Abstract
Persistent inflammation disrupts functional recovery after spinal cord injury (SCI). Peroxisome proliferator-activated receptor gamma (PPAR-γ) activation promotes functional recovery in SCI rats by inhibiting inflammatory cascades and increasing neuronal survival. We sought to clarify the relationship between PPAR-γ activation and NACHT, LRR and PYD domain-containing protein 3 (NLRP3) inflammasome suppression, and the role of NF-κB in activating the NLRP3 inflammasome in neurons. In SCI rats, we found that rosiglitazone (PPAR-γ agonist) inhibited the expression of caspase-1. In in vitro neurons, G3335 (PPAR-γ antagonist) reversed the rosiglitazone-induced inhibition of caspase-1, interleukin 1 (IL-1β), and interleukin 6 (IL-6). Rosiglitazone inhibited the expression of NLRP3, caspase-1, IL-1β, and IL-6. However, the activator of NLRP3 could counteract this inhibition induced by PPAR-γ activation. NF-κB did not participate in the process of rosiglitazone-induced inhibition of NLRP3. Consistent with our in vitro results, we verified that locomotor recovery of SCI rats in vivo was regulated via PPAR-γ, NLRP3, and NF-κB. These results suggest that PPAR-γ activation exerts an anti-inflammatory effect by suppressing the NLRP3 inflammasome—but not NF-κB—in neurons and that PPAR-γ activation is a promising therapeutic target for SCI.
Highlights
Spinal cord injury (SCI), which is a kind of high disabling injury, has gradually increased with the expansion of human activities
In spinal cord injury (SCI) rats, we found that rosiglitazone (PPAR-γ agonist) inhibited the expression of caspase-1
These results suggest that PPAR-γ activation exerts an anti-inflammatory effect by suppressing the NLRP3 inflammasome—but not NF-κB—in neurons and that PPAR-γ activation is a promising therapeutic target for SCI
Summary
Spinal cord injury (SCI), which is a kind of high disabling injury, has gradually increased with the expansion of human activities. It leads to a loss of sensation and motor functions, as well as multiple organ dysfunctions [1]. Trauma in SCI triggers intraparenchymal inflammation and systemic immune activation, which further exacerbates neuropathology and stimulates tissue repair [2]. The inflammasome is a multiprotein oligomer that is responsible for the activation of inflammatory responses [5]. Inflammasome activation is a potential mediator of neuroinflammation. Some researchers have suggested that inflammasome activation is the essential step of neuroinflammation and a key trigger for inflammation-induced neu-
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