Correction of age-associated defects in dendritic cells enables CD4+ T cells to eradicate tumors.

Defective host defenses later in life are associated with changes in immune cell activities, suggesting that age-specific considerations are needed in immunotherapy approaches. In this study, we found that PD-1 and CTLA4-based cancer immunotherapies are unable to eradicate tumors in elderly mice. This defect in anti-tumor activity correlated with two known age-associated immune defects: diminished abundance of systemic naive CD8+ T cells and weak migratory activities of dendritic cells (DCs). We identified a vaccine adjuvant, referred to as a DC hyperactivator, which corrects DC migratory defects in the elderly. Vaccines containing tumor antigens and DC hyperactivators induced T helper type 1 (TH1) CD4+ T cells with cytolytic activity that drive anti-tumor immunity in elderly mice. When administered early in life, DC hyperactivators were the only adjuvant identified that elicited anti-tumor CD4+ T cells that persisted into old age. These results raise the possibility of correcting age-associated immune defects through DC manipulation.

Phosphoinositide Interactions Position cGAS at the Plasma Membrane to Ensure Efficient Distinction between Self- and Viral DNA.

The presence of DNA in the cytosol of mammalian cells is an unusual event that is often associated with genotoxic stress or viral infection. The enzyme cGAS is a sensor of cytosolic DNA that induces interferon and inflammatory responses that can be protective or pathologic, depending on the context. Along with other cytosolic innate immune receptors, cGAS is thought to diffuse throughout the cytosol in search of its DNA ligand. Herein, we report that cGAS is not a cytosolic protein but rather localizes to the plasma membrane via the actions of an N-terminal phosphoinositide-binding domain. This domain interacts selectively with PI(4,5)P2, and cGAS mutants defective for lipid binding are mislocalized to the cytosolic and nuclear compartments. Mislocalized cGAS induces potent interferon responses to genotoxic stress, but weaker responses to viral infection. These data establish the subcellular positioning of a cytosolic innate immune receptor as a mechanism that governs self-nonself discrimination.

A critical review on the synthesis of NH2-MIL-53(Al) based materials for detection and removal of hazardous pollutants.

Nowadays, emerging hazardous pollutants have caused many harmful effects on the environment and human health, calling for the state of the art methods for detection, qualification, and treatment. Metal-organic frameworks are porous, flexible, and versatile materials with unique structural properties, which can solve such problems. In this work, we reviewed the synthesis, activation, and characterization, and potential applications of NH2-MIL-53(Al). This material exhibited intriguing breathing effects, and obtained very high surface areas (182.3-1934 m2/g) with diverse morphologies. More importantly, NH2-MIL-53(Al) based materials could be used for the detection and removal of various toxic pollutants such as organic dyes, pharmaceuticals, herbicides, insecticides, phenols, heavy metals, and fluorides. We shed light on plausible adsorption mechanisms such as hydrogen bonds, π-π stacking interactions, and electrostatic interactions onto NH2-MIL-53(Al) adsorbents. Interestingly, NH2-MIL-53(Al) based adsorbents could be recycled for many cycles with high stability. This review also recommended that NH2-MIL-53(Al) based materials can be a good platform for the environmental remediation fields.

Roles of ß-Indole Acetic Acid (IAA) Producing Endophytic Bacteria on the Recovery of Plant Growth and Survival Ability of Sugarcane Infected White Leaf Disease (SWLD).

ß-Indole acetic acid is produced in the rhizosphere by endophytic bacteria and promotes plant growth. Effects of bacterial IAA producers (BIPs) on plant growth and recovery of sugarcane seedlings infected with phytoplasma causing white leaf disease (SWLD) were examined. Fifty-five endophytic bacteria isolated from rice roots were collected from the Mekong River Delta, Vietnam. Seven isolates showed ß-Indole acetic acid production in culture medium supplemented with tryptophan. Interestingly, two of them (BC17 and BTII2) produced the highest ß-Indole acetic acid after 4 days of culture. Based on 16S rRNA sequences and phylogenetic analysis, the BC17 and BTII2 isolates were identified as Delftia lacustris and Rahnella aquatilis, respectively. Plant growth induced by the BC17 and BTII2 isolates showed statistically significant differences in height, root length and fresh weight of rice seedlings compared with non-treatment as the control. Treatment of two bacterial isolates in SWLD infected sugarcane plants also showed differences in height of sugarcane seedlings, while gradual symptoms of exposure decreased plant mortality compared to non-treatment as the control. BIPs were shown to be efficient biofertilizer inoculants that promoted plant growth and also ameliorated damage caused by phytoplasma-associated diseases at the sugarcane seedling stage.

