Systemic Clearance of Radiation-Induced Apoptotic Cells by SIGN-R1 and Complement Factors and their Involvement in Autoimmune Diseases

AbstractApoptosis and clearance of dead cells is highly evolutionarily conserved from nematode to humans, which is crucial to the growth and development of multicellular organism. Fail to remove apoptotic cells often lead to homeostasis imbalance, fatal autoimmune diseases, and neurodegenerative diseases. Small ubiquitin-related modifiers (SUMOs) modification is a post-translational modification of ubiquitin proteins mediated by the sentrin-specific proteases (SENPs) family. SUMO modification is widely involved in many cellular biological process, and abnormal SUMO modification is also closely related to many major human diseases. Recent researches have revealed that SUMO modification event occurs during apoptosis and clearance of apoptotic cells, and plays an important role in the regulation of apoptotic signaling pathways. This review summarizes some recent progress in the revelation of regulatory mechanisms of these pathways and provides some potential researching hotpots of the SUMO modification regulation to apoptosis.

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Radiation-induced inflammation and autoimmune diseases

Military Medical Research ◽

10.1186/s40779-018-0156-7 ◽

2018 ◽

Vol 5 (1) ◽

Cited By ~ 30

Author(s):

Rasoul Yahyapour ◽

Peyman Amini ◽

Saeed Rezapour ◽

Mohsen Cheki ◽

Abolhasan Rezaeyan ◽

...

Keyword(s):

Autoimmune Diseases ◽

Radiation Induced

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C4d Deposition after Allogeneic Renal Transplantation in Rats Is Involved in Initial Apoptotic Cell Clearance

Cells ◽

10.3390/cells10123499 ◽

2021 ◽

Vol 10 (12) ◽

pp. 3499

Author(s):

Stefan Reuter ◽

Dominik Kentrup ◽

Alexander Grabner ◽

Gabriele Köhler ◽

Konrad Buscher ◽

...

Keyword(s):

Complement Activation ◽

Apoptotic Cell ◽

Human Kidney ◽

Positive Staining ◽

Apoptotic Cells ◽

Complement Factors ◽

Antibody Mediated Rejection ◽

Apoptotic Cell Clearance ◽

Cell Clearance ◽

Renal Transplantations

In the context of transplantation, complement activation is associated with poor prognosis and outcome. While complement activation in antibody-mediated rejection is well-known, less is known about complement activation in acute T cell-mediated rejection (TCMR). There is increasing evidence that complement contributes to the clearance of apoptotic debris and tissue repair. In this regard, we have analysed published human kidney biopsy transcriptome data clearly showing upregulated expression of complement factors in TCMR. To clarify whether and how the complement system is activated early during acute TCMR, experimental syngeneic and allogeneic renal transplantations were performed. Using an allogeneic rat renal transplant model, we also observed upregulation of complement factors in TCMR in contrast to healthy kidneys and isograft controls. While staining for C4d was positive, staining with a C3d antibody showed no C3d deposition. FACS analysis of blood showed the absence of alloantibodies that could have explained the C4d deposition. Gene expression pathway analysis showed upregulation of pro-apoptotic factors in TCMR, and apoptotic endothelial cells were detected by ultrastructural analysis. Monocytes/macrophages were found to bind to and phagocytise these apoptotic cells. Therefore, we conclude that early C4d deposition in TCMR may be relevant to the clearance of apoptotic cells.

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Contribution of histidine-rich glycoprotein in clearance of immune complexes and apoptotic cells: Implications for ameliorating autoimmune diseases

Autoimmunity ◽

10.1080/08916930701358883 ◽

2007 ◽

Vol 40 (4) ◽

pp. 260-266 ◽

Cited By ~ 5

Author(s):

Nick N. Gorgani ◽

Argyrios N. Theofilopoulos

Keyword(s):

Autoimmune Diseases ◽

Immune Complexes ◽

Apoptotic Cells

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DNA damage responses in relation to late effects following radiotherapy for early breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.10626 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 10626-10626

Author(s):

Melvin Chua

Keyword(s):

