EPCR/PAR1 biased signaling regulates perfusion recovery and neovascularization in peripheral ischemia
Bochenek et al. report that endothelial cell EPCR/PAR1 biased signaling regulates regenerative peripheral angiogenesis by increasing NO bioavailability. The cover image shows hemoglobin (red) and EPCR (purple) expression in human microvascular endothelial cells under hypoxic conditions.
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Review
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Abstract
Heterotopic ossification (HO) is the formation of ectopic bone that is primarily genetically driven (fibrodysplasia ossificans progressiva [FOP]) or acquired in the setting of trauma (tHO). HO has undergone intense investigation, especially over the last 50 years, as awareness has increased around improving clinical technologies and incidence, such as with ongoing wartime conflicts. Current treatments for tHO and FOP remain prophylactic and include NSAIDs and glucocorticoids, respectively, whereas other proposed therapeutic modalities exhibit prohibitive risk profiles. Contemporary studies have elucidated mechanisms behind tHO and FOP and have described new distinct niches independent of inflammation that regulate ectopic bone formation. These investigations have propagated a paradigm shift in the approach to treatment and management of a historically difficult surgical problem, with ongoing clinical trials and promising new targets.
Authors
Charles D. Hwang, Chase A. Pagani, Johanna H. Nunez, Masnsen Cherief, Qizhi Qin, Mario Gomez-Salazar, Balram Kadaikal, Heeseog Kang, Ashish R. Chowdary, Nicole Patel, Aaron W. James, Benjamin Levi
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Research Articles
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Abstract
The ribosomal protein S6 kinase 1 (S6K1) is a relevant effector downstream of the mammalian target of rapamycin complex 1 (mTORC1), best known for its role in the control of lipid homeostasis. Consistent with this, mice lacking the S6k1 gene have a defect in their ability to induce the commitment of fat precursor cells to the adipogenic lineage, which contributes to a significant reduction of fat mass. Here, we assess the therapeutic blockage of S6K1 in diet-induced obese mice challenged with LY2584702 tosylate, a specific oral S6K1 inhibitor initially developed for the treatment of solid tumors. We show that diminished S6K1 activity hampers fat mass expansion and ameliorates dyslipidemia and hepatic steatosis, while modifying transcriptome-wide gene expression programs relevant for adipose and liver function. Accordingly, decreased mTORC1 signaling in fat (but increased in the liver) segregated with defective epithelial-mesenchymal transition and the impaired expression of Cd36 (coding for a fatty acid translocase) and Lgals1 (Galectin 1) in both tissues. All these factors combined align with reduced adipocyte size and improved lipidomic signatures in the liver, while hepatic steatosis and hypertriglyceridemia were improved in treatments lasting either 3 months or 6 weeks.
Authors
Aina Lluch, Sonia R. Veiga, Jèssica Latorre, José M. Moreno-Navarrete, Núria Bonifaci, Van Dien Nguyen, You Zhou, Marcus Höring, Gerhard Liebisch, Vesa M. Olkkonen, David Llobet-Navas, George Thomas, Ruth Rodríguez-Barrueco, José M. Fernández-Real, Sara C. Kozma, Francisco J. Ortega
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Blood clot formation initiates ischemic events, but coagulation roles during postischemic tissue repair are poorly understood. The endothelial protein C receptor (EPCR) regulates coagulation, as well as immune and vascular signaling, by protease activated receptors (PARs). Here, we show that endothelial EPCR-PAR1 signaling supports reperfusion and neovascularization in hindlimb ischemia in mice. Whereas deletion of PAR2 or PAR4 did not impair angiogenesis, EPCR and PAR1 deficiency or PAR1 resistance to cleavage by activated protein C caused markedly reduced postischemic reperfusion in vivo and angiogenesis in vitro. These findings were corroborated by biased PAR1 agonism in isolated primary endothelial cells. Loss of EPCR-PAR1 signaling upregulated hemoglobin expression and reduced endothelial nitric oxide (NO) bioavailability. Defective angiogenic sprouting was rescued by the NO donor DETA-NO, whereas NO scavenging increased hemoglobin and mesenchymal marker expression in human and mouse endothelial cells. Vascular specimens from patients with ischemic peripheral artery disease exhibited increased hemoglobin expression, and soluble EPCR and NO levels were reduced in plasma. Our data implicate endothelial EPCR-PAR1 signaling in the hypoxic response of endothelial cells and identify suppression of hemoglobin expression as an unexpected link between coagulation signaling, preservation of endothelial cell NO bioavailability, support of neovascularization, and prevention of fibrosis.
