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Adhesion-Dependent Modulation of Macrophage K+ Channels

*.

* Margaret Colden-Stanfield Ph.D—Morehouse School of Medicine, Department of Physiology, MEB 349, 720 Westview Drive, SW Atlanta, Georgia 30310, USA. Email:ude.msm@dleifnatsm

Integrins and Ion Channels: Molecular Complexes and Signaling, edited by Andrea Becchetti and Annarosa Arcangeli.
© 2009 Landes Bioscience
Read this chapter in the Madame Curie Bioscience Database here.

Integrin-mediated adhesion of monocytes not only triggers cell rolling and diapedesis, it also activates ionic permeability changes resulting in monocyte activation, maturation and differentiation. Mononuclear phagocytes possess voltage-dependent inwardly rectifying K+ (Kir) currents and delayed outwardly, rectifying K+ (Kdr) currents that are modulated by tissue origin, adherence, presence of growth factors or cytokines and the functional or differentiation state of the cells. This chapter reviews the exploration of Kir and Kdr channels in mononuclear phagocytes over the last 30 years with an emphasis on culturing conditions, modulation by substrates and role in macrophage function. It has only been recent that successful attempts have been made to study these K+ currents in monocytes/macrophages as they may be engaged in the human body which may serve as the foundation for the development of novel therapeutic agents targeting macrophage Kir/Kdr channel activity to favorably influence risk factors for hypertension, atherosclerosis and diabetes.

Introduction

Adhesion of monocytes to extracellular matrix molecules or other cells which is mediated by the engagement of several different families of integrins, not only triggers cell rolling and diapedesis, it also activates other signaling pathways that involve ionic permeability changes resulting in monocyte activation, maturation and differentiation. Mononuclear phagocytes primarily possess three distinct voltage-dependent K+ currents: inwardly rectifying (Kir), delayed, outwardly, rectifying (Kdr) as well as inwardly rectifying Ca2+-activated K+ currents that are modulated by tissue origin, adherence, presence of growth factors or cytokines and the functional or differentiation state of the cells. The characterization of these K+ currents has predominantly been performed under in vitro experimental conditions in which immature monocytes or macrophages were attached to nonphysiologic substrates such as tissue culture polystyrene (plastic) or glass coverslips. The characterization of Kir and Kdr currents on polystyrene/glass and their modulation by adherence to more physiologically relevant substrates and their role in monocytic activation/differentiation is the focus of this chapter.

Inwardly Rectifying K+ (Kir) Currents

Gallin et al1-12 have been pioneers in describing K+ currents initially in murine spleen macrophages in the mid 70's using high resistance intracellular microelectrode recordings and later in the 80's and 90's with the advent of the patch-clamp technique in macrophages derived from peripheral blood (PB) monocytes isolated by density gradient centrifugation or thioglycollate-induced peritoneal macrophages. Table 1 summarizes the salient features of Kir currents in monocyte/macrophages. Kir currents are present in 33% of long-term cultured human PB-derived macrophages and are characterized by (1) activation at potentials negative to –60 mV, (2) better conduction of inward current than outward current, (3) dependence on voltage and extracellular K+ concentration, (4) inactivation at more negative potentials, (5) block by Ba2+, Cs+ and Rb+, (6) Kir2.1 subunit primarily underlying the functional current and (7) the ability to set resting membrane potential (Vrest) closer to EK.9,11,13-14 As 28 pS Kir channels are believed to underlie the macroscopic whole-cell Kir currents in human macrophages adherent to uncoated glass, a similar 37 pS Kir channel is evident in PB-derived macrophages adherent to uncoated polystyrene for less than 4 h.15 Murine J774.1 macrophages (29 pS) and peritoneal macrophages adherent to polystyrene or glass for periods of 1 to 14 days possess larger amplitude Kir currents than acutely adherent cells.3-4,16-22 The current decays over time once the whole-cell configuration is established (washout). G protein activators such as GTPγS enhance the rate of washout while preventing the activation of G proteins with GDPβS stabilizes whole-cell Kir currents.18-21 Overnight exposure to exogenous Gram-negative bacterial endotoxin, lipopolysaccharide (LPS), reduces Kir magnitude in J774.1 macrophages.19 Although acutely applied (5 min) exogenous LPS does not affect Kir currents, a 60-90 min exposure to intracellular LPS completely attenuates Kir currents in human macrophages.23 The ability to express and functionally record J774.1 Kir currents in Xenopus oocytes and subsequent isolation and cloning of cDNA encoding for IRK1 Kir channels from J774.1 macrophages provided the original classification of Kir channels in macrophages at the molecular level.24-25

Table 1. Inwardly rectifying K+ (Kir) currents in mononuclear phagocytes.

