Review Article
Open Access
Regulation of Murine Dendritic Cell Functions by Calcium
Channels
Gabriela Mellado-Sanchez, Hector Vivanco-Cid, and Adriana Sumoza-Toledo*
Multidisciplinary Laboratory of Biomedical Sciences, Institute of Medico-Biological, Research Campus
Veracruz Universidad Veracruzana, Iturbide S/N. CP. 91700, Veracruz, Mexico
*Corresponding author: Adriana Sumoza-Toledo, Multidisciplinary Laboratory of Biomedical Sciences, Institute of Medico-Biological, Research
Campus Veracruz Universidad Veracruzana, Iturbide S/N. CP. 91700, Veracruz, Mexico, Tel: 2299318011; E-mail:
@
Received: July 14, 2014; Accepted: September 13, 2014; Published: September 28, 2014
Citation: Mellado-Sanchez G, Vivanco-Cid H, Sumoza-Toledo A (2014) Regulation of Murine Dendritic Cell Functions by Calcium
Channels. SOJ Immunol 2(2): 1-6. http://dx.doi.org/10.15226/soji/2/2/00113
Abstract Top
Dendritic Cells (DCs) are highly potent Antigen-Presenting Cells
(APCs) that have a key role in mediating tolerance or immunity
to self and non-self antigens. In their immature stage DCs are
highly phagocytic and undergo a maturation process after taking
up an antigen. DC maturation is characterized by activation of
mechanisms of antigen presentation, increased expression of Major
Histocompatibility Complex (MHC) class II and co-stimulatory
molecules in the plasma membrane, and secretion of cytokines
and chemokines. Despite the fact that the role of calcium (Ca2+) in
DC function has been clearly established, regulation of Ca2+ signals
in these cells is not well known. However, recently it has been
demonstrated that functional capacitative Ca2+ release-activated
Ca2+ (CRAC), Transient Receptor Potential Melastatin-2(TRPM2)
and TRP Vanilloid- 1 (TRPV1) channels are critical for mouse DC
maturation and migration. Also, Ryanodine Receptor-1 (RyR1)
signaling activated by L-type Ca2+ channel CaV1.2 cause rapid MHC-II
expression in the plasma membrane of DCs. The understanding of the
regulation of Ca2+ signals in DCs is essential, to potentially modulate
DC functions in disease processes. Therefore, in this review, we
discuss recent studies on the expression and roles of Ca2+ channels in
DC biology and function.
Keywords: Calcium; Dendritic cells; Ion channels; CRAC; TRPM2; TRPV1; RyR
Keywords: Calcium; Dendritic cells; Ion channels; CRAC; TRPM2; TRPV1; RyR
Introduction
Dendritic cells (DCs) are Antigen-Presenting Cells (APCs) that
play a critical role in the regulation of both: innate and adaptive
immune responses. Initially, DCs were described by Ralph
Steinman in 1973 [1], as a different immune cell population in
the spleen and lymph nodes of mice. DCs are the only APCs that
have the ability to induce a primary immune response in naïve T
lymphocytes, and therefore they are considered the most potent
APCs, influencing the type and quality of the response [2]. DCs
can exist in two main states: In a steady state immature Dendritic
Cells (iDCs) and fully mature DCs (mDCs). The distinction
between immature and mature DCs is based on phenotypic
markers and biological functions [3]. iDCs lack or have low levels
of several important accessory molecules that mediate binding
and stimulation of T cells, such as CD40, CD54, CD58, CD80, CD83
and CD86. They also express high levels of intracellular Major Histocompatibility Complex (MHC) class II molecules. On the cell
surface, iDCs express high levels of chemokine receptors such as
CCR1, CCR5, and CCR6. Functionally, iDCs are characterized by
high endocytic activity and low T-cell stimulation potential [4-
7]. Phenotypic maturation is characterized by down-regulation
of the capacity to capture antigens and up regulation of antigen
processing and presentation functions. The mDCs phenotype
is characterized by expression of high levels on the surface of
MHC II, CCR7, CD40, CD54, CD80, CD83, CD86, CD58 and low
expression of CCR1, CCR5, CCR6 [4-7]. DCs are also able to interact
with other cells besides T cells, such as Natural Killer (NK) cells,
neutrophils, and epithelial cells [8-10]. Other critical roles of
DCs in immunity are the maintenance of B cell function, the
establishment of immunological memory, and the maintenance
of peripheral tolerance [11].