Authors
Magdalena L. Bochenek, Rajinikanth Gogiraju, Stefanie Großmann, Janina Krug, Jennifer Orth, Sabine Reyda, George S. Georgiadis, Henri M. Spronk, Stavros Konstantinides, Thomas Münzel, John H. Griffin, Philipp Wild, Christine Espinola-Klein, Wolfram Ruf, Katrin Schäfer
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Synaptic dysfunction is a manifestation of several neurobehavioral and neurological disorders. A major therapeutic challenge lies in uncovering the upstream regulatory factors controlling synaptic processes. Plant homeodomain (PHD) finger proteins are epigenetic readers whose dysfunctions are implicated in neurological disorders. However, the molecular mechanisms linking PHD protein deficits to disease remain unclear. Here, we generated a PHD finger protein 21B–depleted (Phf21b-depleted) mutant CRISPR mouse model (hereafter called Phf21bΔ4/Δ4) to examine Phf21b’s roles in the brain. Phf21bΔ4/Δ4 animals exhibited impaired social memory. In addition, reduced expression of synaptic proteins and impaired long-term potentiation were observed in the Phf21bΔ4/Δ4 hippocampi. Transcriptome profiling revealed differential expression of genes involved in synaptic plasticity processes. Furthermore, we characterized a potentially novel interaction of PHF21B with histone H3 trimethylated lysine 36 (H3K36me3), a histone modification associated with transcriptional activation, and the transcriptional factor CREB. These results establish PHF21B as an important upstream regulator of synaptic plasticity–related genes and a candidate therapeutic target for neurobehavioral dysfunction in mice, with potential applications in human neurological and psychiatric disorders.
Authors
Eunice W.M. Chin, Qi Ma, Hongyu Ruan, Camille Chin, Aditya Somasundaram, Chunling Zhang, Chunyu Liu, Martin D. Lewis, Melissa White, Tracey L. Smith, Malcolm Battersby, Wei-Dong Yao, Xin-Yun Lu, Wadih Arap, Julio Licinio, Ma-Li Wong
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Membrane instability and disruption underlie myriad acute and chronic disorders. Anxa6 encodes the membrane-associated protein annexin A6 and was identified as a genetic modifier of muscle repair and muscular dystrophy. To evaluate annexin A6’s role in membrane repair in vivo, we inserted sequences encoding green fluorescent protein (GFP) into the last coding exon of Anxa6. Heterozygous Anxa6gfp mice expressed a normal pattern of annexin A6 with reduced annexin A6GFP mRNA and protein. High-resolution imaging of wounded muscle fibers showed annexin A6GFP rapidly formed a repair cap at the site of injury. Injured cardiomyocytes and neurons also displayed repair caps after wounding, highlighting annexin A6–mediated repair caps as a feature in multiple cell types. Using surface plasmon resonance, we showed recombinant annexin A6 bound phosphatidylserine-containing lipids in a Ca2+- and dose-dependent fashion with appreciable binding at approximately 50 μM Ca2+. Exogenously added recombinant annexin A6 localized to repair caps and improved muscle membrane repair capacity in a dose-dependent fashion without disrupting endogenous annexin A6 localization, indicating annexin A6 promotes repair from both intracellular and extracellular compartments. Thus, annexin A6 orchestrates repair in multiple cell types, and recombinant annexin A6 may be useful in additional chronic disorders beyond skeletal muscle myopathies.
