A makrofágok által termelt retinoid szerepe a szöveti transzglutamináz keletkezésében és a dexametazon fagocitózis fokozó hatásában

Rapid and effective clearance of apoptotic cells by phagocytes is essential for maintaining tissue homeostasis. Transglutaminase 2 (TG2) expressed both in apoptotic and engulfing cells ensures fast recognition and removal of apoptotic cells.T cells differentiate in the thymus, and during their selection processes 95% of the newly produced cells die and clear. For the in vivo induction of TG2 factors found in the thymic environment are required. We found that some of such factors are vitamin A derivatives, which are produced in macrophages engulfing apoptotic cells in a lipid sensing receptor-dependent manner. Retinoid produced by engulfing macrophages contribute to the TG2 expression in apoptotic thymocytes in vivo. We found that retinoids are also produced in macrophages exposed to a glucocorticoid hormone dexamethasone, which enhances the phagocytic capacity of macrophages. Retinoids were required for glucocorticoid-induced enhancement of long-term phagocytosis by promoting efficient upregulation of lipid sensing receptors, which can promote the rapid and early removal of dying cells.Az apoptotikus sejtek gyors és hatékony eltávolítása a fagociták által nélkülözhetetlen a szöveti homeosztázis fenntartásához. Mind az apoptotikus, mind a fagocitáló sejtek kifejeznek 2-es típusú transzglutaminázt (TG2) amely részt vesz az elhaló sejtek gyors felismerésében és eltávolításában. A tímuszban, az újonnan létrehozott T sejtek több mint 95%-a elhal a szelekciós folyamatok során, majd eltakarítódik a fagociták által. A TG2 in vivo indukciójához olyan faktorok szükségesek, melyek a tímikus környezetben vannak jelen. Azt találtuk, hogy ezen faktorok közt szerepelnek az A vitamin származékai, melyeket lipid érzékelő magreceptorok közvetítésével az apoptotikus sejteket fagocitáló makrofágok termelnek. A fagocitáló makrofágok által termelt retinoid hozzájárul az apoptotikus timociták in vivo TG2 expressziójához. Továbbá, a makrofágok retinoidot termelnek egy glükokortikoid hormon, a dexametazon hatására is, amelyről ismert, hogy fokozza a makrofágok fagocitáló képességét. A retinoidok lipid érzékelő receptorokat aktiválnak, melyek elősegítik az apoptotikus sejtek hatékony eltávolítását, ezáltal hozzájárulnak a glükokortikoid-indukálta hosszútávú fagocitózishoz

Anti-inflammatory Mechanisms Triggered by Apoptotic Cells during Their Clearance

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Anti-inflammatory Mechanisms Triggered by Apoptotic Cells during Their Clearance

In the human body, billions of cells die by apoptosis every day. The subsequent clearance of apoptotic cells by phagocytosis is normally efficient enough to prevent secondary necrosis and the consequent release of cell contents that would induce inflammation and trigger autoimmunity. In addition, apoptotic cells generally induce an anti-inflammatory response, thus removal of apoptotic cells is usually immunologically silent. Since the first discovery that uptake of apoptotic cells leads to transforming growth factor (TGF)-β and interleukin (IL)-10 release by engulfing macrophages, numerous anti-inflammatory mechanisms triggered by apoptotic cells have been discovered, including release of anti-inflammatory molecules from the apoptotic cells, triggering immediate anti-inflammatory signaling pathways by apoptotic cell surface molecules via phagocyte receptors, activating phagocyte nuclear receptors following uptake and inducing the production of anti-inflammatory soluble mediators by phagocytes that may act via paracrine or autocrine mechanisms to amplify and preserve the anti-inflammatory state. Here, we summarize our present knowledge about how these anti-inflammatory mechanisms operate during the clearance of apoptotic cells

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

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