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Exuberant Ca²⁺ Signaling in Neutrophils: A Cause for Concern

Mohammed M. Sayeed

M. M. Sayeed is in the Departments of Physiology and Surgery and the Burn and Shock Trauma Institute, Loyola University Medical Center, Maywood, IL 60153.

	Abstract

 
Under inflammatory conditions after burn/trauma injuries, circulating neutrophils are frequently hyperactive, contributing to excessive superoxide production and related tissue damage. Although normal neutrophil activation is cooperatively controlled by Ca²⁺-independent and Ca²⁺-linked signaling pathways, exuberant Ca²⁺-linked signaling appears to cause neutrophil hyperactivation in the injury conditions.

	Introduction

Top Introduction O2- production: role of... Signaling to O2- production:... Signaling modulations in burn... Concluding remarks References

 
Leukocyte responses in mammalian organisms occur episodically not only after infectious challenges (bacterial, fungal, viral, or parasitic), but also after seemingly noninfectious (nonseptic) injury conditions, such as trauma and burn. Although early inflammatory phases after nonseptic challenges are probably independent of an invading pathogen, later phases are often complicated by pathogen invasion of the host organisms. The inflammatory response in the absence of a pathogen may be initiated by traumatized/burned tissue products serving as non-self "antigens." An advanced state of inflammation ensuing in mammalian hosts after nonseptic or septic injuries has been referred to as the systemic inflammatory response syndrome (SIRS) (4). A hallmark of SIRS is the release of inflammatory mediators primarily, but not exclusively, from the leukocytes. At present, there is an exhaustive list of mediators identifiable in SIRS; inclusive in this list are cytokines tumor necrosis factor- (TNF-), interleukin-1 (IL-l), IL-6, and IL-8; lipids platelet-activating factor (PAF) and prostaglandin E₂; and reactive molecular species superoxide anion (O₂^–) and nitric oxide (8). If appropriately regulated in terms of their temporal release pattern and magnitude of release, the mediators have the potential to play adaptive roles in the host's defense against the antigens/pathogens (9). Such adaptive roles are played through the actions of mediators on leukocytes, resulting in leukocyte responses that provide for neutralization and/or inactivation of the antigen/pathogen and protection of host cells/tissues.

However, the outcome of leukocyte responses resulting from actions of mediators in SIRS is often damage and, ultimately, death of host cells/tissues. The host cell/tissue damage could occur not only from the actions of mediators leading to attenuated or disturbed leukocyte responses but also from actions of mediators causing an excessive or exaggerated response. Such maladaptive up- and downregulations of leukocyte responses can arise from inappropriate mediator release, mediator-receptor interactions, and/or receptor-mediated leukocyte signaling. An excessive neutrophil O₂^–-generating response after trauma/burn conditions appears to be inappropriate in the early phases of injury; it can potentially cause O₂^–-mediated host tissue damage (10). Such an inappropriate neutrophil response could understandably be related to inappropriate activation of the signaling pathways linked to O₂^– generation. Recent studies have supported a role of altered Ca²⁺ signaling-related intracellular pathways in the exaggerated neutrophil O₂^–-generating response (13). Figure 1 illustrates the role of burn/trauma-induced inflammatory mediators in neutrophil activation and its consequences.

View larger version (47K): [in this window] [in a new window]   FIGURE 1. Schematic illustration of septic and/or nonseptic injuries leading to release of inflammatory mediators that play roles in "priming" and subsequent "activation" of circulating neutrophils. Also shown is transendothelial migration (infiltration) of activated neutrophils into tissues and their interactions with extracellular matrix and host tissues that may become targets of "oxidant fire" (O2–) from neutrophils. Release of O2– intracellularly in a presumed "controlled" manner allows for inactivation/neutralization of pathogens/antigens engulfed by neutrophils. Tumor necrosis factor- (TNF-), granulocyte-macrophage colony stimulatory factor (GMCSF), and granulocyte colony-stimulating factor (GCSF) mainly serve as priming agents; formyl-methionyl-leucyl-phenyl alanine (f-MLP), leukotriene B4 (LTB4), platelet-activating factor (PAF), complement fragment C5a, and interleukin (IL)-8 can act as both priming agents for resting neutrophils and activating agents for preprimed neutrophils.

