Review

Authors: Garth Lawrence Burn, Alessandro Foti, Gerben Marsman...

Neutrophils are immune cells with unusual biological features that furnish potent antimicrobial properties. These cells phagocytose and subsequently kill prokaryotic and eukaryotic organisms very efficiently. Importantly, it is not only their ability to attack microbes within a constrained intracellular compartment that endows neutrophils with antimicrobial function. They can unleash their effectors into the extracellular space, where, even post-mortem, their killing machinery can endure and remain functional. The antimicrobial activity of neutrophils must not be misconstrued as being microbe specific and should be viewed more generally as biotoxic. Outside of fighting infections, neutrophils can harness their noxious machinery in other contexts, like cancer. Inappropriate or dysregulated neutrophil activation damages the host and contributes to autoimmune and inflammatory disease. Here we review a number of topics related to neutrophil biology based on contemporary findings.

Topics: Animals; Extracellular Space; Humans; Inflammation; Neutrophil Activation; Neutrophils; Phagocytosis

PubMed: 34260886
DOI: 10.1016/j.immuni.2021.06.006

Review

Authors: Elvira Mass, Falk Nimmerjahn, Katrin Kierdorf...

Macrophages are innate immune cells that form a 3D network in all our tissues, where they phagocytose dying cells and cell debris, immune complexes, bacteria and other waste products. Simultaneously, they produce growth factors and signalling molecules - such activities not only promote host protection in response to invading microorganisms but are also crucial for organ development and homeostasis. There is mounting evidence of macrophages orchestrating fundamental physiological processes, such as blood vessel formation, adipogenesis, metabolism and central and peripheral neuronal function. In parallel, novel methodologies have led to the characterization of tissue-specific macrophages, with distinct subpopulations of these cells showing different developmental trajectories, transcriptional programmes and life cycles. Here, we summarize our growing knowledge of macrophage diversity and how macrophage subsets orchestrate tissue development and function. We further interrelate macrophage ontogeny with their core functions across tissues, that is, the signalling events within the macrophage niche that may control organ functionality during development, homeostasis and ageing. Finally, we highlight the open questions that will need to be addressed by future studies to better understand the tissue-specific functions of distinct macrophage subsets.

Topics: Humans; Macrophages; Phagocytosis; Signal Transduction; Biology

PubMed: 36922638
DOI: 10.1038/s41577-023-00848-y

Review

Authors: Léonie Dejas, Karin Santoni, Etienne Meunier...

Neutrophils are among the most abundant immune cells, representing about 50%- 70% of all circulating leukocytes in humans. Neutrophils rapidly infiltrate inflamed tissues and play an essential role in host defense against infections. They exert microbicidal activity through a variety of specialized effector mechanisms, including phagocytosis, production of reactive oxygen species, degranulation and release of secretory vesicles containing broad-spectrum antimicrobial factors. In addition to their homeostatic turnover by apoptosis, recent studies have revealed the mechanisms by which neutrophils undergo various forms of regulated cell death. In this review, we will discuss the different modes of regulated cell death that have been described in neutrophils, with a particular emphasis on the current understanding of neutrophil pyroptosis and its role in infections and autoinflammation.

Topics: Humans; Neutrophils; Pyroptosis; Phagocytosis; Apoptosis

PubMed: 37939552
DOI: 10.1016/j.smim.2023.101849

Authors: V Hartenstein, P Martinez

Living cells depend on a constant supply of energy-rich organic molecules from the environment. Small molecules pass into the interior of the cell via simple diffusion or active transport carried out by membrane bound transporters; macromolecules, or entire cells, are taken up by endocytosis/phagocytosis, and are degraded intracellularly in specialized membrane bound compartments (lysosomes). Whereas all cells are capable of transporting molecules through the membrane, the efficient procurement, digestion and uptake of nutrients have become the function of specialized cell types and organs, forming the digestive system in multicellular animals. In mammals, for example, the digestive system is comprised of glandular organs with classes of cells specialized in the secretion of enzymes for the extracellular digestion of food particles (e.g., exocrine cells of the salivary gland, pancreas), as well as other organs with absorptive function (e.g., small intestine). Numerous other cell types, such as smooth muscle cells, neurons and enteroendocrine cells, are associated with glandular cells and intestinal cells to promote the digestive process.

