the survival rate of this inflammatory complication. These results suggest that leukotriene B4 receptors play a critical mediatory role in the development of endotoxic shock. Our findings would contribute to the discovery of therapeutic targets for endotoxic shock.
Single Receptor reciprocity as message encrypted in CD40-ligand
Authors: Saha Bhaskar , Ghosh Soumyakanti , Sarode Aditya 
Published: January 2023

Abstract
Interaction between CD40-Ligand (CD40L) and CD40 results in cellular signaling that regulates immune responses against pathogens, autoantigens, tumors and transplantation antigens. The 115–155 amino acids stretch is responsible for CD40L functions and mutations therein results in XIgM syndrome. We hypothesize that each of these amino acids of CD40L encodes specific message. These messages are decoded by CD40 signaling and are expressed as a specific profile of functions. Each single substitution in the XIgM-related amino acids in the 115–155 41-mer peptides in CD40L selectively altered CD40 signaling and effector functions- cytokine productions, HMGCoA reductase, ceramide synthase, inducible nitric oxide synthase and arginase expression, and control of Leishmania infection. There were sets of peptides that triggered reciprocal functions from the same receptor CD40. These results suggest residue-specific encryption of a distinct set of messages. These messages collectively frame CD40L pleiotropy and offer a result-driven ligand manipulation strategy for generating antagonists or superagonists as immunotherapeutics.
Suppression of Inflammasome Activation by IRF8 and IRF4 in cDCs is Critical for T cell Priming
Authors: McDaniel Margaret , Pasare Chandrashekhar 
Published: January 2023

Abstract
Activation of inflammasome leads to pyroptotic cell death thereby eliminating the replicative niche of virulent pathogens, a process integral to innate immunity. While inflammasome-associated cytokines such as IL-1β and IL-18 have an established role in T cell function, whether inflammasome activation in dendritic cells (DCs) is critical for T cell priming is not clear. Here, we discover that inflammasome activation in conventional DCs (cDCs) is detrimental to the induction of adaptive immunity. We found that lymphoid organ resident cDCs actively suppress inflammasome activation to avoid pyroptotic cell death. This protection from inflammasome-induced cell death is critical for both CD4 and CD8 T cell priming. Transcription factors IRF8 and IRF4, in cDC1s and cDC2s respectively, mediate this suppression of inflammasome activation by limiting the expression of inflammasome-associated genes. We show that reduced expression of IRF8 leads to aberrant inflammasome activation in cDC1s which hampers subsequent CD8 T cell priming. Conversely, overexpression of either of IRF4 or IRF8 is sufficient to inhibit inflammasome activation in macrophages. These results uncover the molecular mechanism of inflammasome suppression in cDCs, and ascribe a novel post-developmental role for IRF4 and IRF8 in cDC function.
A high throughput screen to identify small molecule activators of IRF3-mediated antiviral apoptotic pathway
Authors: Chattopadhyay Saurabh , Glanz Anna , Chawla Karan , Rahman Tia , Walters Dean , Varghese Merina , Steimle Grace , Taylor Travis 
Published: January 2023

Abstract
The transcription factor interferon (IFN) regulatory factor 3 (IRF3) provides cellular antiviral response by expressing IFN and antiviral genes. In addition to the transcriptional activation, IRF3 triggers a direct pro-apoptotic pathway, RIPA, in virus-infected cells. The pathway of IRF3 activation in RIPA is independent of and distinct from the transcriptional activation of IRF3 (Chattopadhyay et al. Immunity, 2016, J Virol, 2013, 2011, EMBO J, 2010). Using knock-in mice expressing transcriptionally-inactive, but RIPA-competent, IRF3 mutant, we demonstrated that RIPA contributes to the antiviral response of the host. Because RIPA is a cellular antiviral pathway, we hypothesized that RIPA-promoting small molecules would act as antiviral agents. To test this, we conducted a high throughput screen of a library of 1,200 FDA-approved compounds to identify RIPA activators. Our screen isolated twenty-four primary candidates with diverse therapeutic activities, e.g. anti-cancer, anti-inflammatory, anti-bacterial, etc. We screened these primary candidates for their antiviral activities against RNA (vesicular stomatitis virus) and DNA (herpes simplex virus-1) viruses. The antiviral screen revealed a small subset of antiviral compounds, which specifically promote RIPA but not the transcriptional pathway of IRF3. We further validated their antiviral activities against additional viruses, e.g. respiratory syncytial virus and vector-borne flaviviruses. Therefore, we report a high throughput screen, which identified novel antiviral compounds that are specific activators of RIPA branch of IRF3. Currently, we are investigating the mechanisms of these RIPA-promoting antiviral compounds.
B cell subsets in pericardial adipose tissues and their role in cardiovascular health
Authors: Wu Lan , Van Kaer Luc 
Published: January 2023

