Macrophage migration inhibitory factor mediates peripheral nerve injury-induced hypersensitivity by curbing dopaminergic descending inhibition

Abstract

Our previous works disclosed the contributing role of macrophage migration inhibitory factor (MIF) and dopaminergic inhibition by lysine dimethyltransferase G9a/Glp complex in peripheral nerve injury-induced hypersensitivity. We herein propose that the proinflammatory cytokine MIF participates in the regulation of neuropathic hypersensitivity by interacting with and suppressing the descending dopaminergic system. The lumbar spinal cord (L-SC) and ventral tegmental area (VTA) are two major locations with significant upregulation of MIF after chronic constriction injury (CCI) of the sciatic nerve, and they display time-dependent changes, along with a behavioral trajectory. Correspondingly, dopamine (DA) content shows the reverse characteristic change to MIF with a time-dependent curve in post-surgical behavior. The levels of both MIF and DA are reversed by the MIF tautomerase inhibitor ISO-1, and a negative relationship exists between MIF and DA. The reversed role of ISO-1 also affects tyrosine hydroxylase expression. Furthermore, CCI induces Th promoter CpG site methylation in the L-SC and VTA areas, and this effect could be abated by ISO-1 administration. G9a/SUV39H1 and H3K9me2/H3K9me3 enrichment within the Th promoter region following CCI in the L-SC and VTA was also decreased by ISO-1. In cultured dopaminergic neurons, rMIF enhanced the recruitment of G9a and SUV39H1, followed by an increase in H3K9me2/H3K9me3. These molecular changes correspondingly exhibited alterations in Th promoter CpG site methylation and pain behaviors. In summary, MIF functions as a braking factor in curbing dopaminergic descending inhibition in peripheral nerve injury-induced hypersensitivity by mediating Th gene methylation through G9a/SUV39H1-associated H3K9 methylation.

Macrophage Migration Inhibitory Factor (MIF) Makes Complex Contributions to Pain-Related Hyperactivity of Nociceptors after Spinal Cord Injury

“…The specificity of recognition of the MIF "pocket" structure by Iso-1 was shown by X-ray crystallography of Iso-1 bound to MIF (Lubetsky et al, 2002;Trivedi-Parmar and Jorgensen, 2018), reinforcing the widespread use of Iso-1 as the canonical MIF inhibitor. Iso-1 has been used extensively in preclinical studies as a MIF inhibitor, including rodent pain experiments (Wang et al, 2010(Wang et al, , 2018Alexander et al, 2012).…”

Alterations of Dopamine-Related Transcripts in A11 Diencephalospinal Pathways after Spinal Cord Injury

“…Though A9 and A10 neurons extend their projections within the brain, previous studies showed that SCI or peripheral nerve injury can change the firing properties of these neurons as well as the release of DA. This suggests an indirect effect of injury on these neurons, such as adaptation or neuroinflammation [ 43 – 45 ]. Following SCI, the increase of gamma-aminobutyric acidergic (GABAergic) neuronal activity in the A10 region suppresses DA neuronal activity and further decreases DA release [ 43 ].…”

“…Following SCI, the increase of gamma-aminobutyric acidergic (GABAergic) neuronal activity in the A10 region suppresses DA neuronal activity and further decreases DA release [ 43 ]. A proinflammatory cytokine, macrophage migration inhibitory factor (MIF), downregulates DA release after peripheral nerve injury [ 45 ]. Collectively, upregulated DA-related genes may be a compensatory response to the deficient release of DA in A9 and A10 nuclei.…”

Sex‐dependent pronociceptive role of spinal α5‐GABAA receptor and its epigenetic regulation in neuropathic rodents

“…The DNMT inhibitor 5‐aza‐2'‐deoxycytidine (5‐Aza‐dC) was obtained from Sigma‐Aldrich and dissolved in 30% DMSO in saline. 5‐Aza‐dC dose was based on previous reports (Fonteneau et al., 2017; Miao et al., 2017; Wang et al., 2018).…”