. 2018 Jul 4;7(7):70. doi: 10.3390/cells7070070

Table 1.

Functional impact of selected ion channels and transporters on inflammation.

1. Modulation of Calcium Currents
1.1 Through Direct Involvement in Calcium Influx/Efflux
1.1.1 SOCE
Channel	Permeability	Expression (immune cells)	Biological effects	Clinical correlates	Ref.
ORAI1	Ca²⁺	Neutrophils, Lymphocytes	Neutrophils: proliferation, degranulation, cytokines production, cell polarization, migrational guidance with LFA1. Lymphocytes: B, T and NK cell proliferation, cytokine production and/or cytotoxicity in vitro; immunity to infection, T cell-mediated autoimmunity and inflammation, and allogeneic T cell responses in vivo; Treg cell development	CRAC channelopathywith immunodeficiency, autoimmunity, lymphoproliferation, muscular hypotonia and ectodermal dysplasia caused by mutations in STIM1 and ORAI1	[10,27,60,61]
ORAI2/3	Ca²⁺	Neutrophils, Lymphocytes	Cell proliferation, Cytokines production	ND	[10,27,60,61]
STIM1	NA	Neutrophils, Lymphocytes, DC, mast cells	Neutrophils: phagocytosis and ROS production Lymphocytes: cytokine production in T and B cells, Treg functionality Mast cells: FcεR-triggered SOCE	ND	[13,14,27,62,63,64]
STIM2	NA	Neutrophils, Lymphocytes, DC, mast cells		Mice deficient of STIM1/2 develop a lymphoproliferative disorder because of dysfunction of Treg cells.	[13,14,27,62,63,64]
IP3Rs	Ca²⁺	All cells	Physiological development of B and T cells	ND	[16,17,18,19]
TRPC1	Ca²⁺, Na⁺	Endothelium	Enhanced vascular permeability after TNF/thrombin stimulation	ND	[65,66,67]
TRPC6	Ca²⁺, Na⁺	Platelets	Dense granules secretion after thrombin stimulation	ND	[68]
1.1.2 ROCE
Channel	Permeability	Expression (immune cells)	Biological effects	Clinical correlates	Ref.
TRPM2	Ca²⁺, Na⁺	Neutrophils, lymphocytes, macrophages and DC	Neutrophils: increased activation and endothelial adhesion Lymphocytes: T cell proliferation and cytokine secretion Macrophages and dendritic cells: regulation of ROS formation	Mice lacking TRPM2 have milder ischaemia-reperfusion injury after myocardial infarction and attenuated experimental brain inflammation	[54,69,70,71,72,73,74,75]
TRPC3	Ca²⁺, Na⁺	Lymphocytes, macrophages	Lymphocytes: T cell activation downstream the TCR Macrophages: enhanced pro-inflammatory activation	Mice: accelerated atherosclerosis	[76,77,78]
TRPC6	Ca²⁺, Na⁺	Lymphocytes, neutrophils, endothelium, platelets	Lymphocytes: T cell activation Neutrophils: chemotaxis, Endothelium: enhanced endothelial permeability and activation Platelets: TXA2-dependent expression of glycoproteins IIb-IIIa and P-selectin, release of platelet dense granules	Mice: TRPC6 ko associates with milder airway hypersensitivity in asthma models Humans: single study suggesting an association between a TRPC6 polymorphism and neuropsychiatric SLE	[79,80,81,82,83,84,85]
TRPV4	Ca²⁺, Na⁺	Macrophages	Cell activation after lung barotrauma.	Mice: exacerbated lung inflammation in acute lung injury and increased inflammatory hyperalgesia	[30]
P2X₁R, P2X₄R	Ca²⁺, Na⁺	Lymphocytes, neutrophils, eosinophils, monocytes/macrophages, mast cells, and DC	Lymphocytes: T cell proliferation; cytokine production; thymocyte apoptosis Macrophages: PGE₂ release, inflammasome activation	ND	[86,87]
P2X₇R	Ca²⁺, Na⁺, other cations		Lymphocytes: T cell survival and cytokine production (downstream the TCR); T cell differentiation into Th17 vs. Treg Macrophages: activation of the NLRP3 inflammasome Mast cells, eosinophils, DC: inflammatory activation	Mice lacking P2X₇R have attenuated allergic airway response, graft vs. host disease, allograft rejection	[88,89,90]
1.1.3 VOCE
Channel	Permeability	Expression (immune cells)	Biological effects	Clinical correlates	Ref.