Authors
Alexis R. Demonbreun, Elena Bogdanovic, Lauren A. Vaught, Nina L. Reiser, Katherine S. Fallon, Ashlee M. Long, Claire C. Oosterbaan, Michele Hadhazy, Patrick G.T. Page, Prem Raj B. Joseph, Gabrielle Cowen, Alexander M. Telenson, Ammaarah Khatri, Katherine R. Sadleir, Robert Vassar, Elizabeth M. McNally
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Acute lung injury (ALI) can cause acute respiratory distress syndrome (ARDS), a lethal condition with limited treatment options and currently a common global cause of death due to COVID-19. ARDS secondary to transfusion-related ALI (TRALI) has been recapitulated preclinically by anti–MHC-I antibody administration to LPS-primed mice. In this model, we demonstrate that inhibitors of PTP1B, a protein tyrosine phosphatase that regulates signaling pathways of fundamental importance to homeostasis and inflammation, prevented lung injury and increased survival. Treatment with PTP1B inhibitors attenuated the aberrant neutrophil function that drives ALI and was associated with release of myeloperoxidase, suppression of neutrophil extracellular trap (NET) formation, and inhibition of neutrophil migration. Mechanistically, reduced signaling through the CXCR4 chemokine receptor, particularly to the activation of PI3Kγ/AKT/mTOR, was essential for these effects, linking PTP1B inhibition to promoting an aged-neutrophil phenotype. Considering that dysregulated activation of neutrophils has been implicated in sepsis and causes collateral tissue damage, we demonstrate that PTP1B inhibitors improved survival and ameliorated lung injury in an LPS-induced sepsis model and improved survival in the cecal ligation and puncture–induced (CLP-induced) sepsis model. Our data highlight the potential for PTP1B inhibition to prevent ALI and ARDS from multiple etiologies.
Authors
Dongyan Song, Jose M. Adrover, Christy Felice, Lisa N. Christensen, Xue-Yan He, Joseph R. Merrill, John E. Wilkinson, Tobias Janowitz, Scott K. Lyons, Mikala Egeblad, Nicholas K. Tonks
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Senescent cells have long been associated with deleterious effects in aging-related pathologies, although recent studies have uncovered their beneficial roles in certain contexts, such as wound healing. We have found that hepatic stellate cells (HSCs) underwent senescence within 2 days after 2/3 partial hepatectomy (PHx) in young (2–3 months old) mice, and the elimination of these senescent cells by using the senolytic drug ABT263 or by using a genetic mouse model impaired liver regeneration. Senescent HSCs secrete IL-6 and CXCR2 ligands as part of the senescence-associated secretory phenotype, which induces multiple signaling pathways to stimulate liver regeneration. IL-6 activates STAT3, induces Yes-associated protein (YAP) activation through SRC family kinases, and synergizes with CXCL2 to activate ERK1/2 to stimulate hepatocyte proliferation. The administration of either IL-6 or CXCL2 partially restored liver regeneration in mice with senescent cell elimination, and the combination of both fully restored liver weight recovery. Furthermore, the matricellular protein central communication network factor 1 (CCN1, previously called CYR61) was rapidly elevated in response to PHx and induced HSC senescence. Knockin mice expressing a mutant CCN1 unable to bind integrin α6β1 were deficient in senescent cells and liver regeneration after PHx. Thus, HSC senescence, largely induced by CCN1, is a programmed response to PHx and plays a critical role in liver regeneration through signaling pathways activated by IL-6 and ligands of CXCR2.
