The specificity of antibodies (Abs) generated to influenza A virus (IAV) infection can significantly alter protection and viral clearance. At present, the impact of age upon this process is relatively unexplored. Here, we evaluated the Ab response in newborn and adult African green monkeys (AGM) following infection with IAV using a strain that enables us to determine the immunodominance (ID) hierarchy of the Ab response to hemagglutinin (HA), the principal target of protective Abs. This revealed altered ID patterns in the early IgM anti-HA response in newborns versus adults that converged over time. While the IgG ID profiles for HA in newborn and adult monkeys were similar, this was not the case for IgA. Importantly, HA stem-specific Abs were generated robustly and similarly in newborns and adults in terms of quality and quantity. Together these results demonstrate that newborns and adults can differ in the Ab ID pattern established following infection and that the ID pattern can vary across isotypes. In addition, newborns have the ability to generate potent HA stem-specific Ab responses. Our findings further the understanding of the newborn response to IAV antigens and inform the development of improved vaccines for this at-risk population.
Elene A. Clemens, Davide Angeletti, Beth C. Holbrook, Masaru Kanekiyo, Matthew J. Jorgensen, Barney S. Graham, Jonathan W. Yewdell, Martha A. Alexander-Miller
The blood hormone erythropoietin (EPO), upon binding to its receptor (EpoR), modulates high fat-diet (HFD)-induced obesity in mice, improves glucose tolerance, and prevents white adipose tissue inflammation. Transgenic mice with constitutive over-expression of human EPO solely in brain (Tg21) were used to assess the neuro-endocrine EPO effect without increasing the hematocrit. Male Tg21-mice resisted HFD-induced weight gain, showed lower serum ACTH, corticosterone and C-reactive protein levels, and prevented myeloid cell recruitment to hypothalamus compared with WT-males. HFD-induced hypothalamic inflammation (HI) and microglial activation were higher in male mice, and Tg21-males exhibited lower increase in HI than WT-males. Physiological EPO function in the brain also showed sexual dimorphism in regulating HFD response. Targeted deletion of EpoR gene expression in neuronal and glial cells worsened HFD-induced glucose intolerance in both male and female mice, but increased weight gain and HI in the hypothalamus in male mice only. Female estrogen production blocked reduced weight gain and HI. Both male and female Tg21-mice kept on normal-chow and HFD showed significantly improved glycemic control. Our data indicates that cerebral EPO regulates weight gain and HI in a sex-dependent response, distinct from EPO regulation of glycemic control, and independent of erythropoietic EPO response.
Soumyadeep Dey, Zhenzhong Cui, Oksana Gavrilova, XiaoJie Zhang, Max Gassmann, Constance T. Noguchi
Most prostate cancers depend on androgens for growth and therefore the mainstay treatment for advanced, recurrent or metastatic prostate cancer is androgen deprivation therapy (ADT). A prominent side effect in patients receiving ADT is an obese frailty syndrome that includes fat gain and sarcopenia, defined as the loss of muscle function accompanied by reduced muscle mass or quality. Mice bearing Pten deficient prostate cancers were examined to gain mechanistic insight into ADT-induced sarcopenic obesity. Castration induced fat gain as well as skeletal muscle mass and strength loss. Catabolic TGFß-family myokine protein levels were increased immediately prior to strength loss and pan-myokine blockade using a soluble receptor (ActRIIB-Fc) completely reversed the castration-induced sarcopenia. The onset of castration-induced strength and muscle mass loss, as well as the increase in catabolic TGFß-family myokine protein levels, were coordinately accelerated in tumor-bearing mice relative to tumor-free mice. Notably, GDF11 increased in muscle after castration only in tumor-bearing mice, but not in tumor free mice. An early surge of GDF11 in prostate tumor tissue and in the circulation suggests that endocrine GDF11 signaling from tumor to muscle is a major driver of the accelerated ADT-induced sarcopenic phenotype. In tumor-bearing mice, GDF11 blockade largely prevented castration-induced strength loss but did not preserve muscle mass, which confirms a primary role for GDF11 in muscle function and suggests an additional role for the other catabolic myokines.