Alarmin-activated B cells accelerate murine atherosclerosis after myocardial infarction via plasma cell-immunoglobulin-dependent mechanisms.

AIMS: Myocardial infarction (MI) accelerates atherosclerosis and greatly increases the risk of recurrent cardiovascular events for many years, in particular, strokes and MIs. Because B cell-derived autoantibodies produced in response to MI also persist for years, we investigated the role of B cells in adaptive immune responses to MI. METHODS AND RESULTS: We used an apolipoprotein-E-deficient (ApoE-/-) mouse model of MI-accelerated atherosclerosis to assess the importance of B cells. One week after inducing MI in atherosclerotic mice, we depleted B cells using an anti-CD20 antibody. This treatment prevented subsequent immunoglobulin G accumulation in plaques and MI-induced accelerated atherosclerosis. In gain of function experiments, we purified spleen B cells from mice 1 week after inducing MI and transferred these cells into atherosclerotic ApoE-/- mice, which greatly increased immunoglobulin G (IgG) accumulation in plaque and accelerated atherosclerosis. These B cells expressed many cytokines that promote humoural immunity and in addition, they formed germinal centres within the spleen where they differentiated into antibody-producing plasma cells. Specifically deleting Blimp-1 in B cells, the transcriptional regulator that drives their terminal differentiation into antibody-producing plasma cells prevented MI-accelerated atherosclerosis. Alarmins released from infarcted hearts were responsible for activating B cells via toll-like receptors and deleting MyD88, the canonical adaptor protein for inflammatory signalling downstream of toll-like receptors, prevented B-cell activation and MI-accelerated atherosclerosis. CONCLUSION: Our data implicate early B-cell activation and autoantibodies as a central cause for accelerated atherosclerosis post-MI and identifies novel therapeutic strategies towards preventing recurrent cardiovascular events such as MI and stroke.

Modular Single-Stage Three-Phase Flyback Differential Inverter for Medium/High-Power Grid Integrated Applications.

This paper proposes a single-stage three-phase modular flyback differential inverter (MFBDI) for medium/high power solar PV grid-integrated applications. The proposed inverter structure consists of parallel modules of flyback DC-DC converters based on the required power level. The MFBDI offers many features for renewable energy applications, such as reduced components, single-stage power processing, high-power density, voltage-boosting property, improved footprint, flexibility with modular extension capability, and galvanic isolation. The proposed inverter has been modelled, designed, and scaled up to the required application rating. A new mathematical model of the proposed MFBDI is presented and analyzed with a time-varying duty-cycle, wide-range of frequency variation, and power balancing in order to display its grid current harmonic orders for grid-tied applications. In addition, an LPF-based harmonic compensation strategy is used for second-order harmonic component (SOHC) compensation. With the help of the compensation technique, the grid current THD is reduced from 36% to 4.6% by diminishing the SOHC from 51% to 0.8%. Moreover, the SOHC compensation technique eliminates third-order harmonic components from the DC input current. In addition, a 15% parameters mismatch has been applied between the flyback parallel modules to confirm the modular operation of the proposed MFBDI under modules divergence. In addition, SiC MOSFETs are used for inverter switches implementation, which decrease the inverter switching losses at high-switching frequency. The proposed MFBDI is verified by using three flyback parallel modules/phase using PSIM/Simulink software, with a rating of 5 kW, 200 V, and 50 kHz switching frequency, as well as experimental environments.

Research and Development Prospects for Sugarcane Industry in Vietnam.