DC Subsets
DCs are widely distributed in all tissues, especially in those
that provide an environmental interface, such as the skin and
mucosal tissues. Similar to other immune cells, DCs are divided
in subsets, which have been shown to possess a differential
ontogeny, morphology, phenotype, transcriptional programs
and functions [12]. In mice, DCs can be subdivided into CD8+
CD11b+ and CD8- CD11b+ conventional DCs (cDCs), a lineage
originated from a myeloid progenitor in the bone marrow. cDCs
characteristically express high levels of MHC class II and the
integrin CD11c, but not B220 marker [13-16]. cDC subsets are
activated by microbial products through cell surface Toll- like
Receptors (TLRs) to produce inflammatory cytokines such as
interleukin (IL)-1, IL-6, IL-12, and tumor necrosis factor-alpha
(TNF-α) and they are specialized in the activation of CD8+ and
CD4+ T cells [17]. They have a predominant role in MHC- II
presentation and immunological tolerance, inducing clonal
deletion of auto reactive T cell or Treg differentiation [18,19].
CD8+ CD11b+ DCs are specialized in the induction of CD8+ T cell
immunity. They are the main source of IL-12 and IL- 15 [18], two
cytokines involved in the differentiation of cytotoxic CD8+ T cells
and have the ability to prime CD8+ T cell responses in a crosspresentation
dependent mechanism [20]. CD8- CD11b+cDCs can
sense pathogens and migrate from non-lymphoid tissues to
regional lymph nodes charged with self and foreign antigens. Other cDCs subsets include migratory CD103+ CD11b- DCs,
CD103- CD11b+ DCs, and Langerhans Cells (LCs), which are
abundant in the intestinal mucosa and skin [21-24]. DCs can
also be originated from a lymphoid progenitor. Plasmacytoid
DCs (pDCs) are the prominent subset of this group, which
phenotypically express CD8α+ CD11b- B220+ DC SING+ [25,26].
The other pDCs specific surface marker is the murine Siglec H
[27]. pDCs are a specialized population that have the ability to
produce very large amounts of interferon alpha/beta (IFN-
α/β) upon activation and a limited ability to prime naïve CD4+
and CD8+ T cells. They are an important DCs subset in viral and
anti-tumoral immunity [26]. Other DCs subsets include in vitro
or in vivo inflammatory or infection-derived DCs, which develop
from monocytes in response to stimulation such as Granulocyte-
Macrophage Colony-Stimulating Factor (GM-CSF), IL-4 and
TNF-α [28]. A summary of DC subsets is showed in Table 1.
Early studies using Ca2+ ionophores and Ca2+ chelators have shown that Ca2+ signals may trigger maturation and functional properties of DCs [29-31]. Intracellular Ca2+ ions are crucial second messengers to initiate signaling pathways for fundamental cellular functions, such as cell cycle, survival, apoptosis, migration, and gene expression[32,33]. Regulation of intracellular Ca2+ concentrations ([Ca2+]i; ~100 nM) involves both Ca2+ entry from the extracellular space and Ca2+ release from intracellular stores, such as calciosomes, Endoplasmic Reticulum (ER), lysosomes, or mitochondria, by specialized pumps and ion channels [32-34]. Although [Ca2+]i increase triggers signaling pathways in the cell, the exquisite spatial and temporal organization of Ca2+ , oscillations, waves and sparks might also provide a code for selective activation of signaling pathways and their duration. For example, a short [Ca2+]i increase is observed in lymphocytes during immunological synapse, release of lytic granules, and cytotoxicity. In contrast, prolonged [Ca2+]i increase regulates cytokine production, cell differentiation, effector
Early studies using Ca2+ ionophores and Ca2+ chelators have shown that Ca2+ signals may trigger maturation and functional properties of DCs [29-31]. Intracellular Ca2+ ions are crucial second messengers to initiate signaling pathways for fundamental cellular functions, such as cell cycle, survival, apoptosis, migration, and gene expression[32,33]. Regulation of intracellular Ca2+ concentrations ([Ca2+]i; ~100 nM) involves both Ca2+ entry from the extracellular space and Ca2+ release from intracellular stores, such as calciosomes, Endoplasmic Reticulum (ER), lysosomes, or mitochondria, by specialized pumps and ion channels [32-34]. Although [Ca2+]i increase triggers signaling pathways in the cell, the exquisite spatial and temporal organization of Ca2+ , oscillations, waves and sparks might also provide a code for selective activation of signaling pathways and their duration. For example, a short [Ca2+]i increase is observed in lymphocytes during immunological synapse, release of lytic granules, and cytotoxicity. In contrast, prolonged [Ca2+]i increase regulates cytokine production, cell differentiation, effector
Figure 1: Calcium channels in DCs: Extracellular signals (chemokines, cytokines, microbial peptides, etc) are recognized by DCs by means of G protein-
coupled receptors or receptor protein tyrosine kinases, activating the formation of 1,4,5-triphosphate (IP3) that in turn binds to IP3 receptors
in the ER and calciosomes, causing Ca2+ release. Decrease in the luminal Ca2+ in the ER is detected by the Stromal Interaction Molecule 1/2 (STIM1/2)
resulting in the activation of Capacitative Ca2+ Release-Activated Ca2+ (CRAC) channels, allowing Ca2+ influx across the plasma membrane. Chemokines
also activate Transient Receptor Potential Melastatin- 2(TRPM2) channels in DC lysosomes. The Ca2+ signals activate transcription factors such as
Nuclear Factor of Activated T cells (NFAT) or Nuclear Factor-κB (NF-κB) for gene expression. TRPM4, a Ca2+ activated TRP channel that allows Na+
into the cell is expressed in the plasma membrane of DCs and indirectly regulates DC functions by decreasing the driving force for Ca2+ entry through
CRAC channels. DCs also express TRP Vanilloid-1 (TRPV1) and Ryanodine receptor (RyR) channels but their functions are still not clear.
