Sex-dependent impact of Il6 deficiency in Parkinson’s disease mice

Parkinson’s disease (PD) is a prevalent neurodegenerative disorder accompanied by neuroinflammation. Many studies have demonstrated that interleukin-6 (IL-6) exhibits both anti-inflammatory and pro-inflammatory effects in the central nervous system, yet its role in PD remains controversial. In this study, Il6^{− /−} (knockout), Il6^+/− , and wild-type mice were utilized to investigate the impact of IL-6 on the pathology of MPTP- or α-Synuclein^A53T-induced PD mice. Our findings revealed that Il6 deficiency exacerbated motor dysfunction in both female and male mice. MPTP intoxication resulted in earlier and more extensive injuries to the dopaminergic system and heightened glial reaction in the nigrostriatal pathway of female Il6^{− /−} mice compared with male Il6^{− /−} mice, which only displayed more severe dopaminergic neuronal loss at 7 days after MPTP administration. Toxic α-Synuclein overexpression in the substantia nigra region caused earlier motor dysfunction and aggravated dopaminergic neurodegeneration in female Il6^{− /−} mice. In Il6^+/− mice, MPTP-induced depletion of dopaminergic nerve fibers was unaffected, although astrocyte activation was attenuated. Moreover, intraperitoneal administration of recombinant IL-6 (rIL-6) partially ameliorated MPTP-induced motor dysfunction and striatal dopaminergic terminal depletion in both wild-type and knockout mice. Our findings underscore the crucial role of IL-6 in the inflammatory pathology of PD, highlighting sex-dependent differences, and suggest that rIL-6 holds potential promise for PD therapy.