Transient receptor potential melastatin subfamily member 2 cation channel regulates detrimental immune cell invasion in ischemic stroke

TY - JOUR

T1 - Transient receptor potential melastatin subfamily member 2 cation channel regulates detrimental immune cell invasion in ischemic stroke

AU - Gelderblom, Mathias

AU - Melzer, Nico

AU - Schattling, Benjamin

AU - Göb, Eva

AU - Hicking, Gordon

AU - Arunachalam, Priyadharshini

AU - Bittner, Stefan

AU - Ufer, Friederike

AU - Herrmann, Alexander M

AU - Bernreuther, Christian

AU - Glatzel, Markus

AU - Gerloff, Christian

AU - Kleinschnitz, Christoph

AU - Meuth, Sven G

AU - Friese, Manuel A

AU - Magnus, Tim

N1 - © 2014 American Heart Association, Inc.

PY - 2014/11/1

Y1 - 2014/11/1

N2 - BACKGROUND AND PURPOSE: Brain injury during stroke results in oxidative stress and the release of factors that include extracellular Ca(2+), hydrogen peroxide, adenosine diphosphate ribose, and nicotinic acid adenine dinucleotide phosphate. These alterations of the extracellular milieu change the activity of transient receptor potential melastatin subfamily member 2 (TRPM2), a nonselective cation channel expressed in the central nervous system and the immune system. Our goal was to evaluate the contribution of TRPM2 to the tissue damage after stroke.METHODS: In accordance with current quality guidelines, we independently characterized Trpm2 in a murine ischemic stroke model in 2 different laboratories.RESULTS: Gene deficiency of Trpm2 resulted in significantly improved neurological outcome and decreased infarct size. Besides an already known moderate neuroprotective effect of Trpm2 deficiency in vitro, ischemic brain invasion by neutrophils and macrophages was particularly reduced in Trpm2-deficient mice. Bone marrow chimeric mice revealed that Trpm2 deficiency in the peripheral immune system is responsible for the protective phenotype. Furthermore, experiments with mixed bone marrow chimeras demonstrated that Trpm2 is essential for the migration of neutrophils and, to a lesser extent, also of macrophages into ischemic hemispheres. Notably, the pharmacological TRPM2 inhibitor, N-(p-amylcinnamoyl)anthranilic acid, was equally protective in the stroke model.CONCLUSIONS: Although a neuroprotective effect of TRPM2 in vitro is well known, we can show for the first time that the detrimental role of TRPM2 in stroke primarily depends on its role in activating peripheral immune cells. Targeting TRPM2 systemically represents a promising therapeutic approach for ischemic stroke.

AB - BACKGROUND AND PURPOSE: Brain injury during stroke results in oxidative stress and the release of factors that include extracellular Ca(2+), hydrogen peroxide, adenosine diphosphate ribose, and nicotinic acid adenine dinucleotide phosphate. These alterations of the extracellular milieu change the activity of transient receptor potential melastatin subfamily member 2 (TRPM2), a nonselective cation channel expressed in the central nervous system and the immune system. Our goal was to evaluate the contribution of TRPM2 to the tissue damage after stroke.METHODS: In accordance with current quality guidelines, we independently characterized Trpm2 in a murine ischemic stroke model in 2 different laboratories.RESULTS: Gene deficiency of Trpm2 resulted in significantly improved neurological outcome and decreased infarct size. Besides an already known moderate neuroprotective effect of Trpm2 deficiency in vitro, ischemic brain invasion by neutrophils and macrophages was particularly reduced in Trpm2-deficient mice. Bone marrow chimeric mice revealed that Trpm2 deficiency in the peripheral immune system is responsible for the protective phenotype. Furthermore, experiments with mixed bone marrow chimeras demonstrated that Trpm2 is essential for the migration of neutrophils and, to a lesser extent, also of macrophages into ischemic hemispheres. Notably, the pharmacological TRPM2 inhibitor, N-(p-amylcinnamoyl)anthranilic acid, was equally protective in the stroke model.CONCLUSIONS: Although a neuroprotective effect of TRPM2 in vitro is well known, we can show for the first time that the detrimental role of TRPM2 in stroke primarily depends on its role in activating peripheral immune cells. Targeting TRPM2 systemically represents a promising therapeutic approach for ischemic stroke.

KW - Animals

KW - Brain Ischemia

KW - Cell Movement

KW - Cells, Cultured

KW - Hippocampus

KW - Immunity, Cellular

KW - Male

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Organ Culture Techniques

KW - Random Allocation

KW - Stroke

KW - TRPM Cation Channels

U2 - 10.1161/STROKEAHA.114.005836

DO - 10.1161/STROKEAHA.114.005836

M3 - SCORING: Journal article

C2 - 25236871

VL - 45

SP - 3395

EP - 3402

JO - STROKE

JF - STROKE

SN - 0039-2499

IS - 11

ER -