Ion Channels and Transporters in Inflammation: Special Focus on TRP Channels and TRPC6
Abstract
:1. Introduction
2. Elementary Immunology: An Expanding Landscape
3. Multiple Roles for Members of the TRP Channel Family in Inflammation
4. TRPC6 and Immune Responses
5. Effects of TRPC6 Activation and Function on Inflamed Tissues
6. Conclusions
Acknowledgments
Conflicts of Interest
References
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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 | |
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 | Mice deficient of STIM1/2 develop a lymphoproliferative disorder because of dysfunction of Treg cells. | |||
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. |
Cav1.1-4 | 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 | T cells | Sustained calcium currents enhancing TCR-related pathways and promoting T cell activation | |||
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] |
GABAA-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] |
Kv1.3 | 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 Kv1.3 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 KCa3.1blockers in several models of inflammatory vasculopathy and autoimmunity. | [47,113,114,115,116] |
Nav1.5 (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] |
Hv1/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] |
Nav1.5 (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− |
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Ramirez, G.A.; Coletto, L.A.; Sciorati, C.; Bozzolo, E.P.; Manunta, P.; Rovere-Querini, P.; Manfredi, A.A. Ion Channels and Transporters in Inflammation: Special Focus on TRP Channels and TRPC6. Cells 2018, 7, 70. https://doi.org/10.3390/cells7070070
Ramirez GA, Coletto LA, Sciorati C, Bozzolo EP, Manunta P, Rovere-Querini P, Manfredi AA. Ion Channels and Transporters in Inflammation: Special Focus on TRP Channels and TRPC6. Cells. 2018; 7(7):70. https://doi.org/10.3390/cells7070070
Chicago/Turabian StyleRamirez, Giuseppe A., Lavinia A. Coletto, Clara Sciorati, Enrica P. Bozzolo, Paolo Manunta, Patrizia Rovere-Querini, and Angelo A. Manfredi. 2018. "Ion Channels and Transporters in Inflammation: Special Focus on TRP Channels and TRPC6" Cells 7, no. 7: 70. https://doi.org/10.3390/cells7070070