Live cell tracking of macrophage efferocytosis during
            <i>Drosophila</i>
            embryo development in vivo

Raymond, Michael H.; Davidson, Andrew J.; Shen, Yi; Tudor, Daniel R.; Lucas, Christopher D.; Morioka, Sho; Perry, Justin C.; Krapivkina, Julia; Perrais, David; Schumacher, Linus J.; Campbell, Robert E.; Wood, Will; Ravichandran, Kodi S.

doi:10.1126/science.abl4430

Cited by 45 publications

(62 citation statements)

References 38 publications

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“…In developing Drosophila adult brains, ILP signaling later participates in neuronal removal when neural circuits undergo remodeling companied by programmed cell death ( Chihara et al, 2014 ; Kessissoglou et al, 2020 ). To maintain brain homeostasis, glial cells prune neuronal processes and remove entire neurons via a phagocytosis mechanism ( Freeman, 2015 ; Kim et al, 2020 ; Bittern et al, 2021 ; Raymond et al, 2022 ). For example in a Drosophila adult injury model involving cutting off the antenna, damaged neurons release ILP ligands that activate glial InRs, leading to augmented expression of glial phagocytosis receptor Draper (Drpr) and subsequent glial engulfment and clearance of axons ( Musashe et al, 2016 ).…”

Section: Part 2: Insulin-like Peptide Signaling In Fxsmentioning

confidence: 99%

Dysregulation of BMP, Wnt, and Insulin Signaling in Fragile X Syndrome

Song

Broadie²

2022

Front. Cell Dev. Biol.

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Drosophila models of neurological disease contribute tremendously to research progress due to the high conservation of human disease genes, the powerful and sophisticated genetic toolkit, and the rapid generation time. Fragile X syndrome (FXS) is the most prevalent heritable cause of intellectual disability and autism spectrum disorders, and the Drosophila FXS disease model has been critical for the genetic screening discovery of new intercellular secretion mechanisms. Here, we focus on the roles of three major signaling pathways: BMP, Wnt, and insulin-like peptides. We present Drosophila FXS model defects compared to mouse models in stem cells/embryos, the glutamatergic neuromuscular junction (NMJ) synapse model, and the developing adult brain. All three of these secreted signaling pathways are strikingly altered in FXS disease models, giving new mechanistic insights into impaired cellular outcomes and neurological phenotypes. Drosophila provides a powerful genetic screening platform to expand understanding of these secretory mechanisms and to test cellular roles in both peripheral and central nervous systems. The studies demonstrate the importance of exploring broad genetic interactions and unexpected regulatory mechanisms. We discuss a number of research avenues to pursue BMP, Wnt, and insulin signaling in future FXS investigations and the development of potential therapeutics.

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Section: Part 2: Insulin-like Peptide Signaling In Fxsmentioning

confidence: 99%

Dysregulation of BMP, Wnt, and Insulin Signaling in Fragile X Syndrome

Song

Broadie²

2022

Front. Cell Dev. Biol.

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“…Because TRMs are the primary professional phagocyte responsible for clearing millions of dead cells daily ( 1 ), the ability to internalize multiple apoptotic cells simultaneously is likely an essential ability ( 53 ). We therefore asked whether butyrate treatment of macrophages alters efferocytosis capacity on a per-cell basis.…”