Breast Cancer ◽

Small Molecule ◽

Ex Vivo ◽

Apoptotic Cells ◽

Breast Cancer Patients ◽

End Joining ◽

Breast Radiotherapy ◽

Dsb Repair ◽

Radiation Induced ◽

Induction Of Apoptosis

10626 Background: In this study, we assessed if induction of apoptosis in G0 blood lymphocytes following ex vivo irradiation correlated with clinical radiosensitivity and DNA double-strand (DSB) repair in breast radiotherapy (RT) patients. Using small molecule inhibitors, we examined the relationship between DSB repair and radiation-induced apoptosis. Methods: Breast cancer patients with minimal (controls) or marked late RT changes (cases) were selected. DSB were quantified by γH2AX/53BP1 immunostaining 0.5 and 24 h after exposure of lymphocytes to 0.5 and 4 Gy, respectively. Induction of apoptosis was assessed 48 h after 8 Gy using a fluorochrome inhibitor of caspases (FLICA) assay. Apoptotic cells were defined by small cell size and positive FLICA signal, measured using flow cytometry. Small molecule DNA-PK (Nu7441) and ATM (Ku55933) inhibitors were used at concentrations of 1 µM and 10 µM, respectively. Results: Despite similar foci induction at 0.5 h, residual foci levels 24 h after 4 Gy differed significantly between cases and controls (Foci per cell = 12.7 in cases, n = 8 vs 10.3 in controls, n = 8, p = 0.002). In contrast to residual foci levels, comparable levels of apoptosis were observed between cases and controls 48 h after 8 Gy. Mean proportion of apoptotic cells was 37.2% in cases and 34.7% in controls (p = 0.413). Residual foci levels were not correlated with levels of apoptosis in lymphocytes of the same patients (R = -0.059, p = 0.785). To determine if apoptosis is modulated by DSB repair, apoptosis measurements were repeated in lymphocytes treated with Nu7441 to inhibit non-homologous end-joining. We observed that Nu7441-treated cells had higher levels of residual foci and apoptosis compared to mock-treated cells, 48 h after 1 Gy. This effect was wholly dependent on an active ATM function as cells treated simultaneously with Nu7441 and Ku55933 had extremely low levels of apoptosis, comparable to levels observed in cells treated with Ku55933 alone. Conclusions: Higher levels of residual DSB observed among radiosensitive patients suggest a role for DSB repair in the pathogenesis of late radiation-induced effects. Induction of apoptosis appears to be dependent on DSB end-joining following exposure to ionising radiation.

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Radiation-induced gastric epithelial apoptosis occurs in the proliferative zone and is regulated by p53, bak, bax, and bcl-2

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00391.2006 ◽

2007 ◽

Vol 292 (2) ◽

pp. G620-G627 ◽

Cited By ~ 18

Author(s):

S. M. C. Przemeck ◽

C. A. Duckworth ◽

D. M. Pritchard

Keyword(s):

Small Intestine ◽

Epithelial Cells ◽

Gastric Epithelium ◽

Apoptotic Cells ◽

Gastric Epithelial Cells ◽

Wild Type ◽

Γ Radiation ◽

Proliferative Zone ◽

Radiation Induced ◽

Hematoxylin And Eosin

Unlike the small intestine and colon where γ-radiation-induced apoptosis has previously been well characterized, the response of murine gastric epithelium to γ-radiation has not been investigated in detail. Apoptosis was therefore assessed on a cell positional basis in gastric antral and corpus glands from adult male mice following γ-radiation. Maximum numbers of apoptotic cells were observed in both antrum and corpus at 48 h and at radiation doses greater than 12 Gy. However, the number of apoptotic cells observed in the gastric epithelium was much lower than observed in the small intestine or colon after similar doses of radiation. Hematoxylin and eosin, caspase 3 immunohistochemistry, and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling detected similar numbers and cell positional distributions of apoptotic cells, hence hematoxylin and eosin was used for subsequent studies. The highest numbers of apoptotic cells were observed at cell positions 5–6 in the antrum and cell positions 15–18 in the corpus. These distributions coincided with the distributions of PCNA-labeled proliferating cells, but not with the distributions of H+-K+-ATPase-labeled parietal cells or TFF2-labeled mucous neck cells. Decreased numbers of apoptotic gastric epithelial cells were observed in p53-null, bak-null, and bax-null mice compared with wild-type counterparts 6 and 48 h after 12 Gy γ-radiation. Significantly increased numbers of apoptotic gastric epithelial cells were observed in bcl-2-null mice compared with wild-type littermates 6 h after 12 Gy γ-radiation. Radiation therefore induces apoptosis in the proliferative zone of mouse gastric epithelium. This response is regulated by the expression of p53, bak, bax, and bcl-2.

