Externalization of Phosphatidylserine May Not Be an Early Signal of Apoptosis in Neuronal Cells, but Only the Phosphatidylserine‐Displaying Apoptotic Cells Are Phagocytosed by Microglia

Adayev, Tatyana; Estephan, Rima; Meserole, Susan; Mazza, Bethanne; Yurkow, Edward J.; Banerjee, Probal

doi:10.1046/j.1471-4159.1998.71051854.x

Cited by 78 publications

(50 citation statements)

References 17 publications

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“…5), expression of anti-apoptotic genes was upregulated by Hopx, whereas expression of pro-apoptotic genes was down-regulated. Among the anti-apoptotic genes positively regulated by Hopx and consequently down-regulated in Hopx À/À Th1 cells was Atp8a1 (APLT) encoding for an aminophospholipidtransporting enzyme important for maintaining phospholipid asymmetry and thus integrity of the cell membrane [36][37][38][39][40]. Expression of Nrn1 (neuritin 1) was also reduced in Hopx-deficient Th1 cells.…”

Section: Hopx Regulates Expression Of Apoptotic Genes and Lowers Sensmentioning

confidence: 99%

Persistence of effector memory Th1 cells is regulated by Hopx

et al. 2010

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Th1 cells are prominent in inflamed tissue, survive conventional immunosuppression, and are believed to play a pivotal role in driving chronic inflammation. Here, we identify homeobox only protein (Hopx) as a critical and selective regulator of the survival of Th1 effector/memory cells, both in vitro and in vivo. Expression of Hopx is induced by T-bet and increases upon repeated antigenic restimulation of Th1 cells. Accordingly, the expression of Hopx is low in peripheral, naïve Th cells, but highly up-regulated in terminally differentiated effector/memory Th1 cells of healthy human donors. In murine Th1 cells, Hopx regulates the expression of genes involved in regulation of apoptosis and survival and makes them refractory to Fas-induced apoptosis. In vivo, adoptively transferred Hopxdeficient murine Th1 cells do not persist. Consequently, they cannot induce chronic inflammation in murine models of transfer-induced colitis and arthritis, demonstrating a key role of Hopx for Th1-mediated immunopathology.Key words: Cell survival . CD4 T cells . Inflammation . Memory cells Supporting Information available onlineIntroduction T-helper type 1 (Th1) cells mediate immune responses to intracellular pathogens, such as viruses, and produce IFN-g as their signature cytokine [1]. IFN-g, together with IL-12 and the transcription factors STAT1, STAT4 and T-bet, promotes the development of Th1 cells [2][3]. T-bet (T-box 21) is considered to act as the master transcription factor critically regulating Th1 lineage commitment [3][4][5]. Apart from their protective role in clearing infections, Th1 cells can initiate and maintain chronic inflammatory diseases, e.g. inflammatory bowel disease [6][7][8][9], uveitis [10], EAE [11,12] and arthritis [13]. In vitro, Th1 cells are much more sensitive to Fas-mediated apoptosis than Th2 or Th17 cells [14][15][16][17][18][19][20]. In vivo, however, effector/memory Th1 cells are abundant in chronically inflamed tissue [21][22][23] and persist over long time periods [24][25][26], suggesting that their sensitivity to Eur. J. Immunol. 2010. 40: 2993-3006 DOI 10.1002 HIGHLIGHTS 2993 FrontlineFas-mediated apoptosis is strictly regulated. Here, we demonstrate that among CD4 1 T cells, the transcriptional cofactor homeobox only protein (Hopx) is expressed by repeatedly restimulated Th1 cells, but not by Th2, Th17 or regulatory T cells. Hopx regulates Fas-mediated apoptosis of effector/memory Th1 cells and is critically required for their persistence in vivo.In vertebrates, Hopx expression originally was detected in the myocardium [27,28]. There, expression of Hopx is induced by the cardiac transcription factor Nkx2-5. Hopx-deficient mice show a complex, incompletely penetrant phenotype. Some Hopxdeficient embryos have a poorly developed myocardium with reduced cell numbers, others show normal, and still others show increased numbers of cardiomyocytes after birth [27,28]. Hopx does not bind to homeobox consensus binding sequences, and it has been postulated that Hopx acts indirectly, partnering with ...

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Section: Hopx Regulates Expression Of Apoptotic Genes and Lowers Sensmentioning

confidence: 99%

Persistence of effector memory Th1 cells is regulated by Hopx

et al. 2010

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“…5,6 The efficient removal of dying cells is important in homeostasis, since it limits accumulation of cellular debris that could be potentially immunogenic or toxic. [7][8][9] However, the role of apoptosis in removing large numbers of cells in inflammation and during the resolution phase remains uncertain. Although human neutrophils undergo apoptosis spontaneously when cultured in vitro, the role of apoptosis in regulating neutrophil turnover in vivo is unclear.…”

Section: Introductionmentioning

confidence: 99%

Human galectin-1, -2, and -4 induce surface exposure of phosphatidylserine in activated human neutrophils but not in activated T cells