Authors
Naiyuan Cheng, Ki-Hyun Kim, Lester F. Lau
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Familial exudative vitreoretinopathy (FEVR) is a hereditary disorder that can cause vision loss. CTNND1 encodes a cellular adhesion protein p120-catenin (p120), which is essential for vascularization with unclear function in postnatal physiological angiogenesis. Here, we applied whole-exome sequencing to 140 probands of FEVR families and identified 3 candidate variants in the human CTNND1 gene. We performed inducible deletion of Ctnnd1 in the postnatal mouse endothelial cells (ECs) and observed typical phenotypes of FEVR with reactive gliosis. Using unbiased proteomics analysis combined with experimental approaches, we conclude that p120 is critical for the integrity of adherens junctions (AJs) and that p120 activates Wnt signaling activity by protecting β-catenin from glycogen synthase kinase 3 beta–ubiqutin–guided (Gsk3β-ubiquitin–guided) degradation. Treatment of CTNND1-depleted human retinal microvascular ECs with Gsk3β inhibitors LiCl or CHIR-99021 enhanced cell proliferation. Moreover, LiCl treatment increased vessel density in Ctnnd1-deficient mouse retinas. Variants in CTNND1 caused FEVR by compromising the expression of AJs and Wnt signaling activity. Genetic interactions between p120 and β-catenin or α-catenin revealed by double-heterozygous deletion in mice showed that p120 regulates vascular development through the Wnt/cadherin axis. In conclusion, variants in CTNND1 can cause FEVR through the Wnt/cadherin axis.
Authors
Mu Yang, Shujin Li, Li Huang, Rulian Zhao, Erkuan Dai, Xiaoyan Jiang, Yunqi He, Jinglin Lu, Li Peng, Wenjing Liu, Zhaotian Zhang, Dan Jiang, Yi Zhang, Zhilin Jiang, Yeming Yang, Peiquan Zhao, Xianjun Zhu, Xiaoyan Ding, Zhenglin Yang
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Acute kidney injury increases morbidity and mortality, and previous studies have shown that remote ischemic preconditioning (RIPC) reduces the risk of acute kidney injury after cardiac surgery. RIPC increases urinary high mobility group box protein-1 (HMGB1) levels in patients, and this correlates with kidney protection. Here, we show that RIPC reduces renal ischemia-reperfusion injury and improves kidney function in mice. Mechanistically, RIPC increases HMGB1 levels in the plasma and urine, and HMGB1 binds to TLR4 on renal tubular epithelial cells, inducing transcriptomic modulation of renal tubular epithelial cells and providing renal protection, whereas TLR4 activation on nonrenal cells was shown to contribute to renal injury. This protection is mediated by activation of induction of AMPKα and NF-κB; this induction contributes to the upregulation of Sema5b, which triggers a transient, protective G1 cell cycle arrest. In cardiac surgery patients at high risk for postoperative acute kidney injury, increased HMGB1 and Sema5b levels after RIPC were associated with renal protection after surgery. The results may help to develop future clinical treatment options for acute kidney injury.
Authors
Jan Rossaint, Melanie Meersch, Katharina Thomas, Sina Mersmann, Martin Lehmann, Jennifer Skupski, Tobias Tekath, Peter Rosenberger, John A. Kellum, Hermann Pavenstädt, Alexander Zarbock
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Although macrophages are undoubtedly attractive therapeutic targets for acute kidney injury (AKI) because of their critical roles in renal inflammation and repair, the underlying mechanisms of macrophage phenotype switching and efferocytosis in the regulation of inflammatory responses during AKI are still largely unclear. The present study elucidated the role of junctional adhesion molecule–like protein (JAML) in the pathogenesis of AKI. We found that JAML was significantly upregulated in kidneys from 2 different murine AKI models including renal ischemia/reperfusion injury (IRI) and cisplatin-induced AKI. By generation of bone marrow chimeric mice, macrophage-specific and tubular cell–specific Jaml conditional knockout mice, we demonstrated JAML promoted AKI mainly via a macrophage-dependent mechanism and found that JAML-mediated macrophage phenotype polarization and efferocytosis is one of the critical signal transduction pathways linking inflammatory responses to AKI. Mechanistically, the effects of JAML on the regulation of macrophages were, at least in part, associated with a macrophage-inducible C-type lectin–dependent mechanism. Collectively, our studies explore for the first time to our knowledge new biological functions of JAML in macrophages and conclude that JAML is an important mediator and biomarker of AKI. Pharmacological targeting of JAML-mediated signaling pathways at multiple levels may provide a novel therapeutic strategy for patients with AKI.