	O2– production: role of inflammatory mediators

Top Introduction O2- production: role of... Signaling to O2- production:... Signaling modulations in burn... Concluding remarks References

 
Although intracellular O₂^– release after phagocytic uptake of pathogens by neutrophils leads to oxidant-mediated pathogen killing and thus to an efficient host defense, excessive O₂^– release in the environment in close proximity outside the neutrophil can cause oxidative host cell/tissue damage at sites traversed by neutrophils during their migration from blood to tissue regions of inflammation/infection (Fig. 1). Such neutrophil-caused oxidant injury is known to occur in pathological conditions of rheumatoid arthritis, myocardial infarction, stroke, acute respiratory distress syndrome (ARDS), and tissue ischemia (10). Inflammatory mediators, which originate from cellular elements (e.g., tissue macrophages, dendritic cells) at sites of inflammation and diffuse into blood, evidently stimulate neutrophils' chemotactic response, which is responsible for their migration to the inflamed tissue sites. The chemotactic mediators are also effective stimuli for neutrophil O₂^– production. Although neutrophil chemotaxis results from membrane skeletal and cytoskeletal changes contributing to adhesion of neutrophils to other cells and the extracellular matrix, the O₂^–-generative effector response is dependent on the ultimate activation of the neutrophil plasma membrane NADPH oxidase (O₂ oxidoreductase).

Some of the chemotactic mediators that activate the O₂^–-generating NADPH oxidase system are activated serum complement fragment C5a, bacteria-derived N-formylated methionyl peptides [e.g., formyl-methionyl-leucyl-phenylalanine (f-MLP)], bioactive lipids PAF and leukotriene B4 (LTB4), and the chemokine IL-8 (1). Inflammatory cytokines TNF-, granulocyte colony-stimulating factor (GCSF), and granulocyte-macrophage colony-stimulating factor (GMCSF) also contribute, but indirectly, to O₂^– production. The chemotactic mediators f-MLP, C5a, PAF, LTB4, and IL-8 bind to neutrophil plasma membrane receptors (the so-called serpentine receptors), which have seven intramembrane peptides in series, with an NH₂-terminal peptide as the extracellular and a COOH-terminal peptide as the cytosolic domain. On the other hand, TNF-, GCSF, and GMCSF bind to a single transmembrane peptide receptor. The activation of NADPH oxidase is also effected by Fc and complement receptors (FcR and CR, respectively), which are involved in the neutrophil's phagocytic and adhesive responses. Neutrophils express two types of FcRs (which bind to the Fc component of immune complexes), FcRII and FcRIII, and two types of CRs (which bind to complement-pathogen complexes), CR1 and CR3. CR3, known as CD11b/CD18 or ß₂-integrin, also binds to its cognate ligand intracellular adhesion molecule 1 (ICAM-1), leading to neutrophil adhesion to a target cell such as the endothelial cell. Neutrophil adhesive molecule L-selectin, which binds to the endothelial cell sialyl-Lewis ligand, also participates in firm neutrophil adhesion to endothelium. Ligation of these phagocytosis- and adhesion-promoting molecules contributes to potentiation of neutrophil O₂^– production (4). In addition, CD11b/CD18 and FcRIII may directly interact to enhance O₂^– production. Recent studies have shown that there is a high degree of coordination between the phagocytic/adhesive effector responses and NADPH oxidase activation in neutrophils (2). The neutrophil's receptor systems involved in O₂^– production are illustrated in Fig. 2.