Sugarcane is one of the most important industrial crops in Vietnam and covers a total of 127,000 hectares of plantation area. In the season 2020-2021, Vietnam has produced 0.763 million tons of sugar (accounting for 0.34% total world sugar production). A current sugarcane production of 7.498 million tons is being used mainly for sugar production for direct consumption, ethanol production, bio-electricity and fertilization. To ensure crop sustainability, various policies and plans have been implemented. Crop breeding and zoning improvement programme significantly influence sugarcane production and sugar yield. Over 25 years since the programme "one million ton of sugar" was promoted, Vietnam currently possesses 25 sugar mills with a total capacity of 110,000 tons of sugarcane per day. Major problems of sugarcane industry as well as research and development have been discussed in this review. Recent research and development work focused on the added values of co-products to ensure sustainability of the sugarcane industry. Molasses will be used for ethanol production, and bagasse is used as the biomass for the alternative energy. Sugarcane and sugar would be the main feedstocks for those bio-economy growths in Vietnam. To keep the sustainable development of the sugar industry, and to meet the demand of the food and non-food requirements, it is necessary to upgrade the sugar value chain through the adoption and the development of co-products of the sugar industry.

Liraglutide pharmacotherapy reduces body weight and improves glycaemic control in juvenile obese/hyperglycaemic male and female rats.

AIMS: To examine whether the glucagon-like peptide-1 receptor agonist liraglutide could be used in juvenile male and female rats as an anti-obesity/diabetic pharmaceutical to prevent not only adolescent obesity/hyperglycaemia, but also early-adult onset obesity. MATERIAL AND METHODS: Pregnant dams were fed either standard chow or a high-fat, high-sucrose diet (HFSD) from gestational day 2, throughout pregnancy and lactation. Offspring were weaned onto the respective maternal diet. Juveniles received daily subcutaneous injection of liraglutide (50 µg/kg, from postnatal day [PND]30 to PND40 and 200 µg/kg from PND40 to PND60) or vehicle. Food intake, body weight and glycaemic levels were evaluated across the experimental period. RESULTS: Chronic liraglutide administration in juveniles prevented body weight gain in males and retained a normoglycaemic profile in both male and female rats. CONCLUSION: These preclinical data suggest that maternal and early-life consumption of an HFSD increases caloric intake, body weight gain and hyperglycaemia, a collective set of unwanted metabolic effects that appear to be treatable in juveniles with liraglutide pharmacotherapy intervention.

Follicular B Cells Promote Atherosclerosis via T Cell-Mediated Differentiation Into Plasma Cells and Secreting Pathogenic Immunoglobulin G.

OBJECTIVE: B cells promote or protect development of atherosclerosis. In this study, we examined the role of MHCII (major histocompatibility II), CD40 (cluster of differentiation 40), and Blimp-1 (B-lymphocyte-induced maturation protein) expression by follicular B (FO B) cells in development of atherosclerosis together with the effects of IgG purified from atherosclerotic mice. APPROACH AND RESULTS: Using mixed chimeric Ldlr-/- mice whose B cells are deficient in MHCII or CD40, we demonstrate that these molecules are critical for the proatherogenic actions of FO B cells. During development of atherosclerosis, these deficiencies affected T-B cell interactions, germinal center B cells, plasma cells, and IgG. As FO B cells differentiating into plasma cells require Blimp-1, we also assessed its role in the development of atherosclerosis. Blimp-1-deficient B cells greatly attenuated atherosclerosis and immunoglobulin-including IgG production, preventing IgG accumulation in atherosclerotic lesions; Blimp-1 deletion also attenuated lesion proinflammatory cytokines, apoptotic cell numbers, and necrotic core. To determine the importance of IgG for atherosclerosis, we purified IgG from atherosclerotic mice. Their transfer but not IgG from nonatherosclerotic mice into Ldlr-/- mice whose B cells are Blimp-1-deficient increased atherosclerosis; transfer was associated with IgG accumulating in atherosclerotic lesions, increased lesion inflammatory cytokines, apoptotic cell numbers, and necrotic core size. CONCLUSIONS: The mechanism by which FO B cells promote atherosclerosis is highly dependent on their expression of MHCII, CD40, and Blimp-1. FO B cell differentiation into IgG-producing plasma cells also is critical for their proatherogenic actions. Targeting B-T cell interactions and pathogenic IgG may provide novel therapeutic strategies to prevent atherosclerosis and its adverse cardiovascular complications.

Cytotoxic and proinflammatory CD8+ T lymphocytes promote development of vulnerable atherosclerotic plaques in apoE-deficient mice.

