Regulation of the phagocytic process involves complex signaling pathways that lead to particle internalization and destruction. Phagocytosis, however, is not a cellular response occurring as an isolated event. Phagocytic signaling involves the regulation of many phagocytosis-associated cell responses that are important for host defense and for the resolution of the inflammatory process. In addition, due to the destructive nature of the phagocytic process, this cell response is tightly controlled, and phagocytes must respond to activation and differentiation signals that modulate their phagocytic efficiency. Presently it is unclear how all these events are coordinated. Available information, however, suggests a model in which phagocytosis-associated cell responses are regulated through signaling pathways that occur in parallel to, and partially overlap those regulating the ingestion process itself. Additionally, activation and differentiation signals appear to potentiate, or modify the utilization important signaling enzymes that regulate phagocytosis, in order to make this process more efficient.

Introduction

The immune system has a specialized subset of cells, named professional phagocytes, equipped for rapidly and efficiently ingesting invading microorganisms at sites of inflammation. These phagocytes are neutrophils and macrophages.¹ Monocytes (the macrophage precursors) are often included among the professional phagocytes, though they display a lower phagocytic response than neutrophils and macrophages.^1,2 Other nonprofessional phagocytes are dendritic cells,^3,4 fibroblasts,⁵ microglia,⁶ and some epithelial cell types.^7,8 An important difference between the phagocytic process of professional and nonprofessional phagocytes is that professional phagocytes respond to a phagocytic stimulus with many associated cell responses. These responses are of great importance in the context of the immune response, during tissue remodeling, and wound healing. Phagocytosis-associated cell responses include immuno-modulatory responses like the generation and release of pro-inflammatory^9,10 and anti-inflammatory mediators,¹¹ and also cell responses of destructive nature such as the respiratory burst,¹² and the release of toxic and microbicidal molecules by degranulation.^13,14 Additionally, in contrast to nonprofessional phagocytes, professional phagocytes are capable of recognizing a wide variety of phagocytic targets, and of ingesting them at a higher rate. However, in order to achieve controlled, yet efficient, phagocytic functions, professional phagocytes must respond to activation and differentiation signals that modulate their phagocytic abilities. The regulation of phagocytosis-associated cell responses and the modulation of phagocytic efficiency thus represent a higher level of complexity for phagocytic signaling. Available evidence of how these events are regulated at the molecular level will be deal with in the next sections.

Regulation of Phagocytosis-Associated Cell Responses

As early as 1977 it was recognized that, in contrast to nonprofessional phagocytes, professional phagocytes were capable of secreting pro-inflammatory mediators in response to a phagocytic stimulus.¹⁵ It is now well established that professional phagocytes respond to a phagocytic stimulus with a wide variety of associated cell responses.^1,2 Phagocytosis-associated cell responses appear to be either inflammatory or anti-inflammatory, predominantly depending on the properties of the phagocytic target. Inflammatory responses include the respiratory burst,¹² the release of pro-inflammatory mediators (cytokines, prostaglandins, and leukotrienes),^9,10 and the release of various microbicidal molecules by degranulation.^13,14 Anti-inflammatory responses are mainly characterized by the production and release of anti-inflammatory cytokines, and the active inhibition of the generation of pro-inflammatory mediators.¹⁰

