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By cleaving sphingomyelin into ceramide, which is an essential component of plasma membrane microdomains, acid sphingomyelinase (Asm) pivotally controls cell signaling. To define how the activation of the Asm/ceramide pathway, which occurs within seconds to minutes upon stress stimuli, influences brain ischemia/reperfusion (I/R) injury, we exposed male and female wildtype mice carrying both alleles of Asm’s gene  sphingomyelinase phosphodiesterase-1  ( Smpd1  + / + ), heterozygously Asm-deficient mice ( Smpd1  +/− ) and homozygously Asm-deficient mice ( Smpd1   −/−  ) of different age (8, 12 or 16 weeks) to 30, 60 or 90 min intraluminal middle cerebral artery occlusion (MCAO). For studying the contribution of brain-invading polymorphonuclear neutrophils (PMN) to I/R injury, PMNs were depleted by delivery of a PMN-specific Ly6G antibody. In male and female mice exposed to 30 min, but not 60 or 90 min MCAO, homozygous  Smpd1   −/−   consistently increased I/R injury, blood–brain barrier permeability and brain leukocyte and PMN infiltration, whereas heterozygous  Smpd1  +/−  reduced I/R injury. Increased abundance of the intercellular leukocyte adhesion molecule ICAM-1 was noted on cerebral microvessels of  Smpd1   −/−   mice. PMN depletion by anti-Ly6G delivery prevented the exacerbation of I/R injury in  Smpd1   −/−   compared with wildtype mice and reduced brain leukocyte infiltrates. Our results show that Asm tempers leukocyte entry into the reperfused ischemic brain, thereby attenuating I/R injury.   Electronic supplementary material  The online version of this article (10.1007/s00395-020-00823-x) contains supplementary material, which is available to authorized users.

basic research in cardiology

Homozygous Smpd1 deficiency aggravates brain ischemia/ reperfusion injury by mechanisms involving polymorphonuclear neutrophils, whereas heterozygous Smpd1 deficiency protects against mild focal cerebral ischemia