Abstract
We have recently reported that murine pericardial adipose tissues house a large number of lymphoid clusters that have been referred to as fat-associated lymphoid clusters. We have further shown that these tertiary lymphoid tissues are enriched with B cells, in particular B-1a cells. These cells continuously produce a low level of IL-10 under unchallenged conditions, and further enhance the production of this cytokine upon stimulation. Following acute myocardial infarction (MI), these cells significantly expand in pericardial adipose tissues, and they accumulate in the infarcted heart during the resolution phase of MI-induced inflammation where they play a protective role by facilitating the termination of MI-induced inflammation. In our efforts to target B cells for the maintenance of cardiac health, we have now performed a comprehensive characterization of B cell subsets in murine pericardial adipose tissues focusing on cytokines. Using cytokine profiling, RNA sequencing and single-cell RNA sequencing analyses, we have found that subsets of B cells in pericardial adipose tissues are fundamentally biased. Whereas B-2 cells are equipped to produce more pro-inflammatory cytokines, B-1a cells are biased towards producing anti-inflammatory cytokines. These results have paved our way in designing effective therapeutic strategy to target subsets of B cells for the treatment of cardiovascular diseases.
Induction of T cell-independent hypermutated and protective IgG and IgA antibody responses by engagement of TLR4 or TLR5 and BCR
Authors: Rivera Carlos Eduardo , Chupp Daniel P , Yan Hui , Im John , Fernandez Maria , Zan Hong , Xu Zhenming , Casali Paolo 
Published: January 2023

Abstract
Somatic hypermutation (SHM) and class-switch DNA recombination (CSR) together with plasma cell and memory B cell differentiation are central to the maturation of the antibody response. Prompted by our finding that CSR and plasma cell differentiation can be induced in vitro by a TLR ligand together with BCR crosslinking, we hypothesized that TLR and BCR co-engagement can induce mature T-independent antibody responses in vivo. To test this hypothesis, we injected Tcrβ−/−Tcrδ−/− mice, which are devoid of T cells, with NP-LPS (co-engaging NP-specific BCR and B-cell TLR4) or Salmonella flagellin (co-engaging flagellin-specific BCR and B-cell TLR5). These mice readily generated class-switched B cells, plasma cells and NP- or flagellin-specific IgG antibodies. The response to NP-LPS, which was also elicited in NSG mice (as defective in most innate immune elements in addition to the absence of T and B cells) grafted with purified B cells, evoked frequent VH region mutations, including the Trp33Leu mutation that would underpin the production of high-affinity anti-NP antibodies even in the absence of sustained germinal center formation, as well as the generation of long-lived memory B cells. These, together with the strong in vivo bactericidal activity of Salmonella flagellin-specific IgG and IgA elicited in Tcrβ−/−Tcrδ−/− mice, demonstrated that TLR/BCR co-engagement can induce mature, anamnestic and protective antibody responses, thereby providing the basis for new TLR-based B cell-targeted vaccine strategies to overcome T cell deficiencies.
IL-27-producing B cells are key regulators of anti-viral immunity and antibody responses
Authors: Pratumchai Isaraphorn , Huang Zhe , Zak Jaroslav , Teijaro John R 
Published: January 2023