The nature of the phagocytic target has a strong influence on the particular cell response that will accompany phagocytosis. Early reports indicated that phagocytosis of IgG-,^16-18 but not complement-opsonized^18,19 particles induced the release of granule enzymes and lipid-derived pro-inflammatory mediators. In contrast, phagocytosis of apoptotic cells by macrophages occurred in the absence of both responses.²⁰ More recently it was found that phagocytosis of apoptotic cells actually increases the secretion of the anti-inflammatory cytokine TGF-β.²¹ Phagocytosis of necrotic cells by macrophages, on the other hand, induces an inflammatory phenotype characterized by the up-regulation of T cell costimulatory molecules, and enhanced ability for antigen presentation.²¹ From these observations it follows that the receptors engaged in the phagocytic process will determine what associated cell responses will be triggered (fig. 1). Phagocytosis mediated by immunoglobulin (Ig) receptors (FcRs) is associated with various inflammatory responses. Phagocytosis mediated by FcγRs (receptors for IgG) or FcαR (receptor for IgA) triggers pro-inflammatory cell responses including the respiratory burst, the release of microbicidal molecules by degranulation, and the production and release of lipid-derived pro-inflammatory factors and cytokines^2,22-25 (fig. 1A). Phagocytosis mediated by complement receptors (CRs), on the other hand, is not always associated with inflammatory cell responses. Phagocytosis mediated by complement receptor 4 (CR4) occurs in association with the respiratory burst²⁶ (fig. 1B). Complement receptor 3 (CR3), on the other hand, recognizes a wide variety of ligands,²⁷ and phagocytosis mediated by this receptor can occur in the absence or presence of the respiratory burst. This will depend on the ligand-binding site engaged on the receptor.²⁸ Engagement of the CR3 binding site for complement, during phagocytosis, does not trigger inflammatory responses.^18,19,26,29 In contrast, when the fibrinogen (a component of the coagulation cascade) binding site,³⁰ or the lectin site (that recognizes microorganism-derived sugars) on CR3^28,31 are engaged phagocytes present a strong respiratory burst and cytotoxic activity (fig. 1C). In contrast to phagocytosis mediated by Fc receptors or complement receptors, phagocytosis of apoptotic cells has been directly associated with anti-inflammatory cell responses¹¹ (fig. 1D). The anti-inflammatory nature of apoptotic cell phagocytosis may be fundamental for the clearance of apoptotic cells during tissue remodeling and wound healing. The engagement of the phosphatidylserine receptor during phagocytosis of apoptotic cells induces the production of anti-inflammatory mediators, and actively suppresses the production of inflammatory mediators.^5,32,33 MER is another receptor with a relevant role in the clearance of apoptotic cells,^34,35 and it was recently found that its stimulation is necessary for down-regulating inflammatory responses.^36,37 Interestingly, engagement of CR3 during phagocytosis of apoptotic cells also appears to down-regulate the production and secretion of pro-inflammatory cytokines.³⁸ Because CR3 may cooperate with the phosphatidylserine receptor during phagocytosis of apoptotic cells,³⁹ it is possible that the anti-inflammatory effect of CR3 is due to simultaneous phosphatidylserine receptor stimulation.

Figure 1

Triggering of phagocytosis-associated cell responses depends on the receptor engaged for phagocytosis. Phagocytosis of immunoglobulin (Ig)-opsonized particles (A) triggers pro-inflammatory responses. Phagocytosis of complement (Cpt)-opsonized particles (more...)

It is currently unclear how these varied cell responses are regulated along with the phagocytic process. In some cases phagocytosis and accompanying cell responses appear to be regulated by parallel signaling pathways that are triggered by the same receptors that mediate phagocytosis (fig. 2). For example, it has been shown that in monocytes FcγR-mediated phagocytosis is regulated through a signaling pathway dependent on PCK, and independent of PI 3-K and ERK⁴⁰ (fig. 2). In the same cells, however, FcγR stimulation triggers a signaling pathway for cytokine production that depends on PI 3-K and ERK⁴⁰ (fig. 2). In other cases phagocytosis and its associated cell responses appear to be regulated through partially overlapping signaling pathways (fig. 3). In professional phagocytes, for instance, FcγR-mediated phagocytosis is regulated through a signaling pathway dependent on phosphatidylinositol 3-kinase (PI 3-K),^41,42 protein kinase C (PKC),^43,44 extracellular signal-regulated kinase (ERK),^40,45,46 Rac,²⁹ and various phospholipases²⁵ (fig. 3). FcγR-mediated phagocytosis, however, can proceed independently of changes in the concentration of intracellular calcium^47,48 (fig. 3). The activation of the respiratory burst, on the other hand, also depends PI 3-K,^49-51 PKC,^49,52 ERK,^53,54 Rac,^55,56 and various phospholipases,^50,57-59 but is in contrast dependent on calcium^60,61 (fig. 3). In macrophages the activity of different PKC isoforms has been ascribed to the regulation of either phagocytosis, or the respiratory burst.⁵² Phagocytosis appears to be regulated by PKCδ, and PKCε, while the respiratory burst is regulated by the PKCα isoform.⁵² This observations suggest that, although the signaling pathways for phagocytosis and the respiratory burst share key signaling enzymes, they may not overlap completely.