Authors
Wei Huang, Bi-Ou Wang, Yun-Feng Hou, Yi Fu, Si-Jia Cui, Jing-Han Zhu, Xin-Yu Zhan, Rong-Kun Li, Wei Tang, Ji-Chao Wu, Zi-Ying Wang, Mei Wang, Xiao-Jie Wang, Yan Zhang, Min Liu, Yu-Sheng Xie, Yu Sun, Fan Yi
×Abstract
Despite being a leading cause of advanced liver disease, alcohol-associated liver disease (ALD) has no effective medical therapies. The circulating proteome, which comprises proteins secreted by different cells and tissues in the context of normal physiological function or in the setting of disease and illness, represents an attractive target for uncovering novel biology related to the pathogenesis of ALD. In this work, we used the aptamer-based SomaScan proteomics platform to quantify the relative concentration of over 1300 proteins in a well-characterized cohort of patients with the spectrum of ALD. We found a distinct circulating proteomic signature that correlated with ALD severity, including over 600 proteins that differed significantly between ALD stages, many of which have not previously been associated with ALD to our knowledge. Notably, certain proteins that were markedly dysregulated in patients with alcohol-associated hepatitis were also altered, to a lesser degree, in patients with subclinical ALD and may represent early biomarkers for disease progression. Taken together, our work highlights the vast and distinct changes in the circulating proteome across the wide spectrum of ALD, identifies potentially novel biomarkers and therapeutic targets, and provides a proteomic resource atlas for ALD researchers and clinicians.
Authors
Jay Luther, Augustin G.L. Vannier, Esperance A. Schaefer, Russell P. Goodman
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Chikungunya virus (CHIKV) is a reemerging mosquito-borne alphavirus responsible for numerous outbreaks. Chikungunya can cause debilitating acute and chronic disease. Thus, the development of a safe and effective CHIKV vaccine is an urgent global health priority. This study evaluated the effectiveness of the live-attenuated CHIKV vaccine VLA1553 against WT CHIKV infection by using passive transfer of sera from vaccinated volunteers to nonhuman primates (NHP) subsequently exposed to WT CHIKV and established a serological surrogate of protection. We demonstrated that human VLA1553 sera transferred to NHPs conferred complete protection from CHIKV viremia and fever after challenge with homologous WT CHIKV. In addition, serum transfer protected animals from other CHIKV-associated clinical symptoms and from CHIKV persistence in tissue. Based on this passive transfer study, a 50% micro–plaque reduction neutralization test titer of ≥ 150 was determined as a surrogate of protection, which was supported by analysis of samples from a seroepidemiological study. In conclusion, considering the unfeasibility of an efficacy trial due to the unpredictability and explosive, rapidly moving nature of chikungunya outbreaks, the definition of a surrogate of protection for VLA1553 is an important step toward vaccine licensure to reduce the medical burden caused by chikungunya.
Authors
Pierre Roques, Andrea Fritzer, Nathalie Dereuddre-Bosquet, Nina Wressnigg, Romana Hochreiter, Laetitia Bossevot, Quentin Pascal, Fabienne Guehenneux, Annegret Bitzer, Irena Corbic Ramljak, Roger Le Grand, Urban Lundberg, Andreas Meinke
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Abstract
Checkpoint inhibitors (CPIs) targeting programmed death-1(PD-1)/programmed death-ligand 1 (PD-L1) and cytotoxic T lymphocyte antigen 4 (CTLA-4) have revolutionized cancer treatment but can trigger autoimmune complications including CPI-induced diabetes (CPI-DM), which occurs preferentially with PD-1 blockade. We found evidence of pancreatic inflammation in patients with CPI-DM with shrinkage of pancreases, increased pancreatic enzymes, and in a case from a patient who died with CPI-DM, peri-islet lymphocytic infiltration. In the NOD mouse model, anti-PD-L1 but not anti-CTLA-4 induces diabetes rapidly. RNA sequencing revealed that cytolytic IFNγ+ CD8+ T cells infiltrated islets with anti-PD-L1. Changes in β cells were predominantly driven by IFNγ and TNFα and included induction of a potentially novel β cell population with transcriptional changes suggesting dedifferentiation. IFNγ increased checkpoint ligand expression and activated apoptosis pathways in human β cells in vitro. Treatment with anti-IFNγ and anti-TNFα prevented CPI-DM in anti-PD-L1 treated NOD mice. CPIs targeting the PD-1/PD-L1 pathway result in transcriptional changes in β cells and immune infiltrates that may lead to the development of diabetes. Inhibition of inflammatory cytokines can prevent CPI-DM, suggesting a strategy for clinical application to prevent this complication.