Chunliu Pan, Neha Jaiswal Agrawal, Yanni Zulia, Shalini Singh, Kai Sha, James L. Mohler, Kevin H. Eng, Joe Chakkalakal, John J. Krolewski, Kent L. Nastiuk
We reported that transgenic mice expressing measles virus nucleocapsid protein (MVNP) in OCLs (MVNP mice) are a Paget’s disease (PD) model, and that osteoclasts (OCLs) from PD patients and MVNP mice express high levels of OCL-derived IGF1 (OCL-IGF1). To determine OCL-IGF1’s role in PD and normal bone remodeling, we generated WT and MVNP mice with targeted deletion of Igf1 in OCLs (Igf1-cKO) and MVNP/Igf1-cKO mice and assessed OCL-IGF1’s effects on bone mass, bone formation rate, ephrinB2/EphB4 expression on OCLs and osteoblasts (OBs) and pagetic bone lesions (PDLs). Forty percent of MVNP mice but no MVNP/Igf1-cKO mice had PDLs. BV/TV was decreased 60% in lumbar vertebrae and femurs of MVNP/Igf1-cKO vs. MVNP mice with PDLs and by 45% vs. all MVNP mice tested. Bone formation rates were decreased 50% in Igf1-cKO and MVNP/Igf1-cKO mice vs. WT and MVNP mice. MVNP mice had increased ephrinB2 and EphB4 levels in OCLs/OBs vs. WT and MVNP/Igf1-cKO, with none detectable in OCLs/OBs of Igf1-cKO mice. Mechanistically, IL-6 induced the increased OCL-IGF1 in MVNP mice. These results suggest that high OCL-IGF1 levels increase bone formation and PDLs in PD by enhancing ephrinB2/EphB4 expression in vivo, and that OCL-IGF1 may possibly contribute to normal bone remodeling.
Kazuaki Miyagawa, Yasuhisa Ohata, Jesus Delgado-Calle, Jumpei Teramachi, Hua Zhou, David W. Dempster, Mark A. Subler, Jolene J. Windle, John Chirgwin, G. David Roodman, Noriyoshi Kurihara
Long-term memory depends on the control of activity-dependent neuronal gene expression, which is regulated by epigenetic modifications. The epigenetic modification of histones is orchestrated by the opposing activities of two classes of regulatory complexes: permissive co-activators and silencing co-repressors. Much work has focused on co-activator complexes, but little is known about the co-repressor complexes that suppress the expression of plasticity-related genes. Here, we define a critical role for the co-repressor SIN3A in memory and synaptic plasticity, showing that postnatal neuronal deletion of Sin3a enhances hippocampal long-term potentiation and long-term contextual fear memory. SIN3A regulates the expression of genes encoding proteins in the post-synaptic density. Loss of SIN3A increases expression of the synaptic scaffold Homer1, alters the mGluR1α- and mGluR5-dependence of long-term potentiation, and increases activation of extracellular signal regulated kinase (ERK) in the hippocampus after learning. Our studies define a critical role for co-repressors in modulating neural plasticity and memory consolidation and reveal that Homer1/mGluR signaling pathways may be central molecular mechanisms for memory enhancement.