Ca_v1.1-4	Ca²⁺	Lymphocytes	T cell survival, differentiation and progression to effector function	ND	[31,32]
1.1.4 Direct calcium entry following upregulation
Channel	Permeability	Expression (immune cells)	Biological effects	Clinical correlates	Ref.
TRPC3	Ca²⁺, Na⁺	Macrophages/microglia	Regulation of cellular activation	Mice: reduced brain inflammation and post-ischaemic myocardial damage	[28,91,92]
TRPC5	Ca²⁺, Na⁺	Lymphocytes	Inhibition of Teff activation by Treg	Mice: protection from experimental arthritis	[93,94]
TRPV1	Ca²⁺, Na⁺	T lymphocytes	Cell activation (by associating to TCR)	ND	[95]
TRPV2	Ca²⁺, Na⁺	Macrophages	Phagocytosis, chemotaxis, following FCγR activation	Mice: TRPV2 deletion prompts accelerated mortality in bacterial infections Humans: cystic Fibrosis macrophages exhibit a defect in TRPV2-mediated calcium influx	[51,96]
TRPV5,6	Ca²⁺, Na⁺	Lymphocytes	Cell activation and proliferation (the channels are constitutively active and regulated by endocytosis or at gene expression level).	ND	[97]
1.2 Through intracellular second messengers
Channel	Permeability	Expression (immune cells)	Biological effects	Clinical correlates	Ref.
TRPM7	Mg²⁺, Ca²⁺	Lymphocytes, macrophages, mast cells	Lymphocytes: activation downstream BCR and TCR; thymocyte development; production of thymocyte growth factor Macrophages: survival and M2 polarisation Mast cells: survival and activation	ND	[98,99,100,101,102,103]
MAGT1	Mg²⁺	Lymphocytes	CD4+ T cell development and activation; immunity to EBV	XMEN syndrome (X-linked mutations in MAGT1)	[104]
ZIP6	Zn²⁺	T cells, DC	T cells: sustained calcium currents enhancing TCR-related pathways and promoting T cell activation DC: inhibition of maturation for antigen presentation	Genetically determined zinc deficit (mutated ZIP4 in the intestinal mucosa) causes acrodermatitis enteropathica with immunodeficiency	[26]
ZIP8	Zn²⁺	T cells	Sustained calcium currents enhancing TCR-related pathways and promoting T cell activation		[26]
1.3 Through alterations of cell polarisation
Channel	Permeability	Expression (immune cells)	Biological effects	Clinical correlates	Ref.
NCX1	Ca²⁺, Na⁺	NeutrophilsMacrophages	Neutrophils: recovery from activation Macrophages: activation, cytokine (TNF) secretion	A single association study suggests potential links among NCX polymorphisms and SLE phenotypes (including severe nephritis)	[11,43,44]
NKCC2	Na⁺, K⁺, 2Cl⁻	Lymphocytes	Adaptation to extracellular hypertonicity, which eventually leads to the activation of the p38/MAPK → NFAT5 → SGK pathway, which favours Th17 differentiation	ND	[37]
ENaC	Na⁺
NHE1	Na⁺, H⁺
TRPM4	Na⁺, Ca²⁺	Lymphocytes, macrophages and DC, mast cells	Lymphocytes: T helper motility and cytokine production (IL2, IL4, and IFNγ). Macrophages: phagocytosis and cytokine release DC: motility Mast cells: regulation of cell activation	Mice: lack of TRPM4 associates with reduced survival in sepsis and more intense anaphylaxis	[105,106,107,108]
GABA_A-R	Cl⁻	Lymphocytes, macrophages and DC, neutrophils	Inhibition of cell activation	In preclinical models GABAergic drugs, protects against type 1 diabetes (T1D), experimental autoimmune encephalomyelitis (EAE), collagen-induced arthritis (CIA), contact dermatitis and allergic asthma. Treatment with gabapentin and pregabalin improved psoriasis (case report).	[49]
CFTR	Cl⁻	Lymphocytes, macrophages	Lymphocytes: modulation of cytokine secretory profile (IL5, IL10) in T cells Macrophages: cytokine release, phagocytosis	Cystic fibrosis	[51,109]
K_v1.3	K⁺	Lymphocytes	Enhanced activation of the NLRP3 inflammasome and of IL1β production. Enhanced cell survival and prolonged activation.	A single phase Ib study on dalazatide (a specific K_v1.3 inhibitor) shows promise. Applications in SLE have been proposed.	[110,111,112]
KCa3.1	K⁺	Lymphocytes, macrophages, endothelium	Lymphocytes: sustained TCR-induced calcium currents to support long-lasting effector functions. Macrophages: activation, chemotaxis, infiltration of atherosclerotic plaques Endothelium: proliferation	Encouraging evidence of efficacy of K_Ca3.1blockers in several models of inflammatory vasculopathy and autoimmunity.	[47,113,114,115,116]
Na_v1.5 (SCN5A)	Na⁺	T cells	Positive selection of thymocytes	ND	[46]
P2X₇R	Ca²⁺, Na⁺ and other cations	Macrophages	Cell death for prolonged depolarisation in case of sustained receptor ligation.	ND	[117]
1.4 Through alterations in the geographical distribution of intracellular calcium
Channel	Permeability	Expression (immune cells)	Biological effects	Clinical correlates	Ref.