View larger version (27K): [in this window] [in a new window]   FIGURE 2. Schematic diagrams showing neutrophils' Ca2+-dependent and Ca2+-independent signaling pathways triggered by ligands acting on cell surface receptors.A: 7-transmembrane-domain system specific for f-MLP, LTB4, C5a, PAF, IL-8. Ca2+-dependent pathways are activated via 7-transmembrane-domain receptor system acting through G protein ß-subunit. PLC-ß, phospholipase C-ß; PLD, phospholipase D; PA,phosphatidic acid; DAG, diacylglycerol; InsP3, inositol 1,4,5-tris phosphate; Ptd Ins P2, phosphatidyl inositol bisphosphate; PKC-ß, protein kinase C-ß. Ca2+ influx is through a membrane ion channel.B: single transmembrane peptide-specific system for TNF-, GMCSF, GCSF; Ca2+-independent pathways are triggered via 7-transmembrane-domain receptor system acting through -subunit of G protein and single transmembrane peptide receptor system. PTK, protein tyrosine kinases; Lyn, a PTK that is autophosphorylated and then interacts with target protein Shc, leading to activation of protein Grb2, p21 Ras, and enzyme phosphatidyl inositol 3-kinase (Ptd Ins 3-K).C: alternative Ca2+-independent pathway via 7-transmembrane-domain system activating through G protein -subunit. MAPK, mitogen activated protein kinase; ERK, extracellular signal related kinase; JNK, c-Jun NH2-terminal kinases; MEK, MAPK-ERK kinase; MEK-K, MEK kinase.D: Fc system for immunoglobulin (Ig) bond immune complexes or heterodimer system specific for ß2-integrin (CD11b/ CD18) ligands. Ca2+-dependent and Ca2+-independent pathways are activated by Fc and heterodimer receptor system.

View larger version (58K): [in this window] [in a new window]   FIGURE 4. Schema showing priming of resting neutrophils and activation of primed neutrophils. Resting neutrophil receptors identified are 7- and single-transmembrane-domain, Fc, and ß2-integrin (also known as CR3 or CD11b/CD18) types. Neutrophil priming can occur via actions of TNF-, GMCSF, and/or GCSF receptors (A andC) to prime neutrophils, or via f-MLP, LTB4, C5a, IL-8, PAF (B); whereas former ligands act primarily via activation of PTK, latter presumably activate both PTK and PLC. PLC activation leads to Ca2+-dependent signaling, whereas PTK activation can lead to Ca2+-independent priming of NADPH oxidase without actual O2– production. Activation of primed cells can occur via 7-transmembrane-domain (A andB) or FcR/ß2-integrin receptors (C), leading to NADPH oxidase activation, resulting in overt O2– production. PLC on open background indicates PLC-ß, and PLC on shaded background indicates PLC-.

	Signaling to O2– production: role of Ca2+-dependent and Ca2+-independent pathways

Top Introduction O2- production: role of... Signaling to O2- production:... Signaling modulations in burn... Concluding remarks References

The activation of neutrophil Fc receptors and ß₂-integrin/L-selectin adhesive molecules involves PTK activation as well as [Ca²⁺]_i elevation due primarily to Ca²⁺ release from the intracellular stores (Fig. 2D) (5). In this case, src family PTK may play a role in tyrosine phosphorylation of PLC- isoform which, like PLC-ß, triggers Ca²⁺/PKC signaling. Thus adhesion of neutrophils to immune complexes (via FcR), and to other cells or matrix (via ß₂-integrin/L-selectin) can also lead to NADPH oxidase activation through Ca²⁺-dependent as well as Ca²⁺-independent pathways.

The O₂^–-generating NADPH oxidase is a multicomponent enzyme comprised of a membrane-bound cytochrome b₅₅₈ unit and several cytosolic factors that translocate to the membrane and form the active enzyme complex upon neutrophil activation (10, 14). The phosphorylation of the cytosolic protein p47phox is one of the early and key events in NADPH oxidase assemblage and is correlated with O₂^– generation (10). Other cytosolic factors that appear to be important are p67phox and Ras-related low-molecular weight GTP-binding protein, Rac2. Both p67phox and Rac2 requirements for O₂^– generation have been shown in human neutrophils. The cytosolic protein p47phox can be phosphorylated at multiple sites. All three cytosolic factors translocate to the membrane and participate in the activation of NADPH oxidase. The upstream signaling contributing to activation of the cytosolic factors (p47phox, p67phox, and Rac2) is not definitively known. PKC would appear to be involved in the activation of p47phox. Both PKC activation and an inhibitory modulation of protein phosphatases play a role in the p47phox phosphorylation and related O₂^– production. Rac activation appears to require src family or other PTK. Thus the signaling components immediately proximal to NADPH oxidase activation are phosphoprotein products of both Ca²⁺-dependent and Ca²⁺-independent pathways.

