Polyamine import and accumulation causes immunomodulation in macrophages engulfing apoptotic cells

McCubbrey, Alexandra L.; McManus, Shannon A; McClendon, Jazalle; Thomas, Stacey M.; Chatwin, Hope B; Reisz, Julie A.; D’Alessandro, Angelo; Mould, Kara J.; Bratton, Donna L.; Henson, Peter M.; Janssen, William J.

doi:10.1016/j.celrep.2021.110222

Cited by 46 publications

(37 citation statements)

References 53 publications

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“…Ornithine may result from apoptotic cell-derived arginine metabolized by arginase-1 ( 73 ). An increased arginase-1 activity in mouse efferocytic macrophages has been confirmed in another study ( 84 ). Then, ornithine may be transformed via ornithine decarboxylase (ODC) into putrescine.…”

Section: Efferocytosis As a Critical Step Triggering The Resolution P...supporting

confidence: 54%

“…Amino-acid levels increase after efferocytosis as a consequence of apoptotic cell-derived protein/peptide degradation. This concerns, in particular arginine, ornithine, lysine and methionine, while no increase of alanine and glycine is detected ( 73 , 84 ). Ornithine may result from apoptotic cell-derived arginine metabolized by arginase-1 ( 73 ).…”

Section: Efferocytosis As a Critical Step Triggering The Resolution P...mentioning

confidence: 98%

“…Digestion of apoptotic cell-derived nucleic acids is critical to avoid exacerbated autoimmune responses ( 69 ). The levels of nucleotides resulting from nucleic acid degradation increase in efferocytic macrophages ( 84 ). This is the case of cytosine for instance ( 84 ).…”

Section: Efferocytosis As a Critical Step Triggering The Resolution P...mentioning

confidence: 99%

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Resolution therapy: Harnessing efferocytic macrophages to trigger the resolution of inflammation

Saas

Vetter²,

Maraux³

et al. 2022

Front. Immunol.

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Several chronic inflammatory diseases are associated with non-resolving inflammation. Conventional anti-inflammatory drugs fail to completely cure these diseases. Resolution pharmacology is a new therapeutic approach based on the use of pro-resolving mediators that accelerate the resolution phase of inflammation by targeting the productive phase of inflammation. Indeed, pro-resolving mediators prevent leukocyte recruitment and induce apoptosis of accumulated leukocytes. This approach is now called resolution therapy with the introduction of complex biological drugs and cell-based therapies. The main objective of resolution therapy is to specifically reduce the duration of the resolution phase to accelerate the return to homeostasis. Under physiological conditions, macrophages play a critical role in the resolution of inflammation. Indeed, after the removal of apoptotic cells (a process called efferocytosis), macrophages display anti-inflammatory reprogramming and subsequently secrete multiple pro-resolving factors. These factors can be used as resolution therapy. Here, we review the different mechanisms leading to anti-inflammatory reprogramming of macrophages after efferocytosis and the pro-resolving factors released by these efferocytic macrophages. We classify these mechanisms in three different categories: macrophage reprogramming induced by apoptotic cell-derived factors, by molecules expressed by apoptotic cells (i.e., “eat-me” signals), and induced by the digestion of apoptotic cell-derived materials. We also evoke that macrophage reprogramming may result from cooperative mechanisms, for instance, implicating the apoptotic cell-induced microenvironment (including cellular metabolites, specific cytokines or immune cells). Then, we describe a new drug candidate belonging to this resolution therapy. This candidate, called SuperMApo, corresponds to the secretome of efferocytic macrophages. We discuss its production, the pro-resolving factors present in this drug, as well as the results obtained in experimental models of chronic (e.g., arthritis, colitis) and acute (e.g., peritonitis or xenogeneic graft-versus-host disease) inflammatory diseases.

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Section: Efferocytosis As a Critical Step Triggering The Resolution P...supporting

confidence: 54%

Section: Efferocytosis As a Critical Step Triggering The Resolution P...mentioning

confidence: 98%

See 1 more Smart Citation

Resolution therapy: Harnessing efferocytic macrophages to trigger the resolution of inflammation

Saas

Vetter²,

Maraux³

et al. 2022

Front. Immunol.