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Retardation of removal of radiation-induced apoptotic cells in developing neural tubes in macrophage galactose-type C-type lectin-1-deficient mouse embryos

Glycobiology ◽

10.1093/glycob/cwj028 ◽

2005 ◽

Vol 15 (12) ◽

pp. 1368-1375 ◽

Cited By ~ 26

Author(s):

Hiroshi Yuita ◽

Makoto Tsuiji ◽

Yuki Tajika ◽

Yoshihisa Matsumoto ◽

Kazuya Hirano ◽

...

Keyword(s):

Mouse Embryos ◽

Apoptotic Cells ◽

Deficient Mouse ◽

Neural Tubes ◽

Radiation Induced ◽

Type C

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Interactions of Apoptotic Cells with Macrophages in Radiation-Induced Bystander Signaling

Radiation Research ◽

10.1667/rr2969.1 ◽

2013 ◽

Vol 179 (2) ◽

pp. 135-145 ◽

Cited By ~ 17

Author(s):

Shubhra Rastogi ◽

Michael Boylan ◽

Eric G. Wright ◽

Philip J. Coates

Keyword(s):

Apoptotic Cells ◽

Radiation Induced

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Defective Efferocytosis in a Murine Model of Sjögren’s Syndrome Is Mediated by Dysfunctional Mer Tyrosine Kinase Receptor

International Journal of Molecular Sciences ◽

10.3390/ijms22189711 ◽

2021 ◽

Vol 22 (18) ◽

pp. 9711

Author(s):

Richard Witas ◽

Astrid Rasmussen ◽

Robert H. Scofield ◽

Lida Radfar ◽

Donald U. Stone ◽

...

Keyword(s):

Autoimmune Disease ◽

Autoimmune Diseases ◽

Sjögren’S Syndrome ◽

Sjögren's Syndrome ◽

Sjogren’S Syndrome ◽

Protective Role ◽

Sjogren's Syndrome ◽

Tyrosine Kinase Receptor ◽

Apoptotic Cells ◽

Sjögren‘S Syndrome

Sjögren’s syndrome (SjS) is a chronic autoimmune disease primarily involving the exocrine glands in which the involvement of the innate immune system is largely uncharacterized. Mer signaling has been found to be protective in several autoimmune diseases but remains unstudied in SjS. Here, we investigated the role of Mer signaling in SjS. Mer knockout (MerKO) mice were examined for SjS disease criteria. SjS-susceptible (SjSS) C57BL/6.NOD-Aec1Aec2 mice were assessed for defective Mer signaling outcomes, soluble Mer (sMer) levels, A disintegrin and metalloprotease 17 (ADAM17) activity, and Rac1 activation. In addition, SjS patient plasma samples were evaluated for sMer levels via ELISA, and sMer levels were correlated to disease manifestations. MerKO mice developed submandibular gland (SMG) lymphocytic infiltrates, SMG apoptotic cells, anti-nuclear autoantibodies (ANA), and reduced saliva flow. Mer signaling outcomes were observed to be diminished in SjSS mice, as evidenced by reduced Rac1 activation in SjSS mice macrophages in response to apoptotic cells and impaired efferocytosis. Increased sMer was also detected in SjSS mouse sera, coinciding with higher ADAM17 activity, the enzyme responsible for cleavage and inactivation of Mer. sMer levels were elevated in patient plasma and positively correlated with focus scores, ocular staining scores, rheumatoid factors, and anti-Ro60 levels. Our data indicate that Mer plays a protective role in SjS, similar to other autoimmune diseases. Furthermore, we suggest a series of events where enhanced ADAM17 activity increases Mer inactivation and depresses Mer signaling, thus removing protection against the loss of self-tolerance and the onset of autoimmune disease in SjSS mice.

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