miR-19a-3p and miR-19b-3p Repress Nurr1 and Nur77 to Promote Microglial Inflammation After Spinal Cord Injury

Abstract

Background: Spinal cord injury (SCI)-induced neuropathic pain affects up to 60% of individuals with SCI and is closely linked to microglia-driven neuroinflammation. Neuroinflammatory processes after SCI are major contributors to the development and persistence of chronic pain. Inflammation and pain are closely related, and the neuroinflammatory consequences of SCI contribute to the chronic, intense pain that many individuals living with SCI experience. MicroRNAs (miRNAs) have emerged as regulators of neuroinflammation. There are higher levels of circulating miR-19a and miR-19b in persons living with SCI with neuropathic pain compared to those with no pain. These miRNAs are associated with altered the miR-19a and miR-19b modulated expression of two neuroprotective genes: Nurr1 and Nur77. Methods: Primary microglia cultures and a rat spinal cord injury model were used to investigate the regulatory effects of miR-19a and miR-19b on Nurr1 and Nur77 expression. Results: Our study shows that miR-19a and miR-19b and their binding sites in Nurr1's 3′ UTR are highly conserved across vertebrates, suggesting functional importance. Through in vitro microglia cultures and in vivo rat SCI models, we demonstrate that these miRNAs negatively regulate modulate Nurr1, Nur77, and inflammatory gene expression. Protein–protein interaction network analysis highlights transcription factors such as MYC, RUNX1, and STAT3 as central to this regulatory networkion. Conclusion: These findings support a model in whichidentify miR-19a and miR-19b contribute to microglia-driven neuroinflammation after SCI and highlight their as potential as therapeutic targets to reduce microglia-mediated neuroinflammation and neuropathic pain. after SCI.