18 research outputs found

    Impact of estrogen on IgG glycosylation and serum protein glycosylation in a murine model of healthy postmenopause

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    IntroductionThe glycosylation of immunoglobulin (Ig) G regulates IgG interaction capability with Fc gamma receptors found in all immune cells. In pathogenic conditions, estrogen can impact IgG levels and glycosylation. Following menopause, when estrogen levels decline affecting the immune system and potentially leading to a heightened susceptibility of immune activation.PurposeIn this study, we aim to determine if estrogen levels can regulate IgG glycosylation in postmenopausal healthy situations.MethodsMice were ovariectomized to simulate an estrogen-deficient postmenopausal status and then treated with 17-beta-estradiol (E2) at different doses and different administration strategies.ResultsUsing a highly sensitive liquid chromatography-tandem mass spectrometry (MS/MS) glycoproteomic method, we demonstrated that E2 treatment increased the degree of glycosylation on IgG-Fc with both galactosylation and sialylation in the position required for interaction with Fc gamma receptors. We also observed that only long-term estrogen deficiency reduces IgG levels and that estrogen status had no impact on total IgG sialylation on both Fab and Fc domains or general glycoprotein sialylation evaluated by ELISA. Furthermore, E2 status did not affect the total sialic acid content of total cells in lymphoid organs and neither B cells nor plasma cells.ConclusionThe study concluded that E2 treatment does not affect total serum glycoprotein sialylation but alters IgG glycosylation, including IgG sialylation, implying that estrogen functions as an intrinsic modulator of IgG sialylation and could thereby be one pathway by which estrogen modulates immunity

    A poli(ADP-ribóz) polimeráz-2 enzim szerepe a DNS hibajavításban és más élettani folyamatokban

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    A poli(ADP-ribóz) polimeráz-2 enzim szerepét mutatja be a DNS hibajavításban és más élettani folyamatokbanBscBiológiag

    Investigation of the association between chronic inflammation and impaired efferocytosis in two mice models

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    Apoptotikus mechanizmusok eredményeképpen naponta több milliárd sejt hal el az emberi szervezetben. Ezen elhalt sejtek eltakarítása kulcsfontosságú a szöveti homeosztázis fenntartásában, nem megfelelő működése viszont több patológiás folyamattal, krónikus gyulladásos betegséggel hozható összefüggésbe (pl. autoimmunitás, 2-es típusú diabétesz és az elhízás). Az elmúlt évtizedekben az elhalt sejtek eltakarításáról kialakult látásmódunk nagyban kiszélesedett. Jelentős számú közlemény született, amely az efferocitózis összetett jelátviteli folyamatait tárta fel. Ennek ellenére számos eleme még mindig ismeretlen maradt. Disszertációmban az elhalt sejtek eltakarításának zavarát és a zavar patológiás következményeit vizsgáltam két knock out (TG2 hiányos, illetve RetSat hiányos) egértörzsben.As a result of apoptotic mechanisms, billions of cells die in the human body every day. Clearance of these dead cells is key to maintaining tissue homeostasis, but its inadequate function may be associated with several pathological processes, chronic inflammatory disease (e.g., autoimmunity, type 2 diabetes, and obesity). In recent decades, our vision of clearing dead cells has widened greatly. A significant number of paper have been published that have revealed complex signaling processes in efferocytosis. Nevertheless, many of its elements remained unknown. In my dissertation, I studyed the defect of dead cell clearance and the pathological consequences in two knock out (TG2 deficient and RetSat deficient) mouse strains

    Intracelluláris cAMP szintet növelő vegyületek hatásának vizsgálata a transzglutamináz 2 enzim kifejeződésére egér tímusz sejtekben

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    A szöveti transzglutamináz (TG2) egy multifunkcionális enzim, mely számos biológiai folyamatban, többek között az apoptózis során is meghatározó szereppel bír. Munkacsoportunk korábbi eredményei azt mutatják, hogy a timociták in vivo apoptózisa során a TG2 indukálódik, in vitro környezetben azonban ez a jelenség nem mutatható ki. Ez arra utal, hogy a TG2 indukciója olyan faktorok közreműködését igényli, melyek csak a szöveti környezetben vannak jelen. Eddigi eredményeink alapján ilyen faktor lehet az apoptotikus sejteket eltakarító makrofágok által termelt TGF-β és a retinoidok. Mivel az adenozin és a PGE2 (melyeket szintén a makrofágok termelnek az apoptotikus sejtek bekebelezése során) az adenilát cikláz útvonalat aktiválja, úgy döntöttünk, hogy vizsgálni fogjuk az adenilát cikláz útvonal TG2 indukciójában betöltött lehetséges szerepét. Előzetes eredményeink azt mutatják, hogy az adenilát-cikláz/PKA útvonal – ezáltal minden olyan vegyület, mely a cAMP szintet növeli – fokozza a TG2 génkifejeződését. Ezek alapján úgy gondoljuk, hogy a makrofágok által termelt és az adenilált-cikláz/PKA jelátvitelt befolyásoló vegyületek önmagukban, illetve a retinoidokkal és a TGF-β-val "együttműködve" hozzájárulhatnak a TG2 génszintű indukciójához a timociták in vivo apoptózis programja során.MSc/MAmolekuláris biológiamagyarBiokémia-genomikanappaliP.J

