The neuroinflammatory triumvirate: NF-κB, NLRP3, and mTOR in spinal cord injury

After spinal cord injury (SCI), there is a finely choreographed neuroinflammatory response that can profoundly influence secondary injury, neuronal apoptosis, the formation of a glial scar, and long-term functional recovery outcomes. The key multifaceted roles within this neuroinflammatory process are mediated through the NF-κB, NLRP3 inflammasome, and mTOR signaling pathways, which function as interconnected networks controlling cytokine production, the reactivity of astrocytes and microglia, autophagy, and apoptosis. Dysregulation of these pathways leads to increased neuroinflammation and chronic neurological deficits.

Emerging preclinical studies demonstrate how targeting single pathways with monotherapy shows modest success; however, with the co-targeting of NF-κB, NLRP3, and mTOR, neuroprotection is achieved through a reduction in inflammatory cascades, stimulation of autophagy, reduction of glial scarring, and ultimately, functional recovery was achieved. New therapeutic strategies, including selective pharmacological inhibitors, multi-gene-based biotechnology, and next-generation biomaterial-assisted therapeutic delivery systems, are emerging and are of interest towards maximizing outcomes while minimizing systemic toxicity. This review details the mechanisms and interactions of NF-κB, NLRP3, and mTOR in SCI, providing a comprehensive overview of upstream regulators, downstream effectors, and feedback loops to regulate cross-talk; emerging multi-target strategies with a view to translational viability and challenges; and the future focus on precision neuroinflammatory modulation. A sophisticated grasp of these interconnected signaling frameworks provides a conceptual framework for next-generation neuroprotective treatments, with the potential to greatly attenuate secondary injury, induce better neural repair, and improve long-term neurological outcomes. Integrative, pathway-targeted approaches have the potential to revolutionize the management of SCI and more effectively expedite the real-world translation of mechanistic-based approaches into clinical interventions.