An Acquired and Endogenous Glycocalyx Forms a Bidirectional “Don’t Eat” and “Don’t Eat Me” Barrier to Phagocytosis

Imbert, Paul R. C.; Sarić, Amra; Pedram, Kayvon; Bertozzi, Carolyn R.; Grinstein, Sergio; Freeman, Spencer A.

doi:10.1016/j.cub.2020.09.082

Cited by 38 publications

(51 citation statements)

References 51 publications

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“…Potential discrepancies between the phagocytic activities of primary Scnn1b- Tg AMs and mucus-treated WT AMs could be explained by the number of mucus-exposed AMs in the in vivo setting. An inhibitory effect was also reported for the endogenous glycocalyx of cancer cells 82 . Imbert et al showed that the glycocalyx of macrophages and their targets could constitute a physiological barrier, hindering efferocytosis and phagocytosis.…”

Section: Discussionmentioning

confidence: 59%

Epigenetic reprogramming of airway macrophages promotes polarization and inflammation in muco-obstructive lung disease

et al. 2021

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Lung diseases, such as cystic fibrosis and COPD, are characterized by mucus obstruction and chronic airway inflammation, but their mechanistic link remains poorly understood. Here, we focus on the function of the mucostatic airway microenvironment on epigenetic reprogramming of airway macrophages (AM) and resulting transcriptomic and phenotypical changes. Using a mouse model of muco-obstructive lung disease (Scnn1b-transgenic), we identify epigenetically controlled, differentially regulated pathways and transcription factors involved in inflammatory responses and macrophage polarization. Functionally, AMs from Scnn1b-transgenic mice have reduced efferocytosis and phagocytosis, and excessive inflammatory responses upon lipopolysaccharide challenge, mediated through enhanced Irf1 function and expression. Ex vivo stimulation of wild-type AMs with native mucus impairs efferocytosis and phagocytosis capacities. In addition, mucus induces gene expression changes, comparable with those observed in AMs from Scnn1b-transgenic mice. Our data show that mucostasis induces epigenetic reprogramming of AMs, leading to changes favoring tissue damage and disease progression. Targeting these altered AMs may support therapeutic approaches in patients with muco-obstructive lung diseases.

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Section: Discussionmentioning

confidence: 59%

Epigenetic reprogramming of airway macrophages promotes polarization and inflammation in muco-obstructive lung disease

et al. 2021

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“…Loss of sialic acid residues (known as desialylation) can induce phagocytosis of apoptotic cells ( 54 ) and senescent cells ( 258 ). Cancer cells are hypersialylated and may overexpress highly sialylated mucins to prevent themselves being phagocytosed ( 267 ).…”

Section: The Phagocytic Codementioning

confidence: 99%

“…Hyaluronic acid (HA, hyaluronan) is a glycosaminoglycan component of extracellular matrix that can bind some cells including macrophages coating them in a negative charge that can inhibit macrophage phagocytosis of other cells ( 267 ). Thus, OxLDL is a potential phagocyte suppressant.…”

Section: The Phagocytic Codementioning

confidence: 99%

The Phagocytic Code Regulating Phagocytosis of Mammalian Cells

et al. 2021

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Mammalian phagocytes can phagocytose (i.e. eat) other mammalian cells in the body if they display certain signals, and this phagocytosis plays fundamental roles in development, cell turnover, tissue homeostasis and disease prevention. To phagocytose the correct cells, phagocytes must discriminate which cells to eat using a ‘phagocytic code’ - a set of over 50 known phagocytic signals determining whether a cell is eaten or not - comprising find-me signals, eat-me signals, don’t-eat-me signals and opsonins. Most opsonins require binding to eat-me signals – for example, the opsonins galectin-3, calreticulin and C1q bind asialoglycan eat-me signals on target cells - to induce phagocytosis. Some proteins act as ‘self-opsonins’, while others are ‘negative opsonins’ or ‘phagocyte suppressants’, inhibiting phagocytosis. We review known phagocytic signals here, both established and novel, and how they integrate to regulate phagocytosis of several mammalian targets - including excess cells in development, senescent and aged cells, infected cells, cancer cells, dead or dying cells, cell debris and neuronal synapses. Understanding the phagocytic code, and how it goes wrong, may enable novel therapies for multiple pathologies with too much or too little phagocytosis, such as: infectious disease, cancer, neurodegeneration, psychiatric disease, cardiovascular disease, ageing and auto-immune disease.

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“…Phagocytosis requires an intimate contact of the macrophage and the target, where the glycocalyx, a layer that surrounds the plasma membrane containing glycolipids, glycoproteins, and surface-associated glycosaminoglycans, acts as a barrier for these contacts. The size and charge of this glycocalyx can be modified and modulated by enzymes or other molecules present on the TME to promote phagocytosis ( 144 ). Of interest, we described that NK cells release histones that bind to and degrade the syndecans on the glycocalyx of multiple myeloma cells ( 145 ), suggesting that by doing this, NK cells might also promote the phagocytosis of tumor cells by macrophages, an event observed during fungal infection ( 146 ).…”

Section: Impact Of Tumor Secretome In the Anti-tumor Activity Of Immune Cellsmentioning

confidence: 99%

Tumor Secretome to Adoptive Cellular Immunotherapy: Reduce Me Before I Make You My Partner

Etxebeste-Mitxeltorena

Rincón-Loza

Martín-Antonio

2021

Front. Immunol.

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Adoptive cellular immunotherapy using chimeric antigen receptor (CAR)-modified T cells and Natural Killer (NK) cells are common immune cell sources administered to treat cancer patients. In detail, whereas CAR-T cells induce outstanding responses in a subset of hematological malignancies, responses are much more deficient in solid tumors. Moreover, NK cells have not shown remarkable results up to date. In general, immune cells present high plasticity to change their activity and phenotype depending on the stimuli they receive from molecules secreted in the tumor microenvironment (TME). Consequently, immune cells will also secrete molecules that will shape the activities of other neighboring immune and tumor cells. Specifically, NK cells can polarize to activities as diverse as angiogenic ones instead of their killer activity. In addition, tumor cell phagocytosis by macrophages, which is required to remove dying tumor cells after the attack of NK cells or CAR-T cells, can be avoided in the TME. In addition, chemotherapy or radiotherapy treatments can induce senescence in tumor cells modifying their secretome to a known as “senescence-associated secretory phenotype” (SASP) that will also impact the immune response. Whereas the SASP initially attracts immune cells to eliminate senescent tumor cells, at high numbers of senescent cells, the SASP becomes detrimental, impacting negatively in the immune response. Last, CAR-T cells are an attractive option to overcome these events. Here, we review how molecules secreted in the TME by either tumor cells or even by immune cells impact the anti-tumor activity of surrounding immune cells.

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An Acquired and Endogenous Glycocalyx Forms a Bidirectional “Don’t Eat” and “Don’t Eat Me” Barrier to Phagocytosis

Cited by 38 publications

References 51 publications

Epigenetic reprogramming of airway macrophages promotes polarization and inflammation in muco-obstructive lung disease

Epigenetic reprogramming of airway macrophages promotes polarization and inflammation in muco-obstructive lung disease

The Phagocytic Code Regulating Phagocytosis of Mammalian Cells

Tumor Secretome to Adoptive Cellular Immunotherapy: Reduce Me Before I Make You My Partner

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