Table 1

Inwardly rectifying K+ (Kir) currents in mononuclear phagocytes.

The use of immortalized human tumor cell lines such as U-937, HL-60 and THP-1 cells has afforded additional strategies to further describe Kir and Kdr currents and their possible involvement in monocyte differentiation.26-28 While all three cancer cell lines can be differentiated with phorbol esters, Vitamin D3 and/or TGF-β to mature macrophages, the HL-60 cell line can also be directed to a neutrophil lineage with exposure to retinoic acid or dimethyl sulfoxide. U-937 monocytes exposed to phorbol 12-myristate 13-acetate (PMA) display 51 pS Kir channels in 48% of the cells.15 Similarly, Kir currents predominate in HL-60 cells differentiated to macrophages by 4-6 days of PMA treatment and can be attenuated by exposure to colony stimulating factor-1 (CSF-1) and GTPγS.29 THP-1 monocytes exhibit many of the K+ conductances present in primary monocytes and macrophages and when present set Vrest to more negative levels.30-31 That is, a small percentage of cells possess Kir currents in immature THP-1 monocytes even after 3 days of adherence to glass or polystyrene. When differentiated to macrophages by PMA treatment, the majority of THP-1 macrophages possess 30 pS Kir channels that underlie the Ba2+- and Cs+-sensitive Kir currents. IRK1 mRNA expression, also known as Kir2.1, is significantly enhanced in PMA-differentiated THP-1 macrophages.30-31

Since THP-1 cells display a variety of adhesion molecules on their surface that mediate their interactions with extracellular matrix molecules and other cells, much of our work has been performed in this monocytic cell line to examine the effects of integrin-ligand interactions on the membrane conductances in monocytes. Our initial novel reporting that a similar Kir current is induced by adherence of THP-1 monocytes to activated endothelial cells (ECs) or purified VCAM-1 suggests that the presence of the Kir current may be involved in monocyte activation and/or differentiation (Fig. 1 ).32 We found that when THP-1 cells are bound to uncoated polystyrene (plastic) or unstimulated EC monolayers for 1-5 h only a small percentage of cells (6-14%) possessed Kir currents with a depolarized Vrest (–19 to –24 mV) (Fig. 1B and D). However, when THP-1 cells become adherent to 24-h lipopolysaccharide (LPS)-treated EC monolayers or purified VCAM-1, Kir currents are expressed in 73-81% of the cells which hyperpolarizes the cells by about 20 mV (Fig. 1A and C). Even a brief (15 min) interaction between THP-1 cells and activated endothelial cell monolayers is sufficient to trigger early signaling events such as the initiation of de novo protein synthesis and tyrosine phosphorylation to induce Kir currents 5 h later. It is the specific interaction of upregulated endothelial or purified VCAM-1 with integrin ligand, very late antigen-4 (VLA-4, α4β1), on the surface of THP-1 monocytes that triggers VLA-4 integrin clustering (Fig. 2) and the time-dependent induction of Kir currents.33 Immunocytochemical staining provides direct evidence that VLA-4 integrin clustering occurs on the surface of THP-1 cells when cells are adherent to LPS-ECs or immobilized VCAM-1. The engagement and clustering of VLA-4 integrins produces a Cs+-sensitive hyperpolarization of Vrest that augments store-depleted Ca2+ influx to enhance Ca2+-mediated interleukin-8 (IL-8) production (Fig. 3), all of which can be mimicked by THP-1 cell interaction with crosslinked, immobilized antibody raised against VLA-4 (αVLA-4x).32-34 Preliminary real-time RT-PCR analyses in our laboratory revealed a 3-fold increase in Kir2.1 (IRK1) mRNA in THP-1 cells with clustered VLA-4 integrins compared to THP-1 monocytes bound to polystyrene. We observed a similar augmentation in Kir2.1 mRNA levels in PMA-differentiated THP-1 macrophages compared to undifferentiated THP-1 monocytes (unpublished observations).

Figure 1. A family of digitized whole-cell currents recorded in THP-1 monocytes adherent to (A) 24-h LPS-activated umbilical vein endothelial cells (LPS-ECs) or (B) polystyrene for 5 h.

Figure 1

A family of digitized whole-cell currents recorded in THP-1 monocytes adherent to (A) 24-h LPS-activated umbilical vein endothelial cells (LPS-ECs) or (B) polystyrene for 5 h. A 450-msec pulse stepping from −160 mV to +120 mV in 20-mV increments (more...)

