Acid sphingomyelinase deficiency protects mitochondria and improves function recovery after brain injury

Abstract

Traumatic brain injury (TBI) is one of the leading causes of disability worldwide and a prominent risk factor for neurodegenerative diseases. The expansion of nervous tissue damage after the initial trauma involves a multifactorial cascade of events including excitotoxicity, oxidative stress, inflammation and deregulation of sphingolipid metabolism that further mitochondrial dysfunction and secondary brain damage. Our studies establish a fundamental role of acid sphingomyelinase (ASM) in the multi‐faceted mechanisms governing secondary brain injury after TBI. The data indicate that TBI‐triggered activation of ASM and upregulation of mitochondrial sphingosine resulted in mitochondrial respiratory chain malfunction leading to an enhanced assembly and activity of the NLRP3 inflammasome, a pivotal factor promoting the neuroinflammatory response to brain injury. The results of our studies provide further support for the emerging role of ASM in repressing the cell maintenance and quality control mechanism, autophagy, which is essential for the neural cell survival after the injury. Thus, knocking down ASM rescued mitochondrial defect, augmented the autophagic flux, downregulated the neuroinflammation and improved the brain function recovery after TBI. Importantly, ASM is involved in the initial stages of progression of astrogliosis, a brain defense mechanism wherein activated astrocytes minimize spread of the neuroinflammation and further tissue repair and regeneration in response to TBI. Our novel findings reveal that ASM, a critical player promoting secondary brain injury and neuroinflammation is uniquely positioned to be a promising target for the development of effective pharmacological treatment of patients with TBI. Support or Funding Information Supported by NIH grant R01NS083544 (TIG) and VA Merit Award I01BX002991 (TIG). This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Crosstalk Between Acid Sphingomyelinase and Inflammasome Signaling and Their Emerging Roles in Tissue Injury and Fibrosis

“…In addition, brain injury triggers increasing in NLRP3 and caspase-1 expression, which is significantly attenuated in ASMdeficient or pharmacologically inhibited mice (Novgorodov et al, 2019). This indicates that ASM-ceramide system is an essential factor for assembling and activating the NLRP3 inflammasome complex in neurological inflammatory cascade.…”

“…This difference in pH reflects the fact that the ASM gene generates two distinct forms of the proteins: secretory ASM (S-ASM) found extracellular and lysosomal ASM (L-ASM) locating in the endo-lysosomal vesicles. Two forms of ASM are resulted from alternative trafficking and posttranslational modification and trafficking of the encoded protein (Ni and Morales, 2006;Wahe et al, 2010;Vazquez et al, 2016). Trafficking of ASM to lysosome is required for clustering of lipid raft in endothelial cells and their function (Jin et al, 2008).…”

“…Acid sphingomyelinase has a fundamental role in mitochondrial dysfunction promoted neuroinflammation and secondary brain injury (Novgorodov et al, 2019). ASM is activated without a change of protein level via post-transcriptional mechanisms in response to traumatic brain injury, which might be due to dimerization of the enzyme (Qiu et al, 2003).…”

Methylprednisolone Induces Neuro-Protective Effects via the Inhibition of A1 Astrocyte Activation in Traumatic Spinal Cord Injury Mouse Models

“…After TSCI, tissues in the spinal cord induce selfdestructive mechanisms termed secondary damage (Romanelli et al, 2019;Pelisch et al, 2020). The main mechanisms of secondary damages after TSCI are excitotoxicity, excessive free radical production, inflammation, and apoptosis (Diaz-Ruiz et al, 2009;Novgorodov et al, 2019). Studies that have focused on reducing neuroinflammation by promoting neuron survival and axon outgrowth have shown some satisfactory therapeutic efficacy (Sun et al, 2018;Lima et al, 2019).…”

Acid sphingomyelinase deficiency exacerbates LPS‐induced experimental periodontitis

“…Mice with ASMase deficiency are animal models for human type A or B Niemann–Pick disease, which is a lysosomal lipid storage disease characterized with hepatosplenomegaly and neurological symptoms (Schuchman & Wasserstein, ). In addition to the studies on the pathogenesis of human type A or B Niemann–Pick disease, mice with ASMase deficiency have been also used as animal model by a large number of studies to define the role of ASMase in human inflammatory diseases (Becker et al, ; Beckmann et al, ; von Bismarck et al, ; Boini, Xia, Koka, Gehr, & Li, ; Chung et al, ; Dannhausen et al, ; Dhami, He, & Schuchman, ; Hoehn et al, ; Ikegami, Dhami, & Schuchman, ; Nakatsuji, Tang, Zhang, Gallo, & Huang, ; Novgorodov et al, ; Opreanu et al, ; Osawa et al, ). Interestingly, while most of these studies demonstrated that ASMase deficiency attenuated inflammation (Becker et al, ; Beckmann et al, ; von Bismarck et al, ; Boini et al, ; Chung et al, ; Dhami et al, ; Hoehn et al, ; Nakatsuji et al, ; Novgorodov et al, ; Opreanu et al, ), a few studies showed that ASMase deficiency enhanced inflammation (Dannhausen et al, ; Ikegami et al, ; Osawa et al, ).…”