	Signaling modulations in burn inflammation: relationship to neutrophil priming

Top Introduction O2- production: role of... Signaling to O2- production:... Signaling modulations in burn... Concluding remarks References

 
Although there is little feasibility of directly measuring O₂^– production by tissue neutrophils under pathological conditions in vivo, there is evidence that circulating neutrophils under such conditions have an enhanced ability to produce O₂^– and to inflict oxidative damage to host tissues (10). Whereas a number of studies of blood neutrophils harvested from human trauma and burn patients have ascertained the enhanced O₂^– response and have evaluated the roles of various inflammatory mediators in its generation (1), fewer studies have investigated intracellular signaling mechanisms responsible for the enhanced response. Recent studies from the author's laboratory assessed the signaling and O₂^– responses in blood neutrophils from rats with 25–30% total body surface area burns (13). The rat model of thermal injury allows for evaluation of effects of burn/trauma inflammation during an early (1–3 days postburn) and a late (7–10 days postburn) injury phase. In neutrophils isolated in physiological media, O₂^– generation was measured after stimulating neutrophils with the chemotactic mediator f-MLP. The f-MLP-stimulated O₂^– production 1–3 days postburn was substantially greater than the marginal response observed in control, sham, or burn rats 7–10 days postinjury. Thus neutrophil respiratory burst occurred during the early but not late burn inflammatory phase. This is in keeping with the concept that hyperactivation of neutrophils in the early periods after severe burns is followed by decreased neutrophil responsiveness (1).

[Ca²⁺]_i in neutrophils was measured before and after f-MLP stimulation using fura 2 fluorescence spectroscopy and imaging techniques (13). A substantially greater elevation in [Ca²⁺]_i occurred on neutrophil stimulation with exogenous f-MLP in the 1–3 day postburn rat groups than in control, sham, or 7–10 day postburn groups. These results clearly indicated enhanced responsiveness of Ca²⁺ signaling in neutrophils during early burn inflammatory phase. Assessments of PKC activation (translocation of the protein kinase activity from cytosol to membrane) in control, sham, and burn rat neutrophils, with and without f-MLP stimulation, yielded results indicating a close relationship between PKC and Ca²⁺ signaling changes. The enhanced Ca²⁺ and PKC signaling in the early phase after burn was correlated with the increased O₂^– production response (Fig. 3). The observed enhanced signaling and effector response can be rationally attributed to priming of neutrophils, in vivo, during early periods of burn inflammation.

View larger version (13K): [in this window] [in a new window]   FIGURE 3. Intracellular Ca2+ concentration ([Ca2+]i), PKC, and O2– responses in blood neutrophils (stimulated with 1 µM f-MLP) from sham and burn rats. Burn rats were subjected to 25–30% total body surface area scald burns (98°C for 5 s), and their blood neutrophils were obtained onday 3 postburn. Sham rats were treated similarly to burn group except 25–30% of total bodysurface area was exposed to 37°C. O2– was measured using ferricytochrome reduction assay, [Ca2+]i was determined using fura 2 microfluorometry, and PKC activation was determined measuring translocation of protein kinase activity into cell membrane fraction. Also shown is effect of treatment of rats with Ca2+ blocker diltiazem (DZ) on [Ca2+]i, PKC, and O2– responses. DZ was administered to rats at 2 and 24 hours after sham or burn procedures.Neutrophils were obtained from animals 3 days after sham or burn procedures. Figure was drawn using data published in Ref. 13.