BACKGROUND: Heart attacks and strokes, leading causes of deaths globally, arise from thrombotic occlusion of ruptured vulnerable atherosclerotic plaques characterized by abundant apoptosis, large necrotic cores derived from inefficient apoptotic cell clearance, thin fibrous caps, and focal inflammation. The genesis of apoptosis and necrotic cores in these vulnerable atherosclerotic plaques remains unknown. Cytotoxic CD8(+) T lymphocytes represent up to 50% of leukocytes in advanced human plaques and dominate early immune responses in mouse lesions, yet their role in atherosclerosis also remains unresolved. METHODS AND RESULTS: CD8(+) T-lymphocyte depletion by CD8α or CD8ß monoclonal antibody in apolipoprotein E-deficient mice fed a high-fat diet ameliorated atherosclerosis by reducing lipid and macrophage accumulation, apoptosis, necrotic cores, and monocyte chemoattractant protein 1, interleukin 1ß, interferon γ, and vascular cell adhesion molecule 1. Transfer of CD8(+) T cells into lymphocyte-deficient, apolipoprotein E-deficient mice partially reconstituted CD8(+) T cells in lymphoid compartments and was associated with CD8(+) T-cell infiltration in lesions, increased lipid and macrophage accumulation, apoptotic cells, necrotic cores, and interleukin 1ß in atherosclerotic lesions. Transfer of CD8(+) T cells deficient in perforin, granzyme B, or tumor necrosis factor α but not interferon γ failed to increase atherosclerotic lesions despite partial reconstitution in the lymphoid system and the presence in atherosclerotic lesions. Macrophages, smooth muscle cells, and endothelial cells were identified as apoptotic targets. CONCLUSIONS: We conclude that CD8(+) T lymphocytes promote the development of vulnerable atherosclerotic plaques by perforin- and granzyme B-mediated apoptosis of macrophages, smooth muscle cells, and endothelial cells that, in turn, leads to necrotic core formation and further augments inflammation by tumor necrosis factor α secretion.

Conventional B2 B cell depletion ameliorates whereas its adoptive transfer aggravates atherosclerosis.

Atherosclerosis is a chronic inflammatory arterial disease characterized by focal accumulation of lipid and inflammatory cells. It is the number one cause of deaths in the Western world because of its complications of heart attacks and strokes. Statins are effective in only approximately one third of patients, underscoring the urgent need for additional therapies. B cells that accumulate in atherosclerotic lesions and the aortic adventitia of humans and mice are considered to protect against atherosclerosis development. Unexpectedly, we found that selective B cell depletion in apolipoprotein E-deficient (ApoE(-/-)) mice using a well-characterized mAb to mouse CD20 reduced atherosclerosis development and progression without affecting the hyperlipidemia imposed by a high-fat diet. Adoptive transfer of 5 × 10(6) or 5 × 10(7) conventional B2 B cells but not 5 × 10(6) B1 B cells to a lymphocyte-deficient ApoE(-/-) Rag-2(-/-) common cytokine receptor γ-chain-deficient mouse that was fed a high-fat diet augmented atherosclerosis by 72%. Transfer of 5 × 10(6) B2 B cells to an ApoE(-/-) mouse deficient only in B cells aggravated atherosclerosis by >300%. Our findings provide compelling evidence for the hitherto unrecognized proatherogenic role of conventional B2 cells. The data indicate that B2 cells can potently promote atherosclerosis development entirely on their own in the total absence of all other lymphocyte populations. Additionally, these B2 cells can also significantly augment atherosclerosis development in the presence of T cells and all other lymphocyte populations. Our findings raise the prospect of B cell depletion as a therapeutic approach to inhibit atherosclerosis development and progression in humans.

Gasdermin Pore Forming Activities that Promote Inflammation from Living and Dead Cells.

Gasdermins are proteins that can self-assemble into membrane channels (also known as pores). These pores can serve as conduits for the secretion of cytosolic molecules, with the most commonly studied being members of the interleukin-1 family of cytokines. However, gasdermin pore forming activities must be tightly regulated, as the channels that they form can lead to a lytic form of cell death known as pyroptosis. Recent studies have revealed multiple mechanisms that control gasdermin activities within cells and identified gasdermin proteins in organisms as diverse as bacteria, humans and yeast. In this Review, we discuss the molecular and cellular mechanisms that regulate gasdermin pore formation. These mechanisms of gasdermin regulation likely explain the flexibility of these proteins to display cell type specific (and potentially organism specific) functions.