Abstract
Emerging evidence indicates that B lymphocytes regulate immunity by producing antibodies, presenting antigens and secreting cytokines that provide signals to other cells to modulate both humoral and cellular immunity. Here, we show that B cells produce IL-27 upon activation by TLR4 and CD40 in the presence of IL-21 in vitro. Using Lymphocytic choriomeningitis virus (LCMV) Clone 13 as a model of a persistent viral infection, we identify plasma B cells as major source of IL-27. Further, we show that IL-27-producing B cells are key players in the regulation of immunity. Mice with conditional B cell–specific IL-27p28 knockout were unable to control persistent LCMV infection and failed to respond to anti-IFNAR1 immunotherapy. The impaired immunity found in these mice was associated with reduced virus-specific IgG2a/2c. In addition, these mice displayed reduced virus-specific CD4+ T cells and T follicular helper (Tfh) cells, suggesting that B-cell-derived cytokines regulate immunity by providing signals to T cells. The effects of Il27ra deletion from T cells mirrors the phenotypes observed in mice lacking B-cell-derived IL-27. In addition, IL-27ra deficient (KO) Tfh cells lost their ability to produce IL-21, resulting in aberrant production of virus-specific antibodies to LCMV clone 13 in IL-27ra KO mice. Finally, RNA-sequencing of virus-specific CD4+ T cells identified IL-27R-dependent genes during persistent LCMV infection. Collectively, our data reveal a central role of plasma cell-derived IL-27 in the regulation of T cell functions. Importantly, our study describes cellular interactions between T and B cells and highlights the importance of virus-specific IgG2a/2c during persistent LCMV infection.
B cell-mediated activation and proliferation of NK cells : crossroads of adaptive and innate immunity
Authors: Im Kyungtaek , Kim Kwanghee , Kim Ji-young , Lee Kyung-mi 
Published: January 2023

Abstract
Belonging to innate immunity, natural killer (NK) cells constitute of circulating lymphocytes which provide a body’s first line of defense against infection and cancer. In the spleen,, NK cells are likely to interact with B cells, but the functional consequence of this interaction remains uncertain. To address this question, we co-cultured primary NK cells with freshly isolated B cells from the spleen and investigated the influence of B cells on NK cells. Here we show that co-presence of B cells in cultures facilitated proliferation of NK cells, as measured CFSE dilution assays. CFSE results showed that proliferation of NK cells by B cells need direct and in direct stimulation. This correlated with microarray data showing that expression of genes involved in the regulation of cell proliferation was significantly increased in NK cells in NK-B co-cultures. NK cells cultured with B cells exhibited higher expression of CD69, B220, CD25 activation markers, suggesting that B cells drastically facilitated NK cell activation. Lack of B cells in mice weakened anti-tumor effect as well as anti-pathogen response, suggesting that NK cells exhibited higher anti-tumor activity in the presence of B cells. The synergistic effect of B cells on NK cell functions also occurred in humans. Given the fact that NK cells can exert a regulatory role in cancer or infection, co-presence of B cells can potentiate the role of NK cells by promoting their proliferation and cytotoxicity.
Characterizing region-specific lymphocyte migration within the post-stroke brain
Authors: Torres Vanessa O. , Poinsatte Katie , Ortega Sterling B , Kong Xiangmei , Plautz Erik J , Ramirez Denise M.O. , Ajay Apoorva , Meeks Julian P , Goldberg Mark P , Stowe Ann M 
Published: January 2023

Abstract

Background
Studies in our lab show that while B cell-depleted mice exhibit motor deficits, impaired neurogenesis, increased anxiety, and spatial memory deficits after stroke, CD8 T cell depletion reduces post-stroke motor deficits. Therefore, we hypothesized that B cells migrate into brain regions outside the infarct to promote post-stroke motor and cognitive recovery, unlike pro-inflammatory CD8 T cells that migrate to the area of injury.

Methods
Naïve donor B or CD8 T cells were labeled with e450 dye and injected i.v. into recipient mice at 7, 24, 48 and 72h after receiving a 60-minute transient middle cerebral artery occlusion (tMCAo). Peripheral and brain lymphocyte migration was assessed using flow cytometry and serial two-photon tomography (STPT) 96h after tMCAo.

Results
e450+ lymphocytes were detected in the periphery 96h after stroke. STPT co-registered with the Common Coordinate Framework (Allen Institute) created a 3D brain reconstruction that identified lymphocyte diapedesis. B cells were found bilaterally in areas outside the ischemic penumbra, such as the olfactory areas (p&lt;0.05) and dentate gyrus (p&lt;0.05), whereas CD8 T cells migrated into ipsilesional areas including the somatosensory cortex (p&lt;0.01) and brainstem (p&lt;0.01).