Figure 2. Immunocytochemical staining of VLA-4 surface antigen on THP-1 monocytes adherent to (A) glass (B) lipopolysaccharide-treated HUVECs (LPS-ECs), (D) immobilized VCAM-1 or (E) crosslinked mAbVLA-4 (αVLA-4x) for 5 h.

Figure 2

Immunocytochemical staining of VLA-4 surface antigen on THP-1 monocytes adherent to (A) glass (B) lipopolysaccharide-treated HUVECs (LPS-ECs), (D) immobilized VCAM-1 or (E) crosslinked mAbVLA-4 (αVLA-4x) for 5 h. Arrows indicate clustering of (more...)

Figure 3. A) Changes in [Ca2+]i in THP-1 monocytes adherent to various substrates.

Figure 3

A) Changes in [Ca2+]i in THP-1 monocytes adherent to various substrates. Representative tracings of [Ca2+]i changes that occur in individual THP-1 monocytes adherent to glass, immobilized VCAM-1 or E-selectin for 5 h after the addition of thapsigargin, (more...)

Eder and Fischer35 first described the presence of Kir channels in the majority of murine bone marrow-derived macrophages (BMDMs) cultured for 7 days on polystyrene in the presence of medium supplemented with supernatant of L-929 fibroblast conditioned media (30%L-929CM) as a source of macrophage colony-stimulating factor (M-CSF). Subsequently, Vicente et al36 more fully characterized analogous Ba2+- or Cs+- sensitive Kir currents by demonstrating the presence of Kir2.1 mRNA and protein levels in murine BMDMs cultured under identical culturing conditions which may regulate proliferation processes in these cells. Interestingly, extended treatment with exogenous LPS or TNFα significantly reduced Kir2.1 mRNA and protein levels and the magnitude of Kir currents in these cells. More recently, we have extended our research focus to murine BMDMs in our efforts to better understand the role of K+ transport mechanisms in events leading to macrophage activation/differentiation and cardiovascular disease states such as hypertension and atherosclerosis. Our initial experiments in murine BMDMs that were first cultured in suspension in Teflon jars for 7 to 11 days with 20%L-929CM-supplemented medium and then attached to polystyrene for <1 h revealed the exclusive presence of Cs+-sensitive Kir currents that increased in magnitude about 3-fold from Day 7 to Day 11 and correlated well with Kir2.1 mRNA expression levels (Fig. 4A and C unpublished observations). A lack of Kdr currents in these cells is not in agreement with previous reports in murine BMDMs35-36 and may be explained by the different culturing conditions of 20%L-929CM and suspension cultures. Our preliminary experiments performed in murine BMDMs with clustered VLA-4 integrins revealed an increased expression of Kdr currents accompanied by reduced Kir currents (Fig. 4A-C). Blockade of VLA-4-induced Kdr currents by margatoxin suggest that Kv1.3 underlies the VLA-4-induced Kdr current elicited during depolarization (Fig. 4D).

Figure 4. A family of digitized whole-cell currents recorded in BM-derived macrophages adherent to (A) polystyrene (POLY) or (B) immobilized, crosslinked anti-VLA-4 (VLA-4x) for 5 h.

Figure 4

A family of digitized whole-cell currents recorded in BM-derived macrophages adherent to (A) polystyrene (POLY) or (B) immobilized, crosslinked anti-VLA-4 (VLA-4x) for 5 h. A 250-msec pulse stepping from −160 mV to +60 mV in 20-mV increments was (more...)

A growing body of work studying ion transport mechanisms in brain microglial cells, the resident macrophages of the central nervous system, confirms the predominant presence of similar Kir currents with 30 pS single-channel conductance in cells cultured on polystyrene up to 2 weeks that possess an ameboid shape reflective of a mature macrophage-like morphology. 37-41 A parallel phenomenon occurs in brain macrophages in that culturing microglial cells with M-CSF enhances the magnitude of Kir currents.42-43 mRNA expression of two of the four Kir subfamilies, IRK1 and ROMK1, have been described in brain macrophages while G proteins and LPS activation modulate these currents implicating a role of the GIRK Kir subfamily.44-45

