Phagosome resolution regenerates lysosomes and maintains the degradative capacity in phagocytes

Lancaster, Charlene E.; Fountain, Aaron; Somerville, Elliott; Sheth, Javal; Dayam, Roaya M; Jacobelli, Vanessa; Somerville, Alex; Terebiznik, Mauricio R.; Botelho, Roberto J.

doi:10.1101/2020.05.14.094722

Cited by 8 publications

(10 citation statements)

References 103 publications

(194 reference statements)

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“…Phagocytosis proceeds in stages which include enveloping of extracellular material by the phagocytic cup, packaging into a phagosome, fusion to mature lysosomes to form a phagolysosome, and resolution of the phagolysosome by fragmentation 67, 68 . Our data suggested that multiple stages of phagocytosis might be regulated by the interferon stimulated genes expressed in cluster 8.…”

Section: Resultsmentioning

confidence: 99%

Type I interferon responsive microglia shape cortical development and behavior

Dorman¹,

Pt²,

Cc³

et al. 2021

Preprint

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Microglia, the innate immune cells of the brain, are exquisitely sensitive to dynamic changes in the brain environment. We used single cell RNA sequencing to define glial responses in the early postnatal somatosensory cortex after partial whisker lesion, revealing transcriptomic shifts in both astrocytes and microglia during the resulting topographic remapping. The most distinct change was the emergence of a type I interferon (IFN-I) responsive microglia population that was rare in the resting cortex but expanded 20-fold after whisker deprivation. The top gene candidate in this cluster, Ifitm3, marked a conserved but transient subset of microglia that were in the process of phagocytosing whole cells. IFITM3 protein identified this subset in vivo, where it was enriched in early microglial phagosomes. Loss of canonical IFN-I signaling in Ifnar1-/- animals resulted in abnormal 'bubble' microglia with deficient phagolysosomal processing. In a meta-analysis of transcriptomes, we identified the IFN-I signature in microglia across a range of pathologies. We identified phagocytic IFITM3+ microglia in two murine disease models: SARS-CoV-2 infection and Alzheimer's Disease. These data reveal the potential of transcriptional profiling after defined perturbation to elicit transient microglial states, and identify a novel role for IFN-I signaling in regulating microglial phagocytosis.

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Section: Resultsmentioning

confidence: 99%

Type I interferon responsive microglia shape cortical development and behavior

Dorman¹,

Pt²,

Cc³

et al. 2021

Preprint

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“…Less is known about the final stage of phagosome resolution and how the phagosome is resorbed to allow the phagocyte to return to homeostasis. However, studies have shown that bacteria‐containing phagolysosomes in macrophages undergo fragmentation through vesicle budding and constriction (Levin et al , 2016 ; Botelho et al , 2020 ; preprint: Lancaster et al , 2020 ).…”

Section: Introductionmentioning

confidence: 99%

A secreted factor NimrodB4 promotes the elimination of apoptotic corpses by phagocytes in Drosophila

et al. 2021

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Programmed cell death plays a fundamental role in development and tissue homeostasis. Professional and non‐professional phagocytes achieve the proper recognition, uptake, and degradation of apoptotic cells, a process called efferocytosis. Failure in efferocytosis leads to autoimmune and neurodegenerative diseases. In Drosophila, two transmembrane proteins of the Nimrod family, Draper and SIMU, mediate the recognition and internalization of apoptotic corpses. Beyond this early step, little is known about how apoptotic cell degradation is regulated. Here, we study the function of a secreted member of the Nimrod family, NimB4, and reveal its crucial role in the clearance of apoptotic cells. We show that NimB4 is expressed by macrophages and glial cells, the two main types of phagocytes in Drosophila. Similar to draper mutants, NimB4 mutants accumulate apoptotic corpses during embryogenesis and in the larval brain. Our study points to the role of NimB4 in phagosome maturation, more specifically in the fusion between the phagosome and lysosomes. We propose that similar to bridging molecules, NimB4 binds to apoptotic corpses to engage a phagosome maturation program dedicated to efferocytosis.

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“…Macrophages engulf cargos into lysosomes, where the abundant enzymes can quickly degrade the exogenous materials, including DNA. [ 12 ] They are also non‐dividing cells and lack of virus receptors, [ 13 ] and thus their gene transfection is inefficient even by virus vectors. Exogenous DNA transfection in macrophages is thus inherently challenging.…”

Section: Methodsmentioning

confidence: 99%

Tumor‐Associated Macrophage and Tumor‐Cell Dually Transfecting Polyplexes for Efficient Interleukin‐12 Cancer Gene Therapy

Qiu

Wang

et al. 2020

Advanced Materials

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Interleukin 12 (IL12) is a potent pro‐inflammatory chemokine with multifunction, including promoting cytotoxic T‐cell‐mediated killing of cancer cells. IL12‐based cancer gene therapy can overcome IL12's life‐threatening adverse effects, but its clinical translation has been limited by the lack of systemic gene‐delivery vectors capable of efficiently transfecting tumors to produce sufficient local IL12. Macrophages inherently excrete IL12, and tumor‐associated macrophages (TAMs) are the major tumor component taking up a large fraction of the vectors arriving in the tumor. It is thus hypothesized that a gene vector efficiently transfecting both cancer cells and TAMs would make the tumor to produce sufficient IL12; however, gene transfection of TAMs is challenging due to their inherent strong degradation ability. Herein, an IL12 gene‐delivery vector is designed that efficiently transfects both cancer cells and TAMs to make them as a factory for IL12 production, which efficiently activates anticancer immune responses and remodels the tumor microenvironment, for instance, increasing the M1/M2 ratio by more than fourfold. Therefore, the intravenously administered vector retards tumor growth and doubles survival in three animal models’ with negligible systemic toxicities. This work reports the first nonviral IL12 gene delivery system that effectively makes use of both macrophages and tumor cells.

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Phagosome resolution regenerates lysosomes and maintains the degradative capacity in phagocytes

Cited by 8 publications

References 103 publications

Type I interferon responsive microglia shape cortical development and behavior

Type I interferon responsive microglia shape cortical development and behavior

A secreted factor NimrodB4 promotes the elimination of apoptotic corpses by phagocytes in Drosophila

Tumor‐Associated Macrophage and Tumor‐Cell Dually Transfecting Polyplexes for Efficient Interleukin‐12 Cancer Gene Therapy

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