Authors
Ana Luisa Perdigoto, Songyan Deng, Katherine C. Du, Manik Kuchroo, Daniel B. Burkhardt, Alexander Tong, Gary Israel, Marie E. Robert, Stuart P. Weisberg, Nancy Kirkiles-Smith, Angeliki M. Stamatouli, Harriet M. Kluger, Zoe Quandt, Arabella Young, Mei-Ling Yang, Mark J. Mamula, Jordan S. Pober, Mark S. Anderson, Smita Krishnaswamy, Kevan C. Herold
Abstract
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) efficacy is complicated by graft-versus-host disease (GVHD), a leading cause of morbidity and mortality after transplant. Despite GVHD prophylaxis, 30-70% of patients develop GVHD resulting in susceptibility to infections, relapse and secondary malignancies. Regulatory T-cells (Tregs) have shown efficacy in preventing GVHD, but variably suppressive at high doses. To enhance in vivo suppressor function, murine Treg were transduced to express an anti-human CD19 chimeric antigen receptor (hCAR19) and infused into lethally irradiated hCD19 transgenic recipients for allo-HSCT. As compared to recipients receiving controlled transduced Tregs, those receiving hCAR19 Tregs had a significant decrease in acute GVHD lethality. GVHD amelioration was accomplished with not only maintenance but potentiation of the graft-versus tumor (GVT) response, as recipient hCD19 B-cells and murine hCD19TBL12luc lymphoma cells were both cleared by allogeneic hCAR19 Tregs. Mechanistically, hCAR19 Tregs killed syngeneic hCD19+ but not hCD19- murine TBL12luc cells in vitro in a perforin-dependent, granzyme B-independent manner. Importantly, cyclophosphamide treated hCD19 transgenic mice given hCAR19 cytotoxic T-lymphocytes without allo-HSCT experienced rapid lethality due to systemic toxicity, whereas hCAR19 Tregs avoided this severe complication. In conclusion, CAR19 Tregs are a novel and effective strategy to suppress GVHD without loss of GVT responses.
Authors
Sara Bolivar-Wagers, Michael L. Loschi, Sujeong Jin, Govindarajan Thangavelu, Jemma H. Larson, Cameron S. McDonald-Hyman, Ethan A. Aguilar, Asim Saha, Brent H. Koehn, Mehrdad Hefazi, Mark J. Osborn, Michael C. Jensen, John E. Wagner, Christopher A. Pennell, Bruce R. Blazar.