TRPC1	Ca²⁺, Na⁺	Neutrophils	Cell polarisation for chemotaxis	ND	[65,66,67]
2. Modulation of intracellular pH and production of reactive oxygen species
Channel	Permeability	Expression (immune cells)	Biological effects	Clinical correlates	Ref.
TRPM2	Ca²⁺, Na⁺	Macrophages and DC	Macrophages and DC: regulation of ROS formation, phagocytosis and bacterial killing	ND	[71,75]
H_v1/VSOP	H⁺	lymphocytes, granulocytes, macrophages and DC	All cells: phagocytosis and ROS production B cells: BCR signalling	Mice: loss of the receptor prompts impaired killing of phagocytosed bacteria, ROS production and migration by leukocytes and impaired antibody responses.	[15,53]
NCX	Ca²⁺, Na⁺	DC	Activation of NADPH oxidase and polarisation towards pro-inflammatory DC.		[42]
ENac	Na⁺
NHE	Na⁺, H⁺
3. Modulation of endosomal pH
Channel	Permeability	Expression (immune cells)	Biological effects	Clinical correlates	Ref.
TRPC6	Ca²⁺, Na⁺	Macrophages	Phagocytosis and bacterial killing	ND	[8]
TRPM2	Ca²⁺, Na⁺	Macrophages and DC	Phagocytosis and bacterial killing	ND	[71,75]
Proton ATPases	H⁺	Macrophages	Phagocytosis and bacterial killing	ND	[118]
Na_v1.5 (SCN5A)	Na⁺	Macrophages	endosomal acidification and phagocytosis. Possible polarisation towards an antinflammatory phenotype	Mice: enhanced recovery from EAE.	[45,119]
CLIC 1	Cl⁻	Macrophages and DC	Phagocytosis, antigen processing and presentation.	ND	[9,120]
4. Modulation of other intracellular signalling pathways
Channel	Permeability	Expression (immune cells)	Biological effects	Clinical correlates	Ref.
TRPC1	Ca²⁺, Na⁺	Macrophages, Mast cells	Macrophages: inhibition of IL1β through other ion channels and transporters Mast-cells: inhibition of calcium-dependent release of TNF in the late phase of cell activation	Mice: delayed recovery from anaphylaxis	[77,121]
5. Other effects
Channel	Permeability	Expression (immune cells)	Biological effects	Clinical correlates	Ref.
SLC5A11	Na⁺, glucose	Leukocytes (low)	Leukocytes: control of cell osmolarity under hypernatriemic environment, energy uptake, TNF-dependent apoptosis	Polymorphisms associated with susceptibility to SLE	[55,122]
CLIC 1	Cl⁻	Macrophages	Modulation of cytokine gene expression and processing (conflicting results)	ND	[9,58,59]
CLIC 4	Cl⁻	Macrophages		ND	[9,58,59]

Abbreviations. Ca_v: voltage-gated calcium channels; CFTR: cystic fibrosis transmembrane conductance regulator; CLIC: chloride intracellular channels; DC: dendritic cells; EAE: experimental allergic encephalomyelitis; ENaC: epithelial sodium channel; GABA_A-R: gamma-aminobutyric acid receptor type A; NADPH: nicotinamide adenine dinucleotide phosphate; NCX1: sodium-calcium exchanger 1; ND: not determined; NHE1: sodium-hydrogen exchanger 1; NKCC2: sodium-potassium-2 chloride exchanger; PGE2: prostaglandin E2; ROCE: receptor-operated calcium entry; SLC5A11: sodium glucose cotransporter; SOCE: store-operated calcium entry; STIM: stromal interaction molecule; TCR, T cell receptor; TRP: transient receptor potential channel; TXA2: thromboxane A2; VOCE: voltage-operated calcium entry; VSOP: voltage-sensing domain only protein; XMEN, X-linked immunodeficiency with Mg²⁺ defect and EBV infection and neoplasia; ZIP: zinc-regulated transporter (ZRT)/iron regulated transporter(IRT)-like protein.