Conclusions
B cell diapedesis differs distinctly from that of CD8 T cells throughout the ischemic brain. While B cells migrate bilaterally into brain regions mediating cognitive deficits and neurogenesis, CD8 T cells exhibit greater unilateral migration into the injured hemisphere, including motor and sensory-related areas. Future directions will determine if the spatial location of CD8 T cells or B cells mediates post-stroke pathology or supports functional recovery, respectively.
A generalized pathway of immunocompromise following central nervous system insult: the release of large immunosuppressive molecules and thymic involution
Authors: Ayasoufi Katayoun , Pfaller Christian K , Khadka Roman , Jin Fang , Zheng Jiaying , Schuelke Matthew R , Evgin Laura , Hansen Michael , Himes Benjamin , Fain Cori , Tritz Zachariah Peter , Goddery Emma , Yokanovich Lila T , Pease Larry R , Vile Richard G. , Johnson Aaron J 
Published: January 2023

Abstract
Immunosuppression following damage to the CNS is a common, yet poorly understood, feature of neurological diseases as diverse as stroke, traumatic brain injury, and glioblastoma. This immunosuppression is a barrier to successful patient outcomes. We sought to define the effect of various brain insults on the thymus and T-cell responses. We tested thymic function following various neurological insults, including viral infection, brain tumor, sterile inflammation, physical injury, and seizures. All brain insults resulted in significant thymic involution that was reversible if the insult was cleared. Thymic involution did not occur following similar peripheral insults. Using parabiosis, we demonstrated that thymic involution was transferable via circulatory routes from glioma-bearing to non-tumor-bearing parabionts. Similarly, serum obtained from mice with ongoing neurological insults potently inhibited T-cell proliferation in vitro. We next fractionated the serum based on molecular weight and tested the resulting fractions’ immunosuppressive potential. Interestingly, we found that serum fractions with large molecular weights of greater than 100 kiloDaltons were responsible for the immunosuppressive properties of serum obtained from glioma-bearing mice. In short, CNS-specific insults, regardless of nature, induce immunosuppression by prompting thymic involution and systemic immunosuppression mediated through circulating factors with large molecular weight. These studies provide evidence of the mechanisms leading to immune deficiencies observed in patients following neurological injuries.
YAP is a novel regulator of CD4+ and CD8+ T cells during activation, differentiation, and anti-tumor immunity
Authors: Szeto Gregory Lee , Stampouloglou Elena , Cheng Nan , Federico Anthony , Slaby Emily , Linton Jonathan , Livingston Natalie , Schneck Jonathan P , Monti Stefano , Varelas Xaralabos 
Published: January 2023

Abstract
Advanced understanding of T cell regulation has fueled cancer immunotherapy, but durable responses remain confined to a minority of patients. Poor responses can be linked to either suppressed T cell function in tumors or “cold” tumors that exclude immune cells. Identifying novel T cell regulators involved in these processes is a high priority. Our studies identified the protein YAP as a novel regulator of T cells. YAP mRNA and protein were rapidly expressed after T cell activation in mouse CD4+ and CD8+ T cells. T cell-specific Yap knockout (YapKO) generated CD4+ and CD8+ T cells that express elevated levels of activation markers (CD25, CD44, CD69) compared to WT cells. YapKO increased the sensitivity of T cells to anti-CD3 dose, and increased CD4+ T cell differentiation efficiency under Th1, Th2, Th17, and Treg skewing conditions. YapKO CD8+ T cells expanded &gt;20-fold more than WT when cultured in engineered hydrogel matrices optimized for T cell expansions and adoptive transfer. Syngeneic tumors grown in T cell YapKO mice had impaired growth and increased immune infiltration compared to tumors in WT hosts. Co-adoptive transfer of YapKO and WT CD8+ T cells showed only YapKO cells infiltrated B16F10 tumors. RNAseq of CD4+ and CD8+ T cells from tumors and draining lymph nodes showed gene expression changes including upregulation of T cell receptor and cytokine signaling pathways in YapKO hosts. T cells from tumor-draining lymph nodes were not significantly different between YapKO and WT. YapKO gene signatures correlated with immune infiltration and survival in multiple human cancers in TCGA. Our data demonstrated YAP is a novel regulator of diverse T cell functions and may be a useful target for enhancing responses to cancer immunotherapy.