TRPM2 cation channel regulates detrimental immune cell invasion in ischemic stroke

Following neuronal apoptosis during ischemic stroke, local and systemic inflammation ensues. Invading neutrophils and macrophages seem to be the major contributors to an exacerbated tissue damage. Brain injury during stroke results in oxidative stress and the release of various factors that include extracellular Ca2+, hydrogen peroxide, adenosine diphosphate ribose, and nicotinic acid adenine dinucleotide phosphate (NAADP). These alterations of the extracellular milieu change the activity of transient receptor potential melastatin subfamily member 2 (TRPM2), a non-selective cation channel highly expressed not only in resident cells of the central nervous system (CNS) but also in the immune system. Here, we characterize the functional contribution of Trpm2 in a murine ischemic stroke model. Gene deficiency of Trpm2 resulted in significantly improved neurological outcome and decreased infarct size. In accordance with current quality guidelines, the protective phenotype in Trpm2 knockout mice could be independently replicated in two laboratories. Besides a moderate neuroprotective effect of Trpm2 deficiency in vitro, ischemic brain invasion by neutrophils and macrophages was particularly reduced in Trpm2-deficient mice. Corroborating a pivotal role of Trpm2 for immune cell invasion during stroke, 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. Thus, targeting TRPM2 represents a promising therapeutic approach for ischemic stroke.