Crosstalk between cytotoxic CD8+ T cells and stressed cardiomyocytes triggers development of interstitial cardiac fibrosis in hypertensive mouse hearts.

Aims: Cardiac fibrosis is central to heart failure (HF), especially HF with preserved ejection fraction (HFpEF), often caused by hypertension. Despite fibrosis causing diastolic dysfunction and impaired electrical conduction, responsible for arrhythmia-induced sudden cardiac death, the mechanisms are poorly defined and effective therapies are lacking. Here we show that crosstalk between cardiac cytotoxic memory CD8+ T cells and overly stressed cardiomyocytes is essential for development of non-ischemic hypertensive cardiac fibrosis. Methods and results: CD8 T cell depletion in hypertensive mice, strongly attenuated CF, reduced cardiac apoptosis and improved ventricular relaxation. Interaction between cytotoxic memory CD8+ T cells and overly stressed cardiomyocytes is highly dependent on the CD8+ T cells expressing the innate stress-sensing receptor NKG2D and stressed cardiomyocytes expressing the NKG2D activating ligand RAE-1. The interaction between NKG2D and RAE-1 results in CD8+ T cell activation, release of perforin, cardiomyocyte apoptosis, increased numbers of TGF-ß1 expressing macrophages and fibrosis. Deleting NKG2D or perforin from CD8+ T cells greatly attenuates these effects. Activation of the cytoplasmic DNA-STING-TBK1-IRF3 signaling pathway in overly stressed cardiomyocytes is responsible for elevating RAE-1 and MCP-1, a macrophage attracting chemokine. Inhibiting STING activation greatly attenuates cardiomyocyte RAE-1 expression, the cardiomyocyte apoptosis, TGF-ß1 and fibrosis. Conclusion: Our data highlight a novel pathway by which CD8 T cells contribute to an early triggering mechanism in CF development; preventing CD8+ T cell activation by inhibiting the cardiomyocyte RAE-1-CD8+ T cell-NKG2D axis holds promise for novel therapeutic strategies to limit hypertensive cardiac fibrosis.

Autologous bone marrow mononuclear cell infusion for liver cirrhosis after the Kasai operation in children with biliary atresia.

AIM: To evaluate the safety and early outcomes of autologous bone marrow mononuclear cell (BMMNC) infusion for liver cirrhosis due to biliary atresia (BA) after Kasai operation. METHODS: An open-label clinical trial was performed from January 2017 to December 2019. Nineteen children with liver cirrhosis due to BA after Kasai operation were included. Bone marrow was harvested through anterior iliac crest puncture under general anesthesia. Mononuclear cells (MNCs) were isolated by Ficoll gradient centrifugation and then infused into the hepatic artery. The same procedure was repeated 6 months later. Serum bilirubin, albumin, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, and prothrombin time were monitored at baseline, 3 months, 6 months, and 12 months after the first transplantation. Esophagoscopies and liver biopsies were performed in patients whose parents provided consent. Mixed-effect analysis was used to evaluate the changes in Pediatric End-Stage Liver Disease (PELD) scores. RESULTS: The average MNC and CD34+ cell counts per kg body weight were 50.1 ± 58.5 × 106/kg and 3.5 ± 2.8 × 106 for the first transplantation and 57.1 ± 42.0 × 106/kg and 3.7 ± 2.7 × 106 for the second transplantation. No severe adverse events associated with the cell therapy were observed in the patients. One patient died 5 months after the first infusion at a provincial hospital due to the rupture of esophageal varices, while 18 patients survived. Liver function was maintained or improved after infusion, as assessed by biochemical tests. The severity of the disease reduced markedly, with a significant reduction in PELD scores. CONCLUSION: Autologous BMMNC administration for liver cirrhosis due to BA is safe and may maintain or improve liver function. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03468699. Name of the registry: Vinmec Research Institute of Stem Cell and Gene Technology. https://clinicaltrials.gov/ct2/show/NCT03468699?cond=biliary+atresia&cntry=VN&draw=2&rank=2 . Registered on March 16, 2018. The trial results will also be published according to the CONSORT statement at conferences and reported in peer-reviewed journals.