Figure 2

Phagocytosis and cytokine production are regulated by separate signaling pathways in monocytes. In monocytes stimulation of immunoglobulin G (IgG) receptors promotes phagocytosis and cytokine production. The signaling pathways that regulate these responses (more...)

Figure 3

Phagocytosis and respiratory burst in professional phagocytes are regulated by partially overlapping signaling pathways. In neutrophils and macrophages stimulation of immunoglobulin G (IgG) receptors triggers phagocytosis and respiratory burst. The signaling (more...)

Modulation of Phagocytic Efficiency

Compared to nonprofessional phagocytes, professional phagocytes present a great ability to recognize phagocytic targets, and ingest them at a higher rate.^1,2 In addition to this, professional phagocytes are able to modulate their phagocytic functions in response to activation and differentiation signals.

Cell Activation and Phagocytic Signaling

Phagocytosis efficiency of IgG- and complement-opsonized targets is up-regulated in response to a wide variety of activating stimuli (fig. 4). These include, bacterial peptides,^62,63 cytokines,^64-68 lipid-derived pro-inflammatory mediators,^64,69,70 and the simultaneous stimulation of additional adhesive or phagocytic receptors.^71-74 How these activation signals up-regulate phagocytic efficiency at the molecular level is still unclear, however, in some cases the activating stimulus appears to potentiate the activation of signaling enzymes with important roles in phagocytosis (fig. 4). For example, neutrophil activation with leukotriene B4 (a lipid-derived pro-inflammatory mediator) results in enhanced Syk activation.⁷⁰ This event correlates with increased phagocytic efficiency towards IgG-opsonized targets,⁷⁰ which is a cell response regulated by Syk.⁷⁵ Similarly, other activating stimuli have been reported to activate enzymes that professional phagocytes require for efficient phagocytosis, particularly ERK and PI 3-K.⁴² Activating stimuli known to activate ERK and/or PI 3-K include, the bacterial peptide fMLP,^76,77 leukotrienes,^78,79 and cytokines such as IL-8,⁸⁰ granulocyte colony-stimulating factor,⁸¹ and granulocyte-macrophage colony-stimulating factor.⁷⁷

Figure 4

Phagocyte activation results in an enhanced phagocytic response. Phagocyte activation by various inflammatory stimuli potentiates the activities of signaling enzymes with important roles in regulating the phagocytic process. This activation enhances the (more...)