Figure 4 shows a diagrammatic representation of the above-described potential stimulations of neutrophils in a milieu of mediators such as those found in the inflammatory phase of burn/trauma injury. The resting neutrophil might be initially stimulated by ligands binding to the single- and/or seven-transmembrane-domain receptors leading to neutrophil priming. During priming, the signaling pathways involved would primarily be the PTK-dependent and Ca²⁺-independent pathways if single peptide receptors were activated. On the other hand, if both the single and seven-peptide receptors were to be triggered, there is the possibility that both Ca²⁺-independent and Ca²⁺-dependent pathways could be activated in a parallel manner. Yet in both scenarios, O₂^– production would be no more than a marginal response as observed in neutrophils harvested from burn rats before they were stimulated with f-MLP in vitro. The primed neutrophils might be activated, in vivo, via actions of the seven-transmembrane-domain ligands or Fc/CR/ß₂-integrin ligands to lead to an overt and potentially intense O₂^– generation due to cumulative activations of the Ca²⁺-dependent and Ca²⁺-independent pathways (as shown in Fig. 4). The finding of the dependency of the O₂^– response in burn rat neutrophils on Ca²⁺ influx allows for a speculation that not only a cumulative but also an interactive/synergic activation of the Ca²⁺-dependent and Ca²⁺-independent pathways leads to the overt O₂^– response. Whereas the maximum potentiation of primed neutrophils after stimulation with the serpentine receptor agonist could plausibly occur in circulation where both priming and "nonpriming" mediators might be present, the potentiation with Fc receptor stimulation is likely with the formation of immune complexes in inflammatory conditions.

The efficacy of diltiazem treatment of postburn rats in modulating Ca²⁺ signaling upregulation and respiratory burst has provided clues to potential therapeutic regimens for abrogating neutrophil priming in injury conditions (13). Diltiazem's effect was likely due to its ability to block Ca²⁺ influx in neutrophils. The efficacy of Ca²⁺ entry blockers may be limited to neutrophil priming phenomena in which respiratory burst is sensitized by Ca²⁺ influx into the primed neutrophils. An alternative way of abrogating neutrophil priming would be to target the initial priming process itself resulting from the actions of primer agonists on resting neutrophils. Inasmuch as initial priming may be triggered in vivo via activation of a variety of neutrophil receptors, namely Fc, ß₂-integrin, serpentine, and single-transmembrane-domain receptors, therapeutic abrogation of initial priming would seem at the outset to require multiple regimens. However, as discussed in the preceding section, priming through all of these receptor systems seems to be more or less universally dependent on activation of PTKs. Thus PTK blockers and Ca²⁺ blockers both remain as prospective therapeutic agents against neutrophil priming in pathophysiological conditions prevailing in early inflammatory phase of trauma/burn injuries.

	Concluding remarks

Top Introduction O2- production: role of... Signaling to O2- production:... Signaling modulations in burn... Concluding remarks References

 
Neutrophil intracellular signaling triggered by neutrophil activating agents have been extensively studied in vitro. The signaling pathways leading to neutrophil O₂^– generation include both the classical PLC-mediated Ca²⁺/PKC sequence as well as a variety of novel protein kinases not dependent on the Ca²⁺ signal, namely PTK, MAPK, and PI3K. The recent burst of knowledge about the roles of the novel kinases in modulating target proteins implicated in the O₂^– response generation and the extensive presence of the Ca²⁺-independent pathways has appropriately taken the limelight away from Ca²⁺ signaling. The Ca²⁺-independent pathways do play critical roles not only in actual generation of O₂^– by neutrophils but also in priming neutrophils and enhancing their potential to produce O₂^– without an actual production. Nevertheless, the activation of preprimed neutrophils could potentially occur via either the Ca²⁺-independent or the Ca²⁺-dependent sequences as redundant pathways. Recent studies in neutrophils harvested from inflammatory conditions prevailing after burn/trauma injuries indicate that the activation of the primed neutrophils, in vivo, may result from potentiating interactions between the Ca²⁺-linked and the Ca²⁺-independent pathways.

	Acknowledgments

 
I gratefully acknowledge the invaluable editorial assistance of my wife Delphine Sayeed and the skillful help of Megan Flanagin in the preparation of the figures.

The research in my laboratory was supported by National Institutes of Health grants GM-53235 and GM-568501.

	References

Top Introduction O2- production: role of... Signaling to O2- production:... Signaling modulations in burn... Concluding remarks References

 

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (14) Citing Articles via Google Scholar Google Scholar Articles by Sayeed, M. M. Search for Related Content PubMed PubMed Citation Articles by Sayeed, M. M.