PPAR-<i>γ</i> Activation Exerts an Anti-inflammatory Effect by Suppressing the NLRP3 Inflammasome in Spinal Cord-Derived Neurons

Abstract

Persistent inflammation disrupts functional recovery after spinal cord injury (SCI). Peroxisome proliferator-activated receptor gamma (PPAR-<i>γ</i>) activation promotes functional recovery in SCI rats by inhibiting inflammatory cascades and increasing neuronal survival. We sought to clarify the relationship between PPAR-<i>γ</i> activation and NACHT, LRR and PYD domain-containing protein 3 (NLRP3) inflammasome suppression, and the role of NF-<i>κ</i>B in activating the NLRP3 inflammasome in neurons. In SCI rats, we found that rosiglitazone (PPAR-<i>γ</i> agonist) inhibited the expression of caspase-1. In <i>in vitro</i> neurons, G3335 (PPAR-<i>γ</i> antagonist) reversed the rosiglitazone-induced inhibition of caspase-1, interleukin 1 (IL-1<i>β</i>), and interleukin 6 (IL-6). Rosiglitazone inhibited the expression of NLRP3, caspase-1, IL-1<i>β</i>, and IL-6. However, the activator of NLRP3 could counteract this inhibition induced by PPAR-<i>γ</i> activation. NF-<i>κ</i>B did not participate in the process of rosiglitazone-induced inhibition of NLRP3. Consistent with our <i>in vitro</i> results, we verified that locomotor recovery of SCI rats <i>in vivo</i> was regulated via PPAR-<i>γ</i>, NLRP3, and NF-<i>κ</i>B. These results suggest that PPAR-<i>γ</i> activation exerts an anti-inflammatory effect by suppressing the NLRP3 inflammasome-but not NF-<i>κ</i>B-in neurons and that PPAR-<i>γ</i> activation is a promising therapeutic target for SCI.