Topics: Animals; Biological Evolution; Digestion; Digestive System; Immune System; Phagocytosis

PubMed: 31478136
DOI: 10.1007/s00441-019-03102-x

Authors: Shicheng Su, Jinghua Zhao, Yue Xing...

Antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) critically contribute to the efficacy of anti-tumor therapeutic antibodies. We report here an unexpected finding that macrophages after ADCP inhibit NK cell-mediated ADCC and T cell-mediated cytotoxicity in breast cancers and lymphomas. Mechanistically, AIM2 is recruited to the phagosomes by FcγR signaling following ADCP and activated by sensing the phagocytosed tumor DNAs through the disrupted phagosomal membrane, which subsequently upregulates PD-L1 and IDO and causes immunosuppression. Combined treatment with anti-HER2 antibody and inhibitors of PD-L1 and IDO enhances anti-tumor immunity and anti-HER2 therapeutic efficacy in mouse models. Furthermore, neoadjuvant trastuzumab therapy significantly upregulates PD-L1 and IDO in the tumor-associated macrophages (TAMs) of HER2 breast cancer patients, correlating with poor trastuzumab response. Collectively, our findings unveil a deleterious role of ADCP macrophages in cancer immunosuppression and suggest that therapeutic antibody plus immune checkpoint blockade may provide synergistic effects in cancer treatment.

Topics: Animals; Antibodies, Monoclonal; Antibody-Dependent Cell Cytotoxicity; B7-H1 Antigen; Breast Neoplasms; Cell Line, Tumor; Cytophagocytosis; DNA-Binding Proteins; Disease Models, Animal; Female; Humans; Immunotherapy; Killer Cells, Natural; Lymphoma; Macrophages; Mice; Mice, Inbred NOD; Mice, SCID; Phagocytosis; Phagosomes; Receptors, IgG

PubMed: 30290143
DOI: 10.1016/j.cell.2018.09.007

Authors: Benjamin Lindner, Tobias Burkard, Michael Schuler...

Phagocytosis is a fundamental mechanism of innate immunity and its impairment is associated with severe chronic diseases, for example, chronic obstructive pulmonary disease. Investigating phagocytosis requires flexible tools and assay conditions, such as different fluorescent particle types, detection colors and readouts. We comprehensively evaluated and optimized phagocytosis assays using particles labeled with fluorescent pH-sensitive pHrodo dyes, facilitating the specific detection of phagocytosed particles. Beads, bacterial and yeast particles labeled with pHrodo red and green were tested for their uptake by THP-1 cells and primary human macrophages by flow cytometry and high-content imaging. Whereas the latter allowed kinetic phagocytosis measurement, the former demonstrated the feasibility of using cell sorting for periods of up to 6 h, enabling downstream applications such as pooled genetic screens.

Topics: Cell Line; Flow Cytometry; Fluorescent Dyes; Humans; Hydrogen-Ion Concentration; Macrophages; Phagocytosis; Rhodamines; THP-1 Cells

PubMed: 32079414
DOI: 10.2144/btn-2020-0003

Authors: Alexandria N Hughes, Bruce Appel

During development, oligodendrocytes contact and wrap neuronal axons with myelin. Similarly to neurons and synapses, excess myelin sheaths are produced and selectively eliminated, but how elimination occurs is unknown. Microglia, the resident immune cells of the central nervous system, engulf surplus neurons and synapses. To determine whether microglia also prune myelin sheaths, we used zebrafish to visualize and manipulate interactions between microglia, oligodendrocytes, and neurons during development. We found that microglia closely associate with oligodendrocytes and specifically phagocytose myelin sheaths. By using a combination of optical, genetic, chemogenetic, and behavioral approaches, we reveal that neuronal activity bidirectionally balances microglial association with neuronal cell bodies and myelin phagocytosis in the optic tectum. Furthermore, multiple strategies to deplete microglia resulted in oligodendrocytes maintaining excessive and ectopic myelin. Our work reveals a neuronal activity-regulated role for microglia in modifying developmental myelin targeting by oligodendrocytes.

Topics: Animals; Animals, Genetically Modified; Microglia; Myelin Sheath; Neurogenesis; Neurons; Oligodendroglia; Phagocytosis; Spinal Cord; Superior Colliculi; Zebrafish

PubMed: 32632287
DOI: 10.1038/s41593-020-0654-2

Review

Authors: Fang Yu, Yangfan Wang, Anne R Stetler...