Cell Differentiation and Phagocytic Signaling

In the immune system neutrophils and macrophages represent the fully differentiated phagocytes. While neutrophils leaving the bone marrow are fully differentiated, macrophages differentiate from circulating monocytes in extra-vascular tissues.⁸² Monocytes display a lower phagocytic response, compared to neutrophils and macrophages, and must respond to activation and differentiation signals in order to achieve optimal phagocytic capacity^1,2 (fig. 5). It has been shown that the monocyte ability to ingest various targets is influenced by their state of differentiation. IgG-coated targets are ingested at a higher rate by mature macrophages, compared to undifferentiated monocytes⁴² (fig. 5, fig. 6). Similarly, the ability to phagocytose via complement receptors is dependent on monocyte maturation.^83,84 While monocytes require an activating stimulus for internalizing complement-coated targets⁸³ (fig. 5), mature macrophages ingest complement-opsonized targets in the absence of additional stimulus⁸³ (fig. 6). Similarly, the ability of monocytes and bone marrow-derived macrophages to recognize and ingest apoptotic cells is inducible, and depends on their state of differentiation^85,86 (fig. 5, fig. 6). While the process of monocyte-to-macrophage differentiation has been relatively well characterized,^9,82,87 the way the differentiation process enhances phagocytic ability is still unclear. Recent work, however, suggests that the differentiation process involves changes in the molecular machinery that regulates phagocytosis (fig. 7, fig.8). In monocytes, the signaling pathway for phagocytosis depends on PKC,⁴² but is independent of PI 3-K and ERK⁴⁰ (fig.7). The process of monocyte-to-macrophage differentiation, however, involves the ordered recruitment of PI 3-K and ERK for phagocytosis regulation.⁴² Thus in mature macrophages phagocytosis of IgG-coated targets is regulated by PKC, and also by PI 3-K and ERK (fig.8). The PKC isoforms required for phagocytosis, however, appear to be different in monocytes and mature macrophages. In monocytes it was found that FcγRI stimulation increases PKC activity corresponding to the membrane translocation of the PKC isoforms δ, ε, and ζ⁸⁸ (fig. 7). In monocyte-differentiated macrophages, on the other hand, FcγRI stimulation leads to PKC activity that corresponds to membrane translocation of the PKC isoforms α, β, and γ^88,89 (fig. 8). It has also been demonstrated that PKC activation in monocyte-differentiated macrophages results in a stronger phagocytic response, compared to that of undifferentiated monocytes.⁴² It is thus possible that by recruiting PI 3-K and ERK for phagocytosis regulation, and by regulating which PKC isoforms are recruited to the membrane, professional phagocytes achieve optimal levels of phagocytosis (fig. 7, fig. 8). Phospholipase A2 (PLA2) is another signaling molecule whose enzymatic activity is necessary for phagocytosis regulation. This enzyme acts down-stream of PKC and ERK, and the product of its enzymatic activity (arachidonic acid) regulates membrane remodeling events, that are necessary for pseudopod extension during phagocytosis.^90,91 During phagocytosis arachidonic acid is released through the enzymatic activity of various PLA2 isoforms,²⁵ and the release of this product also appears to be subjected to differentiation-dependent modulation. In monocytes arachidonic acid is released solely by calcium independent-PLA2, under PKC control^44,92,93 (fig. 7). In macrophages, on the other hand, arachidonic acid is released by calcium dependent-PLA2, under ERK and p38 MAPK control,^94,95 and also by a calcium-independent PLA2, under PKC control⁹⁶ (fig. 8). It is thus likely that by modulating the signaling pathways leading to arachidonic acid release, professional phagocytes also achieve an optimal phagocytic function. It thus appears that the process of monocyte-to-macrophage differentiation involves changes in the utilization of key signaling enzymes, whose activity may result in an enhanced phagocytic function.

Figure 5

Recognition and ingestion of phagocytic targets by monocytes. Monocytes recognize and ingest immunoglobulin (Ig)-opsonized particles at low levels (A). Phagocytosis of complement (Cpt)-opsonized particles does not occur, unless the cell is activated by (more...)

Figure 6

Recognition and ingestion of phagocytic targets by macrophages. Macrophages recognize and ingest very efficiently immunoglobulin (Ig)-opsonized targets (A), complement (Cpt)-opsonized targets (B), and also apoptotic cells (C).

Figure 7

Signaling pathway for phagocytosis in monocytes. Monocytes ingest immunoglobulin G (IgG)-opsonized particles through a signaling pathway dependent on the protein kinase C (PKC) isoforms δ, ε, and ξ, and on calcium-independent phospholipase (more...)

Figure 8

Signaling pathway for phagocytosis in professional phagocytes. Professional phagocytes ingest immunoglobulin G (IgG)-opsonized particles through a signaling pathway dependent on phosphatidylinositol 3-kinase (PI 3-K), extracellular signal-regulated kinase (more...)