DC subsets |
CD8α |
CD103 |
CD205 |
CD11b |
B220 or CD45RA |
DC-SING |
Langerin (CD207) |
MHC class II |
CD11c |
pDCs |
+ |
- |
- |
- |
+ |
++ |
- |
+ |
+ |
CD8α+ DCs |
+ |
low |
+ |
+ |
- |
- |
+/- |
++ |
+++ |
CD8α-CD11b+ DCs |
- |
+/- |
+ |
+ |
- |
ND |
- |
++ |
+++ |
CD103+ DCs |
- |
+ |
++ |
- |
- |
- |
+ |
++ |
++ |
Lung |
- |
+ |
- |
+ |
- |
- |
- |
++ |
++ |
Langerhans cells |
- |
- |
++ |
+ |
- |
- |
++ |
++ |
++ |
Monocyte-derived inflammatory DCs |
- |
- |
- |
+ |
- |
+ |
- |
++ |
++ |
Table 1: Dendritic cell subsets.
functions, etc. The present review addresses the role of Ca2+
channels in DC functions [33,35].
Ca2+ Release-Activated Ca2+ Channels (CRAC) in DC
The main mechanism for Ca2+ entry in immune cells, including
DCs, is the Store-Operated Ca2+ Entry (SOCE). SOCE is activated
by Ca2+ release from the intracellular stores and involves the
activation of Capacitative Ca2+ Release-Activated Ca2+ (CRAC)
channels in the plasma membrane (Figure 1) [34,36,37].
SOCE-mediated Ca2+ influx provides ions not only for signaling
purposes, but also for ER and calciosomes store refilling. SOCE
activation can be initiated by stimulation of G protein-coupled
receptors or stimulation of receptor protein tyrosine kinases
by external signals (cytokines, chemokines, bacterial peptides,
etc), leading to activation of Phospholipase C (PLC) that in turn
hydrolyzes phosphatidylinositol- 4,5- bisphosphate (PIP2) to
release Inositol-1,4,5-triphosphate (IP3) and Diacylglycerol
(DAG) [33,34].The subsequent binding of IP3 to IP3 receptors in
the ER and calciosomes causes a rapid and transient Ca2+ release,
raising the [Ca2+]i (Figure 1). On the other hand, the decrease in
the luminal Ca2+ in the ER is detected by the stromal interaction
molecule 1/2 (STIM1, STIM2; Ca2+ sensors; Figure 1), resulting
in its conformational change (oligomerization and aggregation)
and activation of CRAC channels [33,34]. CRAC channels, which
pore is formed by CRACM/Orai 1-3 proteins, then allow influx
of extracellular Ca2+ across the plasma membrane (Figure 1).
CRAC are highly Ca2+-selective, low conductance channels with
a characteristic inwardly rectifying current-voltage relationship
[33,34]. Interestingly, Orai and STIM proteins may have different
tissue distribution, selectivity and conductivity for Ca2+.
As a result of [Ca2+]i increase several signaling pathways
and transcription factors are activated, such as the calmodulincalcineurin
pathway that activate the Nuclear Factor of Activated
T cells (NFAT), the Ca2+- dependent kinase-calmodulin (CaMK)
pathway which activate the Cyclic-adenosine monophosphate-
Responsive Element Binding protein (CREB), and the nuclear
factor B (NFκB) pathway. Moreover, the DAG formed from PIP2
hydrolysis can activate the Protein kinase C pathway (PKC), and
Ras-mitogen-activated protein kinase, which ultimately activate
transcription factors such as Activating Protein-2 (AP-2) and
NFκB [33,34].
