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Review
20 February 2018
The Neutrophil’s Choice: Phagocytose vs Make Neutrophil Extracellular Traps
Angelo A. Manfredi
2 more and 
Norma Maugeri
Neutrophils that had phagocytosed apoptotic cells or activated platelets fail to be activated when challenged with further inflammatory stimuli. Neutrophil extracellular traps (NETs) formation was monitored by confocal microscopy. Cathepsin G was revealed by immunofluorescence (Alexa Fluor 541, red), and DNA was counterstained with Hoechst and apoptotic cells preloaded with CFSE (equivalent to Alexa 488, green). (A) Unstimulated neutrophils; (B) neutrophils challenged with apoptotic cells; (C) neutrophils that had phagocytosed apoptotic cells and then were after adherence further stimulated with recombinant IL-8. (D) β2 integrins were determined by flow cytometry in resting neutrophils (basal value), neutrophils with adherent tethered PS + cargos (platelets or apoptotic LCL cells), or neutrophils with intracellular PS + cargos (platelets or apoptotic LCL cells) after further stimulation with fMLP or IL-8. Results (mean ± SEM) are expressed as the percentage of basal value. Adapted from Ref. (51, 128).

Neutrophils recognize particulate substrates of microbial or endogenous origin and react by sequestering the cargo via phagocytosis or by releasing neutrophil extracellular traps (NETs) outside the cell, thus modifying and alerting the environment and bystander leukocytes. The signals that determine the choice between phagocytosis and the generation of NETs are still poorly characterized. Neutrophils that had phagocytosed bulky particulate substrates, such as apoptotic cells and activated platelets, appear to be “poised” in an unresponsive state. Environmental conditions, the metabolic, adhesive and activation state of the phagocyte, and the size of and signals associated with the tethered phagocytic cargo influence the choice of the neutrophils, prompting either phagocytic clearance or the generation of NETs. The choice is dichotomic and apparently irreversible. Defects in phagocytosis may foster the intravascular generation of NETs, thus promoting vascular inflammation and morbidities associated with diseases characterized by defective phagocytic clearance, such as systemic lupus erythematosus. There is a strong potential for novel treatments based on new knowledge of the events determining the inflammatory and pro-thrombotic function of inflammatory leukocytes.

26,463 views
179 citations
Review
30 January 2018

As the body continues to grow and age, it becomes essential to maintain a balance between living and dying cells. Macrophages and dendritic cells play a central role in discriminating among viable, apoptotic, and necrotic cells, as selective and efficient phagocytes, without inducing inappropriate inflammation or immune responses. A great deal has been learnt concerning clearance receptors for modified and non-self-ligands on potential targets, mediating their eventual uptake, disposal, and replacement. In this essay, we assess current understanding of the phagocytic recognition of apoptotic cells within their tissue environment; we conclude that efferocytosis constitutes a more complex process than simply removal of corpses, with regulatory interactions between the target and effector cells, which determine the outcome of this homeostatic process.

33,042 views
163 citations
Review
25 January 2018

Toxic substances and microbial or food-derived antigens continuously challenge the liver, which is tasked with their safe neutralization. This vital organ is also important for the removal of apoptotic immune cells during inflammation and has been previously described as a “graveyard” for dying lymphocytes. The clearance of apoptotic and necrotic cells is known as efferocytosis and is a critical liver function to maintain tissue homeostasis. Much of the research into this form of immunological control has focused on Kupffer cells, the liver-resident macrophages. However, hepatocytes (and other liver resident cells) are competent efferocytes and comprise 80% of the liver mass. Little is known regarding the mechanisms of apoptotic and necrotic cell capture by epithelia, which lack key receptors that mediate phagocytosis in macrophages. Herein, we discuss recent developments that increased our understanding of efferocytosis in tissues, with a special focus on the liver parenchyma. We discuss the impact of efferocytosis in health and in inflammation, highlighting the role of phagocytic epithelia.

13,642 views
56 citations
Review
01 November 2017
Pro-Resolving Mediators in Regulating and Conferring Macrophage Function
Jesmond Dalli
 and 
Charles N. Serhan
Microvesicles and apoptotic neutrophils are a nidus for specialized pro-resolving mediator (SPM) biosynthesis during efferocytosis. Microvesicles or neutrophils were enriched in deuterium-labeled essential fatty acids and the conversion of these essential fatty acids to lipid mediators and their pathway markers/precursors was assessed during efferocytosis using lipid mediator profiling. (A) Relative contribution to lipid mediator biosynthesis by microvesicles and apoptotic neutrophils. (B) Cartoon depicting the process of trancellular biosynthesis during efferocytosis.