Evolution-inspired redesign of the LPS receptor caspase-4 into an interleukin-1ß converting enzyme.

Innate immune signaling pathways comprise multiple proteins that promote inflammation. This multistep means of information transfer suggests that complexity is a prerequisite for pathway design. Herein, we test this hypothesis by studying caspases that regulate inflammasome-dependent inflammation. Several caspases differ in their ability to recognize bacterial LPS and cleave interleukin-1ß (IL-1ß). No caspase is known to contain both activities, yet distinct caspases with complementary activities bookend an LPS-induced pathway to IL-1ß cleavage. Using caspase-1/4 hybrid proteins present in canines as a guide, we identified molecular determinants of IL-1ß cleavage specificity within caspase-1. This knowledge enabled the redesign of human caspase-4 to operate as a one-protein signaling pathway, which intrinsically links LPS detection to IL-1ß cleavage and release, independent of inflammasomes. We identified caspase-4 homologues in multiple carnivorans which display the activities of redesigned human caspase-4. These findings illustrate natural signaling pathway diversity and highlight how multistep innate immune pathways can be condensed into a single protein.

[The surgeon René Guillet (1913-2002).His actions in the hilly regions of France in Aian and Haut-Jura in 1944]. / Le chirurgien René Guillet (1913-2002). Son action dans les maquis de l'Ain et du Haut-Jura en 1944.

In 1943, René Guillet, a young surgeon in the Department of Professor Mallet-Guy, took part in the Resistance as he helped the wounded men in the hospital of Edouard Herriot. René Guillet joined the French Army of the Resistance on June 6, 1944. Then, in July 1944, he took care of the wounded men in the hospital of Oyonnax with doctor Parker, an English surgeon in the French hospital in London. Although it was very dangerous, the two doctors managed to transfer the wounded to Geneva.

Comparative Effectiveness of Mild or Conventional GnRH-Antagonist Protocols for Ovarian Stimulation in Poor Responders (Poseidon Group 4).

Background and Aims: A panel of experts (the Poseidon Group) introduced a new and more detailed stratification for poor ovarian responders in order to predict the prognosis of IVF outcome according to the sensitivity to FSH. However, various arguments about the management strategy of these patients still remain, including the convenience and the cost. Therefore, this study was conducted to compare the efficacy of mild and conventional GnRH antagonist ovarian stimulation prescribed in patients classified in Poseidon Group 4. Methods: This retrospective cohort study included 359 poor responder patients (Poseidon Group 4) treated with mild or conventional GnRH antagonist stimulation regimens from 8/2017 to 7/2019 at Tam Anh Hospital ART Center. The main outcomes were the index of Follicular Output Rate (FORT) or Follicle to Oocyte Index (FOI), the number of day-2 embryos and top-quality embryos obtained. The t-test and Mann-Whitney U test in SPSS v25.0 was used to analyze the continuous data and Chi-squared/Exact test was used for binary variables. Multiple linear regression analysis was done by using Stata versions 15.0 to measure association between primary endpoints with stimulation regimen controlled for covariates and possible confounding factors. Results: In the overall group of poor responders, the conventional GnRH antagonist protocol performed better than the mild protocol. Subsequently, data were analyzed according to the AFC. In women with AFC < 3, no significant differences were observed between the 2 regimens regarding FORT (p = 0.71), FOI (p = 0.12), the number of day-2-embryos (p = 0.052) and the number of top-quality embryos (p = 0.26). In contrast, in women with AFC ≥ 3, mild stimulation regimen resulted in significantly poorer outcome compared to the conventional GnRH antagonist regimen, regarding FORT (p < 0.01), FOI (p < 0.01), the number of day-2-embryos (p < 0.01) and top-quality embryos (p = 0.01). Conclusions: Considering poor responders classified in Poseidon Group 4, both ovarian stimulation regimens resulted in similar outcome for patients with a very low ovarian reserve (AFC < 3). In contrast, the GnRH conventional antagonist protocol with maximum initial FSH dose (300-375 IU/day) and supplementary LH (75-150 IU/day) was more effective than the mild one for patients whose ovarian reserve was less reduced. The Clinical Trial was approved by the Ethnical Biomedical Research Committee Tam Anh General Hospital.