Although the presence of CRAC currents and its role in DC maturation have previously been demonstrated in mouse DCs [36], it has only recently been shown that Orai2 and STIM2 are most abundant in DCs [38]. Furthermore, recruitment of Orai2 and STIM2 towards the immunological synapse has been observed during antigen presentation of DC to T lymphocytes [38]. Likewise, studies using CRAC blockers have shown that this channel plays an important role in DC maturation, cytokine production (TNF-α and IL-6) and chemotaxis [37]. DC maturation can be triggered in vitro by increasing [Ca2+]i by stimulating them with peptidoglycan (PGN), CpG DNA, microbial products like Lipopolysaccharide (LPS) [39,40], or ionophores [29-31]. It has also been suggested that LPS, PGN and CpG induced activation of PLC γ2 [39], which in turn acts on PIP2 to produce IP3 that leads to Ca2+ release from intracellular stores; followed by CRAC channel activation (reviewed in [34]) causing the nuclear translocation of calcineurin-dependent NFAT factor and cytokine production, such as IL-2 [33,41]. On other hand, DC maturation with Ca2+ ionophoresis associated with NFκB activation, likely by activating Calcium/Calmodulin-dependent Kinase II (CaMKII), which inactivates NFκB-inhibiting molecule IkB similar to what has been shown in T cells [42].
In addition, DC chemotaxis depends on Ca2+ influx. DC chemotactic response to chemokines, including (C-X-C motif) ligand 12 (CXCL12) and (C-C motif) ligand 21 (CCL21), results in PLC activation, IP3 production, Ca2+ release from intracellular stores, and subsequent activation of CRAC channels and Ca2+ influx [31,40,43,44].
Although the presence of CRAC currents and its role in DC maturation have previously been demonstrated in mouse DCs [36], it has only recently been shown that Orai2 and STIM2 are most abundant in DCs [38]. Furthermore, recruitment of Orai2 and STIM2 towards the immunological synapse has been observed during antigen presentation of DC to T lymphocytes [38]. Likewise, studies using CRAC blockers have shown that this channel plays an important role in DC maturation, cytokine production (TNF-α and IL-6) and chemotaxis [37]. DC maturation can be triggered in vitro by increasing [Ca2+]i by stimulating them with peptidoglycan (PGN), CpG DNA, microbial products like Lipopolysaccharide (LPS) [39,40], or ionophores [29-31]. It has also been suggested that LPS, PGN and CpG induced activation of PLC γ2 [39], which in turn acts on PIP2 to produce IP3 that leads to Ca2+ release from intracellular stores; followed by CRAC channel activation (reviewed in [34]) causing the nuclear translocation of calcineurin-dependent NFAT factor and cytokine production, such as IL-2 [33,41]. On other hand, DC maturation with Ca2+ ionophoresis associated with NFκB activation, likely by activating Calcium/Calmodulin-dependent Kinase II (CaMKII), which inactivates NFκB-inhibiting molecule IkB similar to what has been shown in T cells [42].
In addition, DC chemotaxis depends on Ca2+ influx. DC chemotactic response to chemokines, including (C-X-C motif) ligand 12 (CXCL12) and (C-C motif) ligand 21 (CCL21), results in PLC activation, IP3 production, Ca2+ release from intracellular stores, and subsequent activation of CRAC channels and Ca2+ influx [31,40,43,44].