Abstract
Lysosomal acid lipase (LAL) is a key enzyme in the metabolic pathway of neutral lipids. In the blood of LAL deficient (lal-/-) mice, increased CD11c+ cells were accompanied by up-regulated PD-L1 expression. Single cell RNA sequencing of lal-/- CD11c+ cells identified two distinctive clusters with a major metabolic shift towards glucose utilization and reactive oxygen species (ROS) over-production. Pharmacologically blocking pyruvate dehydrogenase in glycolysis not only reduced CD11c+ cells and their PD-L1 expression, but also reversed their capabilities of T cell suppression and tumor growth stimulation. Colony-stimulating factor 1 receptor (CSF1R) plays an essential role in controlling lal-/- CD11c+ cell homeostasis and function and PD-L1 expression. Inhibition of LAL activity by pharmacological inhibitor increased CD11c, PD-L1 and CSF1R levels in both normal murine myeloid cells and human blood cells. Tumor-bearing mice and human non-small-cell lung cancer (NSCLC) patients also showed CD11c+ cell expansion with PD-L1 and CSF1R up-regulation and immunosuppression. There were positive correlations among CD11c, PD-L1 and CSF1R expression and negative correlations with LAL expression in lung cancer and melanoma patients using the TCGA database and patient samples. Therefore, CD11c+ cells switched their functions to immune suppression and tumor growth stimulation through CSF1R/PD-L1 upregulation and metabolic reprogramming.
Authors
Ting Zhao, Sheng Liu, Xinchun Ding, Erica M. Johnson, Nasser H. Hanna, Kanhaiya Singh, Chandan K. Sen, Jun Wan, Hong Du, Cong Yan
Abstract
Pneumocystis is the most common fungal pulmonary infection in children under 5. In children with primary immunodeficiency, Pneumocystis often presents at 3-6 months that coincides with the nadir of maternal IgG and where IgM is the dominant immunoglobulin isotype. Since B cells are the dominant antigen-presenting cells for Pneumocystis, we hypothesized the presence of fungal specific IgMs in human and mice and that these IgM specificities would predict T cell antigens. We detected fungal specific IgMs in human and mouse serum and utilized immunoprecipitation to determine if any antigens were similar across donors. We then assessed T cell responses to these antigens. We found anti-Pneumocystis IgM in wild-type mice as well as Aicda-/- mice and in human cord blood. Immunoprecipitation of Pneumocystis murina with human cord blood identified shared antigens among these donors. Using class II MHC binding prediction, we designed peptides with these antigens and identified robust peptide specific lung T cell responses after P. murina infection. After mice were immunized with two of the antigens, adoptive transfer of vaccine elicited CD4+ T cells showed effector activity suggesting that these antigens contain protective Pneumocystis epitopes. These data support the notion that germline encoded IgM B-cell receptors are critical in antigen presentation and T cell priming in early Pneumocystis infection.
Authors
Kristin Noell, Guixiang Dai, Dora Pungan, Anna Ebacher, Janet E. McCombs, Samuel J. Landry, Jay K. Kolls
Abstract
In rodent models of type 2 diabetes (T2D), central administration of fibroblast growth factor 1 (FGF1) normalizes elevated blood glucose levels in a manner that is sustained for weeks or months. Increased activity of NPY/AgRP neurons in the hypothalamic arcuate nucleus (ARC) is implicated in the pathogenesis of hyperglycemia in these animals, and the ARC is a key brain area for the antidiabetic action of FGF1. We therefore sought to determine whether FGF1 inhibits NPY/AgRP neurons, and if so whether this inhibitory effect is sufficiently durable to offer a feasible explanation for sustained diabetes remission induced by central administration of FGF1. Here we show that FGF1 inhibits ARC NPY/AgRP neuron activity, both after icv injection in vivo and when applied ex vivo in a slice preparation, and that the underlying mechanism involves increased input from presynaptic GABAergic neurons. Following central administration, the inhibitory effect of FGF1 on NPY/AgRP neurons is also highly durable, lasting for at least two weeks. To our knowledge, no precedent for such a prolonged inhibitory effect exists. Future studies are warranted to determine whether NPY/AgRP neuron inhibition contributes to the sustained antidiabetic action elicited by icv FGF1 injection in rodent models of T2D.
Authors
Eunsang Hwang, Jarrad M. Scarlett, Arian F. Baquero, Camdin Bennett, Yanbin Dong, Dominic Chau, Jenny M. Brown, Aaron J. Mercer, Thomas H. Meek, Kevin L. Grove, Bao Anh N. Phan, Gregory J. Morton, Kevin W. Williams, Michael W. Schwartz