Stowell

Karmakar

Stowell

et al. 2006

Blood

156

150

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IntroductionThe physiologic causes of leukocyte turnover in homeostasis and during disease conditions are not well understood. It is believed that leukocytes are partly eliminated by programmed cell death or apoptosis 1-4 through phagocytosis by macrophages, dendritic cells, or neighboring cells. 5,6 The efficient removal of dying cells is important in homeostasis, since it limits accumulation of cellular debris that could be potentially immunogenic or toxic. [7][8][9] However, the role of apoptosis in removing large numbers of cells in inflammation and during the resolution phase remains uncertain. Although human neutrophils undergo apoptosis spontaneously when cultured in vitro, the role of apoptosis in regulating neutrophil turnover in vivo is unclear. 6,[10][11][12] Apoptosis impairs cellular functions and might impair proinflammatory functions of neutrophils. 13 However, excessive neutrophil influx with loss of membrane integrity during late apoptotic events could contribute to neutrophil-mediated injury of surrounding viable parenchymal tissue. 14 Exuberant apoptosis may therefore be proinflammatory instead of anti-inflammatory, [15][16][17] presumably due to the release of cellular contents prior to phagocytic removal. In this regard, nonapoptotic neutrophils can be cleared by phagocytosis in vivo. 18 Finally, factors known to induce or to block apoptosis, such as ligation of Fas/FasL and expression of bcl-2, respectively, do not alter neutrophil turnover in mouse models. [19][20][21][22] These studies suggest that unidentified factors may be involved in the phagocytic removal of viable, rather than apoptotic, cells.The removal of apoptotic cells occurs partly through tethering to phagocytic cells due to receptor-ligand interactions involving recognition of phosphatidylserine (PS) exposed on the surfaces of apoptotic cells. 23 Surface PS is recognized by a defined PS-receptor in macrophages 24 and by other receptors. [25][26][27] However, PS exposure in leukocytes can occur independently of apoptosis. 28,29 Thus, factors that induce PS exposure independently of apoptosis may be involved in leukocyte turnover.Recently, we showed that galectin-1 (Gal-1), a prototypical homodimeric member (subunit ϳ 14.5 kDa) of the galectin family, which has immunomodulatory functions, [30][31][32][33][34] can induce PS exposure in activated, but not resting, neutrophils, independently of cell death, while concomitantly rendering them sensitive to phagocytic recognition and removal. 35 We also found that the signaling pathway of Gal-1 in activated neutrophils is unique and involves elevations of cytosolic Ca 2ϩ and mobilization of PS through the actions of Src kinases and phospholipase C␥. 36 However, there are many conflicting reports about galectin's effects on leukocytes. Several groups have reported that Gal-1 induces apoptosis along with PS exposure in vitro of activated T lymphocytes and several T-leukemic cell lines. [37][38][39] It has also been reported that human Gal-2, a protein structurally related to Gal-1, ind...

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“…As mentioned earlier, phosphatidylserine (PS) is normally sequestered to the inner leaflet of the plasma membrane due to the action of a flippase [1,[7][8][9], which is chemically named as aminophospholipid translocase (APTL) or aminophospholipid flippase [1][2][3]. During programmed cell death, the loss of the aminophospholipid asymmetry, which is typical for healthy cells, leads to the appearance of PS on the cell surface.…”

Section: Introductionmentioning

confidence: 99%

“…During programmed cell death, the loss of the aminophospholipid asymmetry, which is typical for healthy cells, leads to the appearance of PS on the cell surface. This externalization of PS serves as a signal for phagocytosis of apoptotic lymphocytes, neutrophils, and neuronal cells by macrophages and microglia [6][7][8]10]. Our earlier studies to analyze the mechanism of this PS externalization established that the enzymatic activity of APTL is inhibited during apoptosis, which could be the prime reason for the observed PS externalization [10].…”

Section: Introductionmentioning

confidence: 99%

Isolation, sequencing, and functional analysis of the TATA-less murine ATPase II promoter and structural analysis of the ATPase II gene

Sobocki

Jayman

Sobocka

et al. 2007

Biochimica et Biophysica Acta (BBA) - Gene Structure and Expres

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The P-type Mg 2+ -ATPase, termed ATPase II (Atp8a1), is a putative aminophospholipid transporting enzyme, which helps to maintain phospholipid asymmetry in cell membranes. In this project we have elucidated the organization of the mouse ATPase II gene and identified its promoter. Located within chromosome 5, this gene spans about 224 kb and consists of 38 exons, three of which are alternatively spliced (exons 7, 8 and 16), giving rise to two transcript variants. Translation of these transcripts results in two ATPase II isoforms (1 and 2) composed of 1164 and 1149 amino acids, respectively. Using RNA ligase-mediated rapid amplification of cDNA ends (RLM-RACE) we identified multiple transcription start sites (TSS) in messages obtained from heart, lung, liver, and spleen. The mouse ATPase II promoter is TATA-less and lacks a consensus initiator sequence. Luciferase reporter analysis of full and core promoters revealed strong activity and little cell type specificity, possibly because more flanking, regulatory sequences are required to cause such tissue specificity. In the neuronal HN2, N18, SN48 cells and the NIH3T3 fibroblast cells, but not in the B16F10 melanoma cells, the core promoter (-318/+193 with respect to the most common TSS) displayed significantly higher activity than the full promoter (-1026/+193). Serial 5′ deletion of the core promoter revealed significant cell type-specific activity of the fragments, suggesting differential expression and use of transcription factors in the five cell lines tested. Additionally distribution of the TSS was organ specific. Such observations suggest tissue-specific differences in transcription initiation complex assembly and regulation of ATPase II gene expression. Information presented here form the groundwork for further studies on the expression of this gene in apoptotic cells.

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Externalization of Phosphatidylserine May Not Be an Early Signal of Apoptosis in Neuronal Cells, but Only the Phosphatidylserine‐Displaying Apoptotic Cells Are Phagocytosed by Microglia

Cited by 78 publications

References 17 publications

Persistence of effector memory Th1 cells is regulated by Hopx

Persistence of effector memory Th1 cells is regulated by Hopx

Human galectin-1, -2, and -4 induce surface exposure of phosphatidylserine in activated human neutrophils but not in activated T cells

Isolation, sequencing, and functional analysis of the TATA-less murine ATPase II promoter and structural analysis of the ATPase II gene

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