Transient Receptor Potential (TRP) Channel in
DC
Our previous study has shown that lysosomal Ca2+ release
through TRP Melastatin-2 (TRPM2) channel, the second member
of the TRP melastatin-related channel family, plays an important
role in DC maturation and chemotaxis (Figure 1) [40]. TRPM2
channel is expressed in DC only in lysosomes [40]. This channel is
synergically activated by Adenosine Diphosphate Ribose (ADPR)
and Ca2+, and allows entry of sodium (Na+), Ca2+, potassium (K+)
and caesium (Cs+) into the cytosol. In addition to Ca2+, cyclic ADPR
(cADPR), hydrogen peroxide (H2O2) and Nicotinic acid Adenine
Dinucleotide Phosphate (NAADP) may directly or indirectly
facilitate TRPM2 gating by ADPR [45]. DCs may produce ADPR by means of CD38 activity, an ectoenzyme that use β-Nicotinamide
Adenine Dinucleotide (β-NAD+) as a substrate to catalyse the
production of ADPR, cADPR, and NAADP, and by activation of
the Poly(ADPR)-Polymerase/Poly(ADP-ribose) Glycohydrolase
(PARP/PARG) pathway during DNA repair, replication and
transcription [45]. DCs lacking TRPM2 channels express reduced
levels of co stimulatory molecules, such as CD80, CD86, MHC-II
and CD83, in the plasma membrane when they are stimulated
with TNF-α and CpG DNA, than TRPM2 expressing-DCs [40]. They
also show reduced Ca2+ signals in response to CXCL12 and CCL21,
affecting the chemotaxis response towards these chemokines
[40]. However, the mechanisms that link CD38 and PARP/PARG
pathways to TRPM2 and to chemokine receptors are still not
clearly understood
DCs also express TRP Vanilloid-1 (TRPV1) protein in their plasma membrane, another non-selective Ca2+ channel of the TRP family, which is activated by capsaicin. But, there is controversial data on the expression and function of this channel in DCs. Earlier studies from Basu and Srivastava showed that extracellular Ca2+ influx via TRPV1 activation induces mouse DC maturation and provokes increase in the expression level of MHC class II and CD86 on the surface [46]. Conversely, O’Connell PJ et al. [47] did not detect TRPV1 transcripts and TRPV1 currents in bone marrow derived-mouse DCs. A recent study by Tóth BI et al. [48] shows molecular and functional expression of TRPV1 channels in monocyte derived-human DCs. Although DC stimulation with capsaicin induces Ca2+ mobilization, this reduces the expression level of maturation markers in DCs, such as CD83 and CCR7 [48]. On the other hand, TRPM4, a Ca2+-activated TRP channel that allows Na+ into the cell, indirectly regulates DC migration but not maturation by decreasing the driving force for Ca2+ entry through CRAC channels [43].
DCs also express TRP Vanilloid-1 (TRPV1) protein in their plasma membrane, another non-selective Ca2+ channel of the TRP family, which is activated by capsaicin. But, there is controversial data on the expression and function of this channel in DCs. Earlier studies from Basu and Srivastava showed that extracellular Ca2+ influx via TRPV1 activation induces mouse DC maturation and provokes increase in the expression level of MHC class II and CD86 on the surface [46]. Conversely, O’Connell PJ et al. [47] did not detect TRPV1 transcripts and TRPV1 currents in bone marrow derived-mouse DCs. A recent study by Tóth BI et al. [48] shows molecular and functional expression of TRPV1 channels in monocyte derived-human DCs. Although DC stimulation with capsaicin induces Ca2+ mobilization, this reduces the expression level of maturation markers in DCs, such as CD83 and CCR7 [48]. On the other hand, TRPM4, a Ca2+-activated TRP channel that allows Na+ into the cell, indirectly regulates DC migration but not maturation by decreasing the driving force for Ca2+ entry through CRAC channels [43].
Ryanodine and Purinergic Receptors in DC
Ryanodine Receptor-1 (RyR1), a channel expressed in
intracellular Ca2+ stores, is also expressed in DCs [49,50]. RyR1
signaling coupled with L-type Ca2+ channel CaV1.2, which has
been also detected in DCs, cause rapid MHC class II expression
in the plasma membrane of DCs [50]. Interestingly, RyRs are also
activated by cADPR and NAADP+, and might contribute through
these pathways to DC maturation [44,51,52]. Finally, DCs express
Purinergic Receptors (P2Rs), P2X (ligand-gated ion channels) and
P2Y (G-protein coupled receptors) on their surface, such as P2X1,
P2X4, and P2X7, and P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, and P2Y14,
respectively. DC stimulation with Adenosine Triphosphate
(ATP), a Damage-Associated Molecular Pattern (DAMP) molecule
released by injured cells during inflammation and necrosis, or
UTP results in characteristic Ca2+ signaling associated to P2X or
P2Y, mainly P2X7 [53-57].
Concluding Remarks
Not much is known about Ca2+ channel expression and
Ca2+ regulation in DCs. Recent studies have addressed the role
of CRAC, TRPV1, TRPM2, RyR1 and CaV1.2 channels in DC
maturation and migration. However, the mechanisms that lead
to activation of these channels during DC function are not well understood. Moreover, future studies still need to address which
channels regulate Ca2+ signals during antigen presentation,
immune synapse, apoptosis, and other DC functions. The meaning
of Ca2+ oscillations, frequency and patterns are unknown, which
might play an important role in establishing and/or maintaining
immunological tolerance or immunity to self and non-self
antigens.
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