Conclusion

Phagocytosis is cell response with important functions in the course of an immune response, but also during tissue remodeling and wound healing. Professional phagocytes are specialized cells capable of performing this function with great efficiency. The phagocytic process, however, is not a cell response that occurs as an isolated event, and a phagocytic stimulus triggers associated cell responses of destructive nature, but also immuno-modulatory cell responses. The concurrent regulation of these cell responses with phagocytosis sometimes involves separate, apparently independent signaling pathways. In other cases, however, although the signaling pathways for phagocytosis and associated responses share key signaling enzymes, these pathways may not be completely overlapping.

Professional phagocytes, in order to achieve controlled, yet efficient, phagocytic functions, must respond to activation and differentiation signals that modulate their phagocytic abilities. On one hand, activating stimulus appears to potentiate the activation of signaling enzymes with important roles in phagocytosis. On the other hand, differentiation signals that control the process of monocyte-to-macrophage differentiation promote a change in the utilization of key signaling enzymes for phagocytosis. This changes thus result in an enhanced phagocytic function.

The regulation of phagocytosis-associated cell responses and the modulation of phagocytic efficiency in response to activation and differentiation signals thus represent a higher level of complexity for phagocytic signaling. Although much work remains to be done in this field, future studies will enable us to better understand the complex signaling networks that regulate fundamental cellular mechanisms of the immune response.

Definitions

Apoptotic cell—Cell that has undergone the process of programmed cell death (apoptosis). This process is the result of the activation of specific signaling pathways, relevant during embryonic development, during the course of the immune response, and during the wound-healing process.

Complement—Family of soluble blood proteins that are part of the innate defense system. These proteins circulate in an inactive form, but become activated by the recognition of molecular components of microorganisms. Activation of complement components promotes their binding to the surface of microorganisms and function as opsonins. Additionally, activation of the complement cascade culminates in the formation of the membrane attack complex, that is capable of forming pores on the membrane of cells and pathogens.

Cytokines—Soluble, hormone-like proteins produced by leukocytes that act as a messengers between cells. Cytokines can stimulate or inhibit the growth and activity of various immune cells, and have effects on the differentiation and proliferation of the hematopoietic stem cells, as well as on the activation of lymphocytes and phagocytes.

Degranulation—Process whereby cells eject the contents of cytoplasmic vesicles (granules), either into a phagosome, or to the exterior of the cell through exocytosis. This process is characteristic of mast cells, basophils, neutrophils, macrophages, eosinophils, and platelets. During this process pro-inflammatory mediators, microbicidal and potentially cytotoxic substances are released from preformed cytoplasmic granules.

Nonprofessional phagocytes—Various cell types with low phagocytic activity. Nonprofessional phagocytes have more limited recognition and ingestion capabilities, compared to professional phagocytes.

Opsonization—Process whereby soluble proteins (such as immunoglobulins or complement components) bind to the surface pathogens and make them susceptible to ingestion by phagocytes.

Professional phagocytes—Specialized subset of cells in the immune system, capable of ingesting cells and pathogens with great efficiency, through the recognition of a wide array of molecular determinants of microorganisms, and also opsonins bound to pathogens and dying cells.

Prostaglandins and leukotrienes—A family of biologically active lipid compounds, derived from arachidonic acid by oxidative metabolism through the cyclooxygenase (prostaglandins), or 5-lipoxygenase (leukotrienes) pathways. They participate in host defense reactions modulating the inflammatory response. They have potent actions on many essential organs and systems, including the cardiovascular, pulmonary, and central nervous system, as well as the gastrointestinal tract and the immune system. Prostaglandins and leukotrienes are released by phagocytes.

Respiratory burst—Increase in oxidative metabolism of phagocytes following uptake of opsonized particles. The activation of the respiratory burst results in the production of toxic reactive-oxygen and nitrogen metabolites with bactericidal properties. These metabolites include hydrogen peroxide, hypohalites and nitric oxide.

Acknowledgements

Research is the author's laboratory is supported by grant 36407-M from Consejo Nacional de Ciencia y Tecnología (CONACyT), México.

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