A molecular platform in neurons regulates inflammation after spinal cord injury

Juan Pablo P de Rivero Vaccari, George Lotocki, Alexander Marcillo, W. Dalton Dietrich, Robert Keane

Research output: Contribution to journalArticle

194 Citations (Scopus)

Abstract

Vigorous immune responses are induced in the immune privileged CNS by injury and disease, but the molecular mechanisms regulating innate immunity in the CNS are poorly defined. The inflammatory response initiated by spinal cord injury (SCI) involves activation of interleukin-1β (IL-1β) that contributes to secondary cell death. In the peripheral immune response, the inflammasome activates caspase-1 to process proinflammatory cytokines, but the regulation of trauma-induced inflammation in the CNS is not clearly understood. Here we show that a molecular platform [NALP1 (NAcht leucine-rich-repeat protein 1) inflammasome] consisting of caspase-1, caspase-11, ASC (apoptosis-associated speck-like protein containing a caspase-activating recruitment domain), and NALP1 is expressed in neurons of the normal rat spinal cord and forms a protein assembly with the X-linked inhibitor of apoptosis protein (XIAP). Moderate cervical contusive SCI induced processing of IL-1β, IL-18, activation of caspase-1, cleavage of XIAP, and promoted assembly of the multiprotein complex. Anti-ASC neutralizing antibodies administered to injured rats entered spinal cord neurons via a mechanism that was sensitive to carbenoxolone. Therapeutic neutralization of ASC reduced caspase-1 activation, XIAP cleavage, and interleukin processing, resulting in significant tissue sparing and functional improvement. Thus, rat spinal cord neurons contain a caspase-1, pro-ILβ, and pro-IL-18 activating complex different from the human NALP1 inflammasome that constitutes an important arm of the innate CNS inflammatory response after SCI.

Original languageEnglish
Pages (from-to)3404-3414
Number of pages11
JournalJournal of Neuroscience
Volume28
Issue number13
DOIs
StatePublished - Mar 26 2008

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Caspase 1
Spinal Cord Injuries
X-Linked Inhibitor of Apoptosis Protein
Inflammasomes
Inflammation
Neurons
Spinal Cord
Interleukin-18
Interleukin-1
Carbenoxolone
Multiprotein Complexes
Interleukins
Central Nervous System Diseases
Wounds and Injuries
Caspases
Neutralizing Antibodies
Innate Immunity
Proteins
Cell Death
Apoptosis

Keywords

  • Caspases
  • Cytokines
  • Inflammasome
  • Inflammation
  • Interleukins
  • Spinal cord injury

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

A molecular platform in neurons regulates inflammation after spinal cord injury. / de Rivero Vaccari, Juan Pablo P; Lotocki, George; Marcillo, Alexander; Dalton Dietrich, W.; Keane, Robert.

In: Journal of Neuroscience, Vol. 28, No. 13, 26.03.2008, p. 3404-3414.

Research output: Contribution to journalArticle

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