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The Journal of Neuroscience, March 26, 2008, 28(13):3404-3414; doi:10.1523/JNEUROSCI.0157-08.2008

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Development/Plasticity/Repair
A Molecular Platform in Neurons Regulates Inflammation after Spinal Cord Injury

Juan Pablo de Rivero Vaccari,¹ George Lotocki,² Alex E. Marcillo,² W. Dalton Dietrich,² and Robert W. Keane¹

¹Department of Physiology and Biophysics and ²Neurological Surgery and Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami, Miami, Florida 33136

Correspondence should be addressed to Robert W. Keane, Department of Physiology and Biophysics, Miller School of Medicine, University of Miami, 1600 NW 10th Avenue, Miami, FL 33136. Email: rkeane{at}miami.edu

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.

Key words: spinal cord injury; inflammasome; interleukins; caspases; cytokines; inflammation

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Received Nov. 12, 2007; accepted Feb. 16, 2008.

Correspondence should be addressed to Robert W. Keane, Department of Physiology and Biophysics, Miller School of Medicine, University of Miami, 1600 NW 10th Avenue, Miami, FL 33136. Email: rkeane{at}miami.edu

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