Macrophages are central in coordinating the host response to both sterile and infective insults. Clearance of apoptotic cells and cellular debris is a key biological action preformed by macrophages that paves the way to the resolution of local inflammation, repair and regeneration of damaged tissues, and re-establishment of function. The essential fatty acid-derived autacoids termed specialized pro-resolving mediators (SPM) play central roles in promoting these processes. In the present article, we will review the role of microvesicles in controlling macrophage efferocytosis and SPM production. We will also discuss the role of both apoptotic cells and microvesicles in providing substrate for transcellular biosynthesis of several SPM families during efferocyotsis. In addition, this article will discuss the biological actions of the recently uncovered macrophage-derived SPM termed maresins. These mediators are produced via 14-lipoxygenation of docosahexaenoic acid that is either enzymatically converted to mediators carrying two hydroxyl groups or to autacoids that are peptide-lipid conjugates, coined maresin conjugates in tissue regeneration. The formation of these mediators is temporally regulated during acute self-limited infectious-inflammation where they promote the uptake and clearance of apoptotic cells, regulate several aspects of the tissue repair and regeneration, and display potent anti-nociceptive actions.

10,866 views
120 citations
Multiple mechanisms of immune modulation following interaction with apoptotic cells in macrophages and dendritic cells (DCs). Multiple mechanisms are used by apoptotic cells to create an immune homeostatic anti-inflammatory state in macrophages and DCs. In apoptotic cells themselves, in parallel with PtdSer exposure, caspase activation plays a critical role by deactivating potential danger-associated molecular patterns (DAMPs) and by releasing “find me” signals such as adenosine monophosphate (AMP), lysophosphatidylcholine (LPC), fractalkine, and sphingosine-1-phosphate (S1P). Apoptotic cells possess a direct immunosuppressive effect by the release of “calming” agents TGF-β, IL-10, adenosine diphosphate (ADP), thrombospondin-1 (TSP-1), and more. Direct binding to PtdSer receptors (PtsR) and indirect binding to TAM receptors, as well as signaling via opsonins/bridging molecules that use additional integrinsor scavenger receptors (ScRs) or complement receptors, act to reprogram the phagocyte, to inhibit toll-like receptors (TLRs), nuclear factor κB (NF-κB), signal transducer and activator of transcription 1 (STAT1), and interferon (IFN) signaling, and to activate liver X receptor (LXR), peroxisome proliferator-activated receptor delta (PPAR-δ), suppressors of cytokine signaling (SOCS) 1/3, and hepatic growth factor (HGF), and to downregulate costimulation and induce induction of indoleamine 2,3 dioxygenase-1 (IDO), that promote tolerogenic phenotype and the induction of T-regulatory (Treg) cell differentiation. The sum of these events leads to downregulation of the inflammatory characteristics of macrophages and DCs, repair, and peripheral tolerance. Pro-inflammatory pattern are marked in red and anti-inflammatory patterns in blue.
12,899 views
89 citations
Orchestrated antiviral mechanisms initiated by the phagocytosis of virus-infected cells. Virus-infected cells are subjected to apoptosis-dependent phagocytosis, which results in the digestion of viruses together with host cells, Virus Removal. At the same time, phagocytes process incorporated viral proteins for the presentation of antigens toward CTLs for their activation, Antigen Presentation. Moreover, phagocytes change the pattern of gene expression at a transcriptional level, so that the repertoire of cytokines shifts to the mitigation of inflammation, Inflammation Resolution; the phagocytic activity of phagocytes is enhanced, Trained Immunity; and virus-specific RNAi is systemically induced, Trained Immunity. CTLs, cytotoxic T lymphocytes.
Review
28 September 2017

Viruses are infectious entities that hijack host replication machineries to produce their progeny, resulting, in most cases, in disease and, sometimes, in death in infected host organisms. Hosts are equipped with an array of defense mechanisms that span from innate to adaptive as well as from humoral to cellular immune responses. We previously demonstrated that mouse cells underwent apoptosis in response to influenza virus infection. These apoptotic, virus-infected cells were then targeted for engulfment by macrophages and neutrophils. We more recently reported similar findings in the fruit fly Drosophila melanogaster, which lacks adaptive immunity, after an infection with Drosophila C virus. In these experiments, the inhibition of phagocytosis led to severe influenza pathologies in mice and early death in Drosophila. Therefore, the induction of apoptosis and subsequent phagocytosis of virus-infected cells appear to be an antiviral innate immune mechanism that is conserved among multicellular organisms. We herein discuss the underlying mechanisms and significance of the apoptosis-dependent phagocytosis of virus-infected cells. Investigations on the molecular and cellular features responsible for this underrepresented virus–host interaction may provide a promising avenue for the discovery of novel substances that are targeted in medical treatments against virus-induced intractable diseases.

18,430 views
87 citations
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Frontiers in Immunology

Roles of Granzymes in Inflammation, Aging, and Autoimmunity
Edited by Christopher Turner, Fehim Esen
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