Morgan S. Bridi, Hannah Schoch, Cédrick Florian, Shane G. Poplawski, Anamika Banerjee, Joshua D. Hawk, Giulia S. Banks, Camille Lejards, Chang-Gyu Hahn, Karl Peter Giese, Robbert Havekes, Nelson Spruston, Ted Abel
A critical component of wound healing is the transition from the inflammatory phase to the proliferation phase to initiate healing and remodeling of the wound. Macrophages are critical for the initiation and resolution of the inflammatory phase during wound repair. In diabetes, macrophages display a sustained inflammatory phenotype in late wound healing characterized by elevated production of inflammatory cytokines such as TNFα. Previous studies have shown that an altered epigenetic program directs diabetic macrophages towards a pro-inflammatory phenotype contributing to a sustained inflammatory phase. Males absent on the first (MOF) is a histone acetyl-transferase (HAT) that has been shown be a co-activator of TNFα-signaling and promote NFκB-mediated gene transcription in prostate cancer cell lines. Based on MOFs role in TNFα/NFκB-mediated gene expression, we hypothesized that MOF influences macrophage-mediated inflammation during wound repair. We used a myeloid-specific Mof knockout (Lyz2Cre Moff/f) and diet-induced obese (DIO) mice, to determine the function of MOF in diabetic wound healing. MOF deficient mice exhibited reduced inflammatory cytokine gene expression. Furthermore, we found that wound macrophages from DIO mice had elevated MOF levels and higher levels of acetylated histone H4K16, MOFs primary substrate of HAT activity, on the promoters of inflammatory genes. We further identified that MOF expression could by stimulated by TNFα and that treatment with Etanercept, an FDA-approved TNFα inhibitor, reduced MOF levels and improved wound healing in DIO mice. This report is the first to define an important role for MOF in regulating macrophage-mediated inflammation in wound repair and identifies TNFα-inhibition as a potential therapy for the treatment of chronic inflammation in diabetic wounds.
Aaron D. denDekker, Frank M. Davis, Amrita D. Joshi, Sonya J. Wolf, Ronald Allen, Jay Lipinski, Brenda Nguyen, Joseph Kirma, Dylan Nycz, Jennifer R. Bermick, Bethany B. Moore, Johann E. Gudjonsson, Steven L. Kunkel, Katherine A. Gallagher
Maintaining cellular proteostasis is essential for oligodendrocyte viability and function; however, its underlying mechanisms remain unexplored. The UPR, comprising three parallel branches IRE1, PERK, and ATF6α, is a major mechanism that maintains cellular proteostasis by facilitating protein folding, attenuating protein translation, and enhancing autophagy and ERAD. Here we reported that impaired UPR in oligodendrocytes via deletion of PERK and ATF6α did not affect developmental myelination, but caused late-onset mature oligodendrocyte dysfunction and death in young adult mice. The detrimental effects of the impaired UPR on mature oligodendrocytes were accompanied by autophagy impairment and intracellular PLP accumulation, and were rescued by PLP deletion. Data indicate that PLP is degraded by autophagy and that intracellular PLP accumulation is cytotoxic to oligodendrocytes. Thus, these findings imply that the UPR is required for maintaining cellular proteostasis and the viability and function of mature oligodendrocytes in adults by regulating autophagy of PLP.
Sarrabeth Stone, Shuangchan Wu, Klaus-Armin Nave, Wensheng Lin
Development of gastric cancer is often preceded by chronic inflammation, but the immune cellular mechanisms underlying this process are unclear. Here we demonstrated that an inflammasome molecule, absent in melanoma 2 (Aim2), was upregulated in gastric cancer patients, and in spasmolytic polypeptide-expressing metaplasia (SPEM) of chronically Helicobacter felis (H. felis)-infected stomachs in mice. However, we found that Aim2 was not necessary for inflammasome function during gastritis. In contrast, Aim2 deficiency led to an increase in gastric CD8+ T cell frequency, which exacerbated metaplasia. These gastric CD8+ T cells from Aim2-/- mice were found to have lost their homing receptor expression (S1pr1 and CD62l), a feature of tissue resident memory T cells (TRM). The process was not mediated by Aim2-dependent regulation of IFN-β, or by dendritic cell-intrinsic Aim2. Rather, Aim2 deficiency contributed to an increased production of Cxcl16 by B cells, which could suppress S1pr1 and CD62l in CD8+ T cells. The study describes a novel function of Aim2 that regulates CD8+ T cell infiltration and retention within chronically inflamed solid organ tissue. This function operates independently of the inflammasome, IFN-β or dendritic cells. We provide evidence that B cells can contribute to this mechanism via Cxcl16.