Section: Resultsmentioning

confidence: 99%

A microbiota-derived metabolite instructs peripheral efferocytosis

Saavedra

Trzeciak

Wang

et al. 2022

Preprint

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The phagocytic clearance of dying cells, termed efferocytosis, is essential for both tissue homeostasis and tissue health during cell death-inducing treatments. Failure to efficiently clear dying cells augments the risk of pathological inflammation and has been linked to a myriad of autoimmune and inflammatory diseases. Although past studies have elucidated local molecular signals that regulate efferocytosis in a tissue, whether signals arising distally also regulate efferocytosis remains elusive. Interestingly, clinical evidence suggests that prolonged use of antibiotics is associated with an increased risk of autoimmune or inflammatory disease development. We therefore hypothesized that intestinal microbes produce molecular signals that regulate efferocytotic ability in peripheral tissue phagocytes. Here, we find that macrophages, the bodys professional phagocyte, display impaired efferocytosis in peripheral tissues in both antibiotic-treated and germ-free mice in vivo, which could be rescued by fecal microbiota transplantation. Mechanistically, the microbiota-derived short-chain fatty acid butyrate directly boosted efferocytosis efficiency and capacity in mouse and human macrophages, with both intestinal and local delivery of butyrate capable of rescuing antibiotic-induced peripheral efferocytosis defects. Bulk mRNA sequencing of primary macrophages treated with butyrate in vitro and single cell mRNA sequencing of macrophages isolated from antibiotic-treated and butyrate-rescued mice revealed specific regulation of phagocytosis-associated transcriptional programs, in particular the induction of programs involved in or supportive of efferocytosis. Surprisingly, the effect of butyrate on efferocytosis was not mediated through G protein-coupled receptor signaling, but instead acted by inhibition of histone deacetylase 3. Strikingly, peripheral efferocytosis was impaired well-beyond withdrawal of antibiotics and, importantly, antibiotic-treated mice exhibited a poorer response to a sterile efferocytosis-dependent inflammation model. Collectively, our results demonstrate that a process essential for tissue homeostasis, efferocytosis, relies on distal molecular signals, and suggest that a defect in peripheral efferocytosis may contribute to the clinically-observed link between broad-spectrum antibiotics use and inflammatory disease.

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“…Tumor necrotic debris caused by hypoxia can release different signals leading to cancer progression [ 159 ]. Macrophages can accumulate in perivascular and perinecrotic niches in tumors [ 160 ] where they can operate as immune scavengers to sweep away cellular debris [ 161 ]. An interesting study demonstrated that the necrotic debris from severely hypoxic cancer cells modulates the communication between tumors and TAMs [ 106 ].…”

Section: Hypoxia-driven Crosstalk Between Tumor Cells and Tamsmentioning

confidence: 99%

The hypoxia-driven crosstalk between tumor and tumor-associated macrophages: mechanisms and clinical treatment strategies

et al. 2022

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Given that hypoxia is a persistent physiological feature of many different solid tumors and a key driver for cancer malignancy, it is thought to be a major target in cancer treatment recently. Tumor-associated macrophages (TAMs) are the most abundant immune cells in the tumor microenvironment (TME), which have a large impact on tumor development and immunotherapy. TAMs massively accumulate within hypoxic tumor regions. TAMs and hypoxia represent a deadly combination because hypoxia has been suggested to induce a pro-tumorigenic macrophage phenotype. Hypoxia not only directly affects macrophage polarization, but it also has an indirect effect by altering the communication between tumor cells and macrophages. For example, hypoxia can influence the expression of chemokines and exosomes, both of which have profound impacts on the recipient cells. Recently, it has been demonstrated that the intricate interaction between cancer cells and TAMs in the hypoxic TME is relevant to poor prognosis and increased tumor malignancy. However, there are no comprehensive literature reviews on the molecular mechanisms underlying the hypoxia-mediated communication between tumor cells and TAMs. Therefore, this review has the aim to collect all recently available data on this topic and provide insights for developing novel therapeutic strategies for reducing the effects of hypoxia.

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Live cell tracking of macrophage efferocytosis during Drosophila embryo development in vivo

Cited by 45 publications

References 38 publications

Dysregulation of BMP, Wnt, and Insulin Signaling in Fragile X Syndrome

Dysregulation of BMP, Wnt, and Insulin Signaling in Fragile X Syndrome

A microbiota-derived metabolite instructs peripheral efferocytosis

The hypoxia-driven crosstalk between tumor and tumor-associated macrophages: mechanisms and clinical treatment strategies

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