title: Exosome-mediated inflammasome signaling after central nervous system injury.
abstract: Neuroinflammation is a response against harmful effects of diverse stimuli and participates in the pathogenesis of brain and spinal cord injury (SCI). The innate immune response plays a role in neuroinflammation following CNS injury via activation of multiprotein complexes termed inflammasomes that regulate the activation of caspase 1 and the processing of the pro-inflammatory cytokines IL-1β and IL-18. We report here that the expression of components of the nucleotide-binding and oligomerization domain (NOD)-like receptor protein-1 (NLRP-1) inflammasome, apoptosis speck-like protein containing a caspase recruitment domain (ASC), and caspase 1 are significantly elevated in spinal cord motor neurons and cortical neurons after CNS trauma. Moreover, NLRP1 inflammasome proteins are present in exosomes derived from CSF of SCI and traumatic brain-injured patients following trauma. To investigate whether exosomes could be used to therapeutically block inflammasome activation in the CNS, exosomes were isolated from embryonic cortical neuronal cultures and loaded with short-interfering RNA (siRNA) against ASC and administered to spinal cord-injured animals. Neuronal-derived exosomes crossed the injured blood-spinal cord barrier, and delivered their cargo in vivo, resulting in knockdown of ASC protein levels by approximately 76% when compared to SCI rats treated with scrambled siRNA. Surprisingly, siRNA silencing of ASC also led to a significant decrease in caspase 1 activation and processing of IL-1β after SCI. These findings indicate that exosome-mediated siRNA delivery may be a strong candidate to block inflammasome activation following CNS injury. We propose the following signaling cascade for inflammasome activation in peripheral tissues after CNS injury: CNS trauma induces inflammasome activation in the nervous system and secretion of exosomes containing inflammasome protein cargo into cerebral spinal fluid. The inflammasome containing exosomes then fuse with target cells to activate the innate immune response in peripheral tissues. We suggest that these findings may be used to develop new therapeutics to treat the devastating inflammation and cell destruction evoked by CNS injuries. IL-1β and IL-18 = pro-inflammatory cytokines.
authors: Neurological Surgery and the Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, Florida, USA.
authors: Juan Pablo
authors: JP
authors: de Rivero Vaccari
authors: Departments of Physiology and Biophysics, University of Miami Miller School of Medicine, Miami, Florida, USA.
authors: Frank
authors: F
authors: Brand
authors: Neurological Surgery and the Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, Florida, USA.
authors: Stephanie
authors: S
authors: Adamczak
authors: Neurological Surgery and the Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, Florida, USA.
authors: Stephanie W
authors: SW
authors: Lee
authors: Neurological Surgery and the Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, Florida, USA.
authors: Jon
authors: J
authors: Perez-Barcena
authors: Neurological Surgery and the Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, Florida, USA.
authors: Michael Y
authors: MY
authors: Wang
authors: Neurological Surgery and the Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, Florida, USA.
authors: M Ross
authors: MR
authors: Bullock
authors: Neurological Surgery and the Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, Florida, USA.
authors: W Dalton
authors: WD
authors: Dietrich
authors: Neurological Surgery and the Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, Florida, USA.|Departments of Physiology and Biophysics, University of Miami Miller School of Medicine, Miami, Florida, USA.
authors: Robert W
authors: RW
authors: Keane
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D055354:Exosomes / Q000502:physiology*; D005260:Female; D006801:Humans; D058847:Inflammasomes / Q000096:biosynthesis* / Q000134:cerebrospinal fluid*; D008297:Male; D008875:Middle Aged; D051381:Rats; D011916:Rats, Inbred F344; D015398:Signal Transduction / Q000502:physiology*; D013119:Spinal Cord Injuries / Q000134:cerebrospinal fluid* / Q000473:pathology; D055815:Young Adult
chemical_list: D058847:Inflammasomes
keywords: brain injury; caspase 1; exosomes; inflammasome; spinal cord injury
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