AIMS

Phagocytosis is the cellular digestion of extracellular particles, such as pathogens and dying cells, and is a key element in the evolution of central nervous system (CNS) disorders. Microglia and macrophages are the professional phagocytes of the CNS. By clearing toxic cellular debris and reshaping the extracellular matrix, microglia/macrophages help pilot the brain repair and functional recovery process. However, CNS resident and invading immune cells can also magnify tissue damage by igniting runaway inflammation and phagocytosing stressed-but viable-neurons.

DISCUSSION

Microglia/macrophages help mediate intercellular communication and react quickly to the "find-me" signals expressed by dead/dying neurons. The activated microglia/macrophages then migrate to the injury site to initiate the phagocytic process upon encountering "eat-me" signals on the surfaces of endangered cells. Thus, healthy cells attempt to avoid inappropriate engulfment by expressing "do not-eat-me" signals. Microglia/macrophages also have the capacity to phagocytose immune cells that invade the injured brain (e.g., neutrophils) and to regulate their pro-inflammatory properties. During brain recovery, microglia/macrophages engulf myelin debris, initiate synaptogenesis and neurogenesis, and sculpt a favorable extracellular matrix to support network rewiring, among other favorable roles. Here, we review the multilayered nature of phagocytotic microglia/macrophages, including the molecular and cellular mechanisms that govern microglia/macrophage-induced phagocytosis in acute brain injury, and discuss strategies that tap into the therapeutic potential of this engulfment process.

CONCLUSION

Identification of biological targets that can temper neuroinflammation after brain injury without hindering the essential phagocytic functions of microglia/macrophages will expedite better medical management of the stroke recovery stage.

Topics: Brain; Brain Injuries; Central Nervous System Diseases; Humans; Macrophages; Microglia; Phagocytes; Phagocytosis

PubMed: 35751629
DOI: 10.1111/cns.13899

Authors: Emily K Lehrman, Daniel K Wilton, Elizabeth Y Litvina...

Microglia regulate synaptic circuit remodeling and phagocytose synaptic material in the healthy brain; however, the mechanisms directing microglia to engulf specific synapses and avoid others remain unknown. Here, we demonstrate that an innate immune signaling pathway protects synapses from inappropriate removal. The expression patterns of CD47 and its receptor, SIRPα, correlated with peak pruning in the developing retinogeniculate system, and mice lacking these proteins exhibited increased microglial engulfment of retinogeniculate inputs and reduced synapse numbers in the dorsal lateral geniculate nucleus. CD47-deficient mice also displayed increased functional pruning, as measured by electrophysiology. In addition, CD47 was found to be required for neuronal activity-mediated changes in engulfment, as microglia in CD47 knockout mice failed to display preferential engulfment of less active inputs. Taken together, these results demonstrate that CD47-SIRPα signaling prevents excess microglial phagocytosis and show that molecular brakes can be regulated by activity to protect specific inputs.

Topics: Animals; CD47 Antigen; Female; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Microglia; Neurogenesis; Neuronal Plasticity; Phagocytosis; Receptors, Immunologic; Synapses

PubMed: 30308165
DOI: 10.1016/j.neuron.2018.09.017

Review

Authors: Ruying Fu, Qingyu Shen, Pengfei Xu...

Microglia, the resident macrophages of the central nervous system, rapidly activate in nearly all kinds of neurological diseases. These activated microglia become highly motile, secreting inflammatory cytokines, migrating to the lesion area, and phagocytosing cell debris or damaged neurons. During the past decades, the secretory property and chemotaxis of microglia have been well-studied, while relatively less attention has been paid to microglial phagocytosis. So far there is no obvious concordance with whether it is beneficial or detrimental in tissue repair. This review focuses on phagocytic phenotype of microglia in neurological diseases such as Alzheimer's disease, multiple sclerosis, Parkinson's disease, traumatic brain injury, ischemic and other brain diseases. Microglial morphological characteristics, involved receptors and signaling pathways, distribution variation along with time and space changes, and environmental factors that affecting phagocytic function in each disease are reviewed. Moreover, a comparison of contributions between macrophages from peripheral circulation and the resident microglia to these pathogenic processes will also be discussed.

Topics: Animals; Central Nervous System Diseases; Humans; Microglia; Phagocytosis; Signal Transduction

PubMed: 24395130
DOI: 10.1007/s12035-013-8620-6