Of macrophages and red blood cells; a complex love story

Back, Djuna Z. de; Kostova, Elena; Kraaij, Marian van; Berg, Timo K. van den; Bruggen, Robin van

doi:10.3389/fphys.2014.00009

Cited by 245 publications

(248 citation statements)

References 105 publications

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“…Eryptotic and senescent erythrocytes share several key features: an increase in exposed phosphatidylserine (PS), increased membrane rigidity, more spherical shape, and decreased size (17,18). The eryptotic/senescent phenotype has been correlated with increased clearance of erythrocytes, primarily through erythrophagocytosis (19)(20)(21). However, mechanical clearance in the spleen (22) and sinusoidal clearance, independent of Kupffer cells, in the liver (16) for a lack of erythrophagocytosis in macrophage-depleted animals.…”

Section: Treatment Of P Falciparum-infected Nod-scid Il2rγmentioning

confidence: 99%

(+)-SJ733, a clinical candidate for malaria that acts through ATP4 to induce rapid host-mediated clearance of Plasmodium

Jiménez-Dı́az

Ebert

Salinas

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

217

291

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Significance Useful antimalarial drugs must be rapidly acting, highly efficacious, and have low potential for developing resistance. (+)-SJ733 targets a Plasmodium cation-transporting ATPase, ATP4. (+)-SJ733 cleared parasites in vivo as quickly as artesunate by specifically inducing eryptosis/senescence in infected, treated erythrocytes. Although in vitro selection of pfatp4 mutants with (+)-SJ733 proceeded with moderate frequency, during in vivo selection of pbatp4 mutants, resistance emerged slowly and produced marginally resistant mutants with poor fitness. In addition, (+)-SJ733 met all other criteria for a clinical candidate, including high oral bioavailability, a high safety margin, and transmission blocking activity. These results demonstrate that targeting ATP4 has great potential to deliver useful drugs for malaria eradication.

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Section: Treatment Of P Falciparum-infected Nod-scid Il2rγmentioning

confidence: 99%

(+)-SJ733, a clinical candidate for malaria that acts through ATP4 to induce rapid host-mediated clearance of Plasmodium

Jiménez-Dı́az

Ebert

Salinas

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

217

291

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“…In this regard, our results on the ability of NK cells to produce IFN-g upon contacting drug-induced senescent MM cells suggest that NK cell-mediated immune clearance of senescent cells not only involves direct killing, but also IFN-g-induced activation of macrophages, which importantly eliminate a number of different types of senescent cells (61,62).…”

Section: Discussionmentioning

confidence: 92%

Reactive Oxygen Species– and DNA Damage Response–Dependent NK Cell Activating Ligand Upregulation Occurs at Transcriptional Levels and Requires the Transcriptional Factor E2F1

Soriani

Iannitto

Ricci

et al. 2014

The Journal of Immunology

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Increasing evidence indicates that cancer cell stress induced by chemotherapeutic agents promote antitumor immune responses and contribute to their full clinical efficacy. In this article, we identify the signaling events underlying chemotherapy-induced NKG2D and DNAM-1 ligand expression on multiple myeloma (MM) cells. Our findings indicate that sublethal doses of doxorubicin and melphalan initiate a DNA damage response (DDR) controlling ligand upregulation on MM cell lines and patient-derived malignant plasma cells in Chk1/2-dependent and p53-independent manner. Drug-induced MICA and PVR gene expression are transcriptionally regulated and involve DDR-dependent E2F1 transcription factor activity. We also describe the involvement of changes in the redox state in the control of DDR-dependent upregulation of ligand surface expression and gene transcriptional activity by using the antioxidant agent N-acetyl-l-cysteine. Finally, in accordance with much evidence indicating that DDR and oxidative stress are major determinants of cellular senescence, we found that redox-dependent DDR activation upon chemotherapeutic treatment is critical for MM cell entry in premature senescence and is required for the preferential ligand upregulation on senescent cells, which are preferentially killed by NK cells and trigger potent IFN-γ production. We propose immunogenic senescence as a mechanism that promotes the clearance of drug-treated tumor cells by innate effector lymphocytes, including NK cells.

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“…1 Erythrophagocytosis is important for RBC turnover and is believed to be executed by the red pulp macrophages or Kupffer cells in the liver. 1,2 The mechanism of RBC clearance under homeostatic conditions is not fully understood and there is no consensus about the removal signals on the RBCs that trigger phagocytosis by macrophages. 2 In general, it is accepted that an accumulation of "eat me" signals triggers phagocytosis of the RBC at the end of its lifespan.…”

Section: Introductionmentioning

confidence: 99%

Human and murine splenic neutrophils are potent phagocytes of IgG-opsonized red blood cells

et al. 2017

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Key Points• In steady state, where no IgGs against RBCs are present, macrophages are the primary phagocytes of RBCs.• In conditions where RBCs are IgGopsonized, neutrophils can have a major effect on RBC clearance.Red blood cell (RBC) clearance is known to occur primarily in the spleen, and is presumed to be executed by red pulp macrophages. Erythrophagocytosis in the spleen takes place as part of the homeostatic turnover of RBCs to remove old RBCs. It can be strongly promoted by immunoglobulin G (IgG) opsonization of RBCs, a condition that can occur as a consequence of autoantibody or alloantibody formation. The purpose of our study was to investigate which phagocytes are involved in IgG-mediated RBC clearance in the human spleen. We developed a highly specific in vitro assay to monitor RBC phagocytosis in total human splenocytes. Surprisingly, we have found that whereas homeostatic clearance of RBCs is primarily a task for splenic macrophages, neutrophils and, to a lesser extent, also monocytes can be a major factor in clearance of IgG-opsonized RBCs. Erythrophagocytosis by neutrophils is strongly dependent on the degree of opsonization of the RBCs. Additionally, the process is enhanced after blocking the "do not eat me" signal CD47 on the opsonized RBCs, which binds signal regulatory protein a, a myeloid inhibitory receptor that restricts phagocytosis. Moreover, RBCs isolated from autoimmune hemolytic anemia patients, opsonized by auto-IgGs, were shown to be readily phagocytosed by neutrophils. Finally, priming of neutrophils by inflammatory mediators such as tumor necrosis factor a and lipopolysaccharide further increases the magnitude of erythrophagocytosis. Collectively, our data suggest that neutrophils contribute significantly to the phagocytosis of antibody-opsonized RBCs, especially under inflammatory conditions. This indicates a hereto unanticipated contribution of neutrophils in RBC phagocytosis, especially under pathological conditions such as alloimmunization or autoimmunization.

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Of macrophages and red blood cells; a complex love story

Cited by 245 publications

References 105 publications

(+)-SJ733, a clinical candidate for malaria that acts through ATP4 to induce rapid host-mediated clearance of Plasmodium

(+)-SJ733, a clinical candidate for malaria that acts through ATP4 to induce rapid host-mediated clearance of Plasmodium

Reactive Oxygen Species– and DNA Damage Response–Dependent NK Cell Activating Ligand Upregulation Occurs at Transcriptional Levels and Requires the Transcriptional Factor E2F1

Human and murine splenic neutrophils are potent phagocytes of IgG-opsonized red blood cells

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