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.
Highlights
Neuropathic pain is a debilitating experience for patients, usually resulting from a direct lesion or disease affecting the somatosensory system and causing a heavy burden for patients, health care providers and society.[1]
These results indicated that constriction injury (CCI) of the sciatic nerve successfully mimicked characteristic allodynia, mechanical hyperalgesia or thermal hyperalgesia following peripheral nerve injury and established chronic neuropathic pain
G9a, SUV39H1, heterochromatin protein 1 (HP1), H3K9me[2], and H3K9me[3] expression in lumbar spinal cord (L-SC) and ventral tegmental area (VTA) Considering that DNA methylation is one characteristic of epigenetic regulation in post-mitotic neurons, combined with the phenomenon of migration inhibitory factor (MIF) regulation of tyrosine hydroxylase (Th) promoter CpG island methylation, we propose that peripheral injury-induced MIF high expression might contribute to the development of central hypersensitivity via epigenetic dopaminergic inhibition because DNA methylation and histone modification are two biologically strongly associated forms of epigenetic regulation
Summary
Neuropathic pain is a debilitating experience for patients, usually resulting from a direct lesion or disease affecting the somatosensory system and causing a heavy burden for patients, health care providers and society.[1]. Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine, and it was first described in 1966 as a proinflammatory cytokine participating in macrophage motility inhibition.[8] MIF usually functions as an inflammatory cytokine, and it is widely involved in a variety of diseases that have inflammatory components, such as infections, cancer, autoimmune diseases and metabolic disorders.[9,10,11] Further, MIF acts as an anterior pituitary hormone secreted in tandem with glucocorticoids to counter-regulate stress responses,[12] and Correspondence: Dr S Wu, Department of Neurology, Qinghai Provincial Peoples Hospital, Xining 811600, China.
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