    Palmitate Inhibits Mouse Macrophage Efferocytosis by Activating an mTORC1-Regulated Rho Kinase 1 Pathway: Therapeutic Implications for the Treatment of Obesity

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    Every day, billions of our cells die and get cleared without inducing inflammation. When, clearance is improper, uncleared cells undergo secondary necrosis and trigger inflammation. In addition, proper efferocytosis would be required for inducing resolution of inflammation, thus clearance deficiencies in the long term lead to development of various chronic inflammatory diseases. Increasing evidence indicates that obesity, itself being a low-grade inflammatory disease, predisposes to a variety of other chronic inflammatory diseases. Previous studies indicated that this later might be partially related to an impaired efferocytosis induced by increased uptake of circulating saturated fatty acids by macrophages in obese people. Here, we show that palmitate inhibits efferocytosis by bone marrow-derived macrophages in a dose-dependent manner. Palmitate triggers autophagy but also activates an energy-sensing mTORC1/ROCK1 signaling pathway, which interferes with the autophagosome–lysosome fusion, resulting in accumulation of the cellular membranes in autophagosomes. We propose that lack of sufficient plasma membrane supply attenuates efferocytosis of palmitate-exposed macrophages. AMP-activated protein kinase activators lead to mTORC1 inhibition and, consequently, released the palmitate-induced efferocytosis block in macrophages. Thus, they might be useful in the treatment of obesity not only by affecting metabolism thought so far. ROCK1 inhibitors could also be considered

    Loss of transglutaminase 2 sensitizes for diet-induced obesity-related inflammation and insulin resistance due to enhanced macrophage c-Src signaling

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    Transglutaminase 2 (TG2) is a multifunctional protein that promotes clearance of apoptotic cells (efferocytosis) acting as integrin β3 coreceptor. Accumulating evidence indicates that defective efferocytosis contributes to the development of chronic inflammatory diseases. Obesity is characterized by the accumulation of dead adipocytes and inflammatory macrophages in the adipose tissue leading to obesity-related metabolic syndrome. Here, we report that loss of TG2 from bone marrow-derived cells sensitizes for high fat diet (HFD)-induced pathologies. We find that metabolically activated TG2 null macrophages express more phospho-Src and integrin β3, unexpectedly clear dying adipocytes more efficiently via lysosomal exocytosis, but produce more pro-inflammatory cytokines than the wild type ones. Anti-inflammatory treatment with an LXR agonist reverts the HFD-induced phenotype in mice lacking TG2 in bone marrow-derived cells with less hepatic steatosis than in wild type mice proving enhanced lipid clearance. Thus it is interesting to speculate whether LXR agonist treatment together with enhancing lysosomal exocytosis could be a beneficial therapeutic strategy in obesity.</p

    Loss of Transglutaminase 2 Sensitizes for DietInduced Obesity-Related Inflammation and Insulin Resistance due to Enhanced Macrophage c-Src Signaling

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    Transglutaminase 2 (TG2) is a multifunctional protein that promotes clearance of apoptotic cells (efferocytosis) acting as integrin β3 coreceptor. Accumulating evidence indicates that defective efferocytosis contributes to the development of chronic inflammatory diseases. Obesity is characterized by the accumulation of dead adipocytes and inflammatory macrophages in the adipose tissue leading to obesity-related metabolic syndrome. Here, we report that loss of TG2 from bone marrow-derived cells sensitizes for high fat diet (HFD)-induced pathologies. We find that metabolically activated TG2 null macrophages express more phospho-Src and integrin β3, unexpectedly clear dying adipocytes more efficiently via lysosomal exocytosis, but produce more pro-inflammatory cytokines than the wild type ones. Anti-inflammatory treatment with an LXR agonist reverts the HFD-induced phenotype in mice lacking TG2 in bone marrow-derived cells with less hepatic steatosis than in wild type mice proving enhanced lipid clearance. Thus it is interesting to speculate whether LXR agonist treatment together with enhancing lysosomal exocytosis could be a beneficial therapeutic strategy in obesity.</p
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