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“…We used spermidine, among the other polyamines, as it has been proved to suppress tumorigenesis in healthy tissues and, in tumors, it contributed to the modulation of cancerrelated functions, including immunoregulation, autophagy, and apoptosis [31]. In the tumor microenvironment, in particular, spermidine can induce the autophagy-dependent release of ATP, which, in turn, promotes immune surveillance [32,33]. Additionally, spermidine demonstrated the ability to alter macrophage immunometabolism and stimulate CD8+ T-cells [34] and memory B-cell responses [35][36][37].…”

Section: Introductionmentioning

confidence: 99%

Nanospermidine in Combination with Nanofenretinide Induces Cell Death in Neuroblastoma Cell Lines

et al. 2022

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A new strategy to cause cell death in tumors might be the increase of intracellular polyamines at concentrations above their physiological values to trigger the production of oxidation metabolites at levels exceeding cell tolerance. To test this hypothesis, we prepared nanospermidine as a carrier for spermidine penetration into the cells, able to escape the polyamine transport system that strictly regulates intracellular polyamine levels. Nanospermidine was prepared by spermidine encapsulation in nanomicelles and was characterized by size, zeta potential, loading, dimensional stability to dilution, and stability to spermidine leakage. Antitumor activity, ROS production, and cell penetration ability were evaluated in vitro in two neuroblastoma cell lines (NLF and BR6). Nanospermidine was tested as a single agent and in combination with nanofenretinide. Free spermidine was also tested as a comparison. The results indicated that the nanomicelles successfully transported spermidine into the cells inducing cell death in a concentration range (150–200 μM) tenfold lower than that required to provide similar cytotoxicity with free spermidine (1500–2000 μM). Nanofenretinide provided a cytostatic effect in combination with the lowest nanospermidine concentrations evaluated and slightly improved nanospermidine cytotoxicity at the highest concentrations. These data suggest that nanospermidine has the potential to become a new approach in cancer treatment. At the cellular level, in fact, it exploits polyamine catabolism by means of biocompatible doses of spermidine and, in vivo settings, it can exploit the selective accumulation of nanomedicines at the tumor site. Nanofenretinide combination further improves its efficacy. Furthermore, the proven ability of spermidine to activate macrophages and lymphocytes suggests that nanospermidine could inhibit immunosuppression in the tumor environment.

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“…Furthermore, tumor cell apoptosis and subsequent efferocytosis by neighboring and/or infiltrating immune cells may enhance the immunosuppressive phenotype. McCubbrey et al demonstrated that LPS-stimulated macrophages co-cultured with apoptotic Jurkat cells exhibited increased spermine uptake and reduced IL1β and IL6 gene expression, while treatment with the Rac-1 inhibitor NSC23766 abolished the increase in polyamine content and reverted IL1β and IL6 expression to near-normal levels [7]. Thus, investigating immune-cell-intrinsic alterations upon systemic DFMO treatment alone and/or in combination with transport inhibitors may provide insight into the anti-tumor efficacy or lack thereof in these treatment groups.…”

Section: Immune Cell-intrinsic Deficiencies In Polyamine Biosynthesis...mentioning

confidence: 99%

Polyamine Depletion Strategies in Cancer: Remodeling the Tumor Immune Microenvironment to Enhance Anti-Tumor Responses

et al. 2022

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Polyamine biosynthesis is frequently dysregulated in cancers, and enhanced flux increases intracellular polyamines necessary for promoting cell growth, proliferation, and function. Polyamine depletion strategies demonstrate efficacy in reducing tumor growth and increasing survival in animal models of cancer; however, mechanistically, the cell-intrinsic and cell-extrinsic alterations within the tumor microenvironment underlying positive treatment outcomes are not well understood. Recently, investigators have demonstrated that co-targeting polyamine biosynthesis and transport alters the immune landscape. Although the polyamine synthesis-targeting drug 2-difluoromethylornithine (DFMO) is well tolerated in humans and is FDA-approved for African trypanosomiasis, its clinical benefit in treating established cancers has not yet been fully realized; however, combination therapies targeting compensatory mechanisms have shown tolerability and efficacy in animal models and are currently being tested in clinical trials. As demonstrated in pre-clinical models, polyamine blocking therapy (PBT) reduces immunosuppression in the tumor microenvironment and enhances the therapeutic efficacy of immune checkpoint blockade (ICB). Thus, DFMO may sensitize tumors to other therapeutics, including immunotherapies and chemotherapies.

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Polyamine import and accumulation causes immunomodulation in macrophages engulfing apoptotic cells

Abstract: Highlights d Efferocytosis triggers macrophages to accumulate polyamines spermidine and spermine d Polyamine accumulation is mediated by Rac1-dependent endocytic import d Inhibition of polyamine import blunts immunomodulation in response to efferocytosis

Cited by 46 publications

References 53 publications

Resolution therapy: Harnessing efferocytic macrophages to trigger the resolution of inflammation

Resolution therapy: Harnessing efferocytic macrophages to trigger the resolution of inflammation

Nanospermidine in Combination with Nanofenretinide Induces Cell Death in Neuroblastoma Cell Lines

Polyamine Depletion Strategies in Cancer: Remodeling the Tumor Immune Microenvironment to Enhance Anti-Tumor Responses

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