A Two-Cell Model for IL-1ß Release Mediated by Death-Receptor Signaling.

Interleukin-1ß (IL-1ß) is a key orchestrator of anti-microbial immunity whose secretion is typically dependent on activation of inflammasomes. However, many pathogens have evolved strategies to evade inflammasome activation. Here we describe an alternative, two-cell model for IL-1ß release where invariant natural killer T (iNKT) cells use the death receptor pathway to instruct antigen-presenting cells to secrete IL-1ß. Following cognate interactions with TLR-primed bone marrow-derived dendritic cells (BMDCs), iNKT cells rapidly translocate intracellular Fas ligand to the surface to engage Fas on BMDCs. Fas ligation activates a caspase-8-dependent signaling cascade in BMDCs that drives IL-1ß release largely independent of inflammasomes. The apoptotic program initiated by Fas ligation rapidly transitions into a pyroptosis-like form of cell death mediated by gasdermin D. Together, our findings support a two-cell model for IL-1ß secretion that may supersede inflammasome activation when cytosolic triggers fail.

Dorsal vagal complex and hypothalamic glia differentially respond to leptin and energy balance dysregulation.

Previous studies identify a role for hypothalamic glia in energy balance regulation; however, a narrow hypothalamic focus provides an incomplete understanding of how glia throughout the brain respond to and regulate energy homeostasis. We examined the responses of glia in the dorsal vagal complex (DVC) to the adipokine leptin and high fat diet-induced obesity. DVC astrocytes functionally express the leptin receptor; in vivo pharmacological studies suggest that DVC astrocytes partly mediate the anorectic effects of leptin in lean but not diet-induced obese rats. Ex vivo calcium imaging indicated that these changes were related to a lower proportion of leptin-responsive cells in the DVC of obese versus lean animals. Finally, we investigated DVC microglia and astroglia responses to leptin and energy balance dysregulation in vivo: obesity decreased DVC astrogliosis, whereas the absence of leptin signaling in Zucker rats was associated with extensive astrogliosis in the DVC and decreased hypothalamic micro- and astrogliosis. These data uncover a novel functional heterogeneity of astrocytes in different brain nuclei of relevance to leptin signaling and energy balance regulation.

B Cell and CD4 T Cell Interactions Promote Development of Atherosclerosis.

Interaction between B and CD4 T cells is crucial for their optimal responses in adaptive immunity. Immune responses augmented by their partnership promote chronic inflammation. Here we report that interaction between B and CD4 T cells augments their atherogenicity to promote lipid-induced atherosclerosis. Genetic deletion of the gene encoding immunoglobulin mu (µ) heavy chain (µMT) in ApoE-/- mice resulted in global loss of B cells including those in atherosclerotic plaques, undetectable immunoglobulins and impaired germinal center formation. Despite unaffected numbers in the circulation and peripheral lymph nodes, CD4 T cells were also reduced in spleens as were activated and memory CD4 T cells. In hyperlipidemic µMT-/- ApoE-/- mice, B cell deficiency decreased atherosclerotic lesions, accompanied by absence of immunoglobulins and reduced CD4 T cell accumulation in lesions. Adoptive transfer of B cells deficient in either MHCII or co-stimulatory molecule CD40, molecules required for B and CD4 T cell interaction, into B cell-deficient µMT-/- ApoE-/- mice failed to increase atherosclerosis. In contrast, wildtype B cells transferred into µMT-/- ApoE-/- mice increased atherosclerosis and increased CD4 T cells in lesions including activated and memory CD4 T cells. Transferred B cells also increased their expression of atherogenic cytokines IL-1ß, TGF-ß, MCP-1, M-CSF, and MIF, with partial restoration of germinal centers and plasma immunoglobulins. Our study demonstrates that interaction between B and CD4 T cells utilizing MHCII and CD40 is essential to augment their function to increase atherosclerosis in hyperlipidemic mice. These findings suggest that targeting B cell and CD4 T cell interaction may be a therapeutic strategy to limit atherosclerosis progression.