Physiologic and Pathophysiologic Roles of Macrophage Kir Channels

Kir channels play pivotal roles in maintenance of Vrest, regulation of the action potential duration, receptor-dependent inhibition of cellular excitability, secretion and absorption of K+ ions across cell membranes and differentiation of several cell types including monocytes, mast cells, cardiomyocytes, skeletal muscle and neuroblastoma cells.46-49 Monocytes are among the first cells present in lesion-prone areas in the development and progression of atherosclerosis. Upon exposure to a variety of signals, monocytes rapidly differentiate into tissue macrophages in the vascular intima. Our work with VLA-4 integrin clustering in THP-1 monocytes/macrophages provides evidence to suggest that long-lived macrophages accumulated at sites of chronic inflammation associated with cardiometabolic disease states are likely to have greater expression of Kir currents which may act as an early signaling event in monocyte differentiation. Mature macrophages express multiple scavenger receptors that facilitate internalization of modified lipoproteins, leading to the development of cholesterol-laden foam cells.50 Lei et al51-53 recently postulated that the expression of Kir and Kdr currents may modulate human monocyte-derived macrophage differentiation into foam cells. Uptake of oxidized low density lipoprotein (oxLDL) into human PB-derived macrophages over a 60 h-period is accompanied by increased cellular total cholesterol, free cholesterol and cholesterol ester. Even though Kir2.1 and Kv1.3 mRNA and protein levels are unchanged during foam cell formation, exposure to BaCl2 (Kir2.1 blocker) or margatoxin (Kv1.3 blocker) reduces cellular cholesterol content following uptake of oxLDL observations that merit further examination.

Delayed, Outwardly Rectifying K+ (Kdr) Currents

Delayed, outwardly rectifying K+ (Kdr) currents in monocytes/macrophages are typically characterized by 1) a threshold activation voltage at approximately –40 mV, 2) inhibition by charybdotoxin, tetraethylammonium chloride, 4-aminopyridine and margatoxin, 3) contributing to a more depolarized Vrest, 4) inactivation at potentials positive to +30 mV and 5) Kv1.3 subunit primarily underlying the functional current. Kdr currents are expressed in the majority of rat and murine peritoneal macrophages,54 murine J774.1 macrophages,16 human monocytes/macrophages23,31-34 and brain macrophages41,55-56 adherent to polystyrene or glass for 1-4 days (Table 2). A less robust Kdr expression is evident in longer-term cultures at a time when Kir currents predominate (Table 1) suggesting a reduction of Kdr current as these cells develop into mature macrophages.17 Conversely, 50% of alveolar macrophages express 4-AP-sensitive Kdr currents after the cells have been bound to polystyrene for a week.13 Human PB monocytes incubated on a confluent astrocyte monolayer for 2 weeks possess Kir currents but newly express Kdr currents.57 Our work with THP-1 monocytes has revealed that although most cells (75%) express Kdr currents regardless of substrate, the magnitude of the Kdr currents is significantly reduced when the cells are adherent to unstimulated ECs, purified E-selectin, VCAM-1 and αVLA-4x compared to polystyrene or LPS-ECs, an observation that warrants further investigation.32-34 Interestingly, our initial recordings in murine BM-derived macrophages illustrates enhanced expression and amplitude levels of Kdr currents when VLA-4 integrins were clustered with αVLA-4x (Fig. 4).

Table 2. Delayed, outwardly rectifying K+ (Kdr) currents in mononuclear phagocytes.

Table 2

Delayed, outwardly rectifying K+ (Kdr) currents in mononuclear phagocytes.

A yin-yang relationship between Kir and Kdr expression levels in monocytes/macrophages is supported by our observations in human THP-1 cells in that there appears to be a balance of expression of these channels as it relates to substrates.32-34 Cells that predominantly express Kir over Kdr currents are more hyperpolarized approaching EK. Blockade of Kdr currents in cells possessing both types of K+ channels become more hyperpolarized indicating that the relative presence of each current contributes to Vrest. Treatment of murine BM with granulocyte macrophage colony-stimulating factor (GM-CSF) for 7 days to produce neutrophils and immature monocytes predominantly express Kdr currents while treatment of BM with macrophage colony-stimulating factor (M-CSF) to generate mature macrophages largely express Kir currents.35-36 Furthermore, in a protocol which promotes macrophage proliferation, the response to LPS or TNFα is stimulatory for Kdr currents but inhibitory for Kir currents in BM-derived macrophages. A preliminary study of K+ currents in BM-derived macrophages under our culturing and recording conditions demonstrated the absence of Kdr currents until cells were incubated on αVLA-4x for 5 h (Fig. 4) which was paralleled by Kv1.3 mRNA levels. A similar yin-yang phenomenon occurs with Kir and Kdr currents when brain microglial cells are treated for 10 days with M-CSF to produce macrophages or granulocyte macrophage colony-stimulating factor (GM-CSF) to produce neutrophils and immature monocytes.42 M-CSF–treated microglia have a Vrest of −66 mV with 75% of cells possessing Kir currents alone and less than 1% only expressing Kdr currents. In contrast, GM-CSF-treated microglia have a Vrest of –59 mV, 48% of cells only express Kdr currents and 12% of cells only possess Kir currents. Further incubation of M-CSF-treated microglia with GM-CSF pushes the cells to express more Kdr currents. Predominant Kir channel expression may be a prerequisite early signaling event for macrophage differentiation as predominant Kdr channel expression may be for macrophage activation.

