ABSTRACT:Peripheral neuropathy is a global health concern that markedly impairs quality of life. Peripheral nerve injury triggers complex interactions between the immune and nervous systems, driving persistent neuroinflammation and neuropathic pain. Macrophage migration inhibitory factor (MIF), a proinflammatory cytokine, has emerged as a key mediator in this process. Macrophage migration inhibitory factor binds to its primary receptor CD74, promotes cytokine release, recruits macrophages into the inflammatory milieu, and amplifies inflammatory responses. ISO-1, a small-molecule, high-affinity MIF inhibitor, targets the tautomerase active site of MIF, disrupts MIF-receptor (including canonical receptor CD74) binding, and thereby mitigates downstream inflammatory response. In this study, we investigated the anti-inflammatory and analgesic effects of ISO-1 in both male and female mice subjected to chronic constriction injury (CCI) of the sciatic nerve. A battery of behavioral, electrophysiological, immunohistochemical, and molecular approaches was used to evaluate the impact of systemic ISO-1 treatment on neuroinflammation and neuropathic pain. Electrophysiological recordings from the superficial dorsal horn neurons in acute spinal cord slices revealed that ISO-1 largely prevented the CCI-induced imbalance between excitatory and inhibitory postsynaptic currents. ISO-1 significantly reduced macrophage infiltration at the sciatic nerve injury site and within dorsal root ganglia. Notably, ISO-1 alleviated mechanical allodynia and thermal hyperalgesia in male mice, but not in female mice, a sex-specific effect corroborated by quantitative PCR analysis of inflammatory mediators. Together, these findings identify ISO-1 as a promising MIF-targeted strategy to counteract neuroinflammation and neuropathic pain after peripheral nerve injury and highlight the importance of sex-specific responses for the development of personalized immunomodulatory therapies.
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