Mohamad El-Zaatari, Shrinivas Bishu, Min Zhang, Helmut Grasberger, Guoqing Hou, Henry R. Haley, Brock A. Humphries, Li-Jyun Syu, Andrzej Dlugosz, Kathryn E. Luker, Gary Luker, Kathryn A. Eaton, Nobuhiko Kamada, Marilia Cascalho, John Y. Kao
Small primary breast cancers can show surprisingly high potential for metastasis. Clinical decision making for tumor aggressiveness, including molecular profiling, relies primarily on analysis of the cancer cells. Here we show that this is insufficient; that the stromal microenvironment of the primary tumor plays a key role in tumor-cell dissemination and implantation at distant sites. We previously described two cancer-associated fibroblasts (CAFs) that either express (CD146pos) or lack (CD146neg) CD146 (official symbol MCAM; alias MUC18). We now find that when mixed with human breast cancer cells, each fibroblast subtype determines the fate of cancer-cells: CD146neg fibroblasts promote increased metastasis compared to CD146pos fibroblasts. Novel quantitative and qualitative proteomic analyses show that CD146pos CAFs produce an environment rich in basement membrane proteins, while CD146neg CAFs exhibit increases in FN1, LOX, and TNC; all over-expressed in aggressive disease. We also show clinically, that CD146neg CAFs predict for likelihood of lymph node involvement even in small primary tumors (<5 cm). Clearly small tumors enriched for CD146neg CAFs require aggressive treatments.
Heather M. Brechbuhl, Alexander S. Barrett, Etana Kopin, Jaime C. Hagen, Amy L. Han, Austin E. Gillen, Jessica Finlay-Schultz, Diana M. Cittelly, Philip Owens, Kathryn B. Horwitz, Carol A. Sartorius, Kirk C. Hansen, Peter Kabos
Altered bone marrow hematopoiesis and immune suppression is a hallmark of myelodysplastic syndrome (MDS). While the bone marrow microenvironment influences malignant hematopoiesis, the mechanism leading to MDS-associated immune suppression is unknown. We tested whether mesenchymal stromal cells (MSCs) contribute to this process. Here, we developed a model to study cultured MSCs from MDS patients compared to similar aged matched normal controls for regulation of immune function. MSCs from MDS patients (MDS-MSC) and healthy donor MSC (HD-MSC) exhibited a similar in vitro phenotype and neither had a direct effect on NK cell function. However, when MDS and HD-MSCs were cultured with monocytes, only the MDS-MSCs acquired phenotypic and metabolic properties of myeloid-derived suppressor cells (MDSCs), with resulting suppression of NK cell function, along with T cell proliferation. A unique MSC transcriptome was observed in MDS-MSCs compared to HD-MSCs, including increased expression of the reactive oxygen species (ROS) regulator, ENC1. High ENC1 expression in MDS-MSC induced suppressive monocytes with increased INHBA, a gene that encodes for a member of the TGFβ superfamily of proteins. These monocytes also had reduced expression of the TGFβ transcriptional repressor MAB21L2, further adding to their immune suppressive function. Silencing ENC1 or inhibiting ROS production in MDS-MSCs abrogated the suppressive function of MDS-MSC conditioned monocytes. In addition, silencing MAB21L2 in healthy MSC conditioned monocytes mimicked the MDS-MSC suppressive transformation of monocytes. Our data demonstrate that MDS-MSCs are responsible for inducing an immune suppressive microenvironment in MDS through an indirect mechanism involving monocytes.
Dhifaf Sarhan, Jinhua Wang, Upasana Sunil Arvindam, Caroline Hallstrom, Michael R. Verneris, Bartosz Grzywacz, Erica Warlick, Bruce R. Blazar, Jeffrey S. Miller
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