Physiologic and Pathophysiologic Roles of Macrophage Kdr Channels

Efforts studying the functional role of Kdr currents in macrophages have focused on their involvement in activation processes and the ability to proliferate. Using a protocol that inhibits proliferation but activates cells, Vicente et al36 demonstrated that Go-arrested BM-derived macrophages treated with LPS or TNF for 24 hrs significantly increases Kdr mRNA and protein levels which underlies enhanced functional whole-cell currents. Single-channel recordings illustrate that Fc-mediated phagocytosis of latex beads by human PB-derived macrophages incubated on glass 1-3 weeks is associated with enhanced inward and outward K+ currents.58 On the other hand, phagocytosis of zymosan, a pathogen extract from Saccharomyces cerevisiae, is not affected by microinjected LPS which reduces both whole-cell Kir and Kdr currents in human PB-derived macrophages adherent to polystyrene for 1 week.23 The capacity of brain microglial cells to act as antigen presenting cells is optimal when microglial are treated with GM-CSF a setting in which Kdr currents predominate.42 LPS activation of rat brain microglial cells also induces Kv1.3 and Kv1.6 mRNA expression within 2-3 h of LPS exposure.44 In murine microglial cells both Kv1.3 and Kv1.5 channel subunit expression is required for the LPS-induced Kdr current and by employing a Kv1.5-/- knockout mouse and an antisense approach, Pannasch et al59 showed that LPS-induced nitric oxide release from murine microglia is reduced in the absence of Kv1.5 in microglia. Margatoxin treatment has also been shown to reduce migration of rat brain macrophages on a fibronectin matrix implicating a role of Kv1.3 channel in this integrin-dependent macrophage function.60

M-CSF-dependent proliferation is inhibited by margatoxin and is accompanied by augmented Kv1.3 expression levels confirming a role of Kv1.3 in BM-derived macrophage proliferation.36 LPS-or TNF-stimulated iNOS protein expression was also inhibited by margatoxin indicating a role of Kv1.3 in macrophage activation. Vicente et al61 further characterized in BM-derived macrophages the expression of Kvβ subunit, their modulation by proliferation and the mode of activation and impact on Kdr current inactivation kinetics. More recently, the co-assembly of Kv1.5 and Kv1.3 subunits to form heterotetrameric channels in BM-derived macrophages influences Kdr current kinetics and could possibly affect macrophage function and potential therapeutic strategies in treating autoimmune and cardiometabolic diseases.62-64

Conclusions

This chapter reviewed the exploration of Kir and Kdr channels in mononuclear phagocytes over the last 30 years with an emphasis on culturing conditions, modulation by substrates and role in macrophage function. It has only been recent that successful attempts have been made to study these K+ currents in monocytes/macrophages as they may be engaged in the human body. Further studies will be necessary to determine the expression levels of other members of the Kir subfamilies: GIRK, ROMK1 and ATPK. As we have demonstrated with chemokine production,33 respiratory burst and other functional endpoints for macrophages are most likely to be enhanced when Kir currents predominate. With the recent introduction of silencing genes through RNA interference technology65-66 and the eventual development of more selective K+ blockers, the identity and role of Kir and Kdr channels in macrophage chemotaxis, the ability to produce a respiratory burst, generate cytokines, engulf pathogens and become a foam cell will most assuredly be elucidated. The study of macrophages isolated from a recently developed mouse with a point mutation (α4Y991A) that blocks α4 integrin signaling67 and possesses reduced metabolic consequences of high fat diet-induced obesity provides an alternative approach to determining the link between integrin-mediated K+ channel activity and macrophage function. These new insights can then be applied in the development of therapeutic agents targeting macrophage Kir/Kdr channel activity to favorably influence risk factors for hypertension, atherosclerosis and diabetes.

Acknowledgments

I would like to thank Drs. Pamela Gunter-Smith and Gary Gibbons for providing feedback on this chapter.

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