To further prove IL-6 to be responsible for the control of inflammation during EAE through gp130 on macrophages/neutrophils, we immunized LysMcre<sup>pos</sup>IL-6R<sup>loxP/loxP</sup> mice.
In addition, naringenin promoted Treg polarization and also prevented IL-6-induced suppression of Treg development via down-regulation of p-Smad2/3 as well as inhibition of IL-6 signaling, and the latter was further supported by the <i>in vivo</i> results showing lower soluble IL-6R but higher soluble gp130 levels in plasma of naringenin-fed compared to the control EAE mice.
An analysis of mice deficient in either astrocytic gp130- Src homology region 2 domain-containing phosphatase 2/Ras/ERK or gp130-STAT1/3 signaling revealed that prevention of astrocyte apoptosis, restriction of demyelination, and T cell infiltration were dependent on the astrocytic gp130-Src homology region 2 domain-containing phosphatase 2/Ras/ERK, but not on the gp130-STAT1/3 pathway, further demonstrating that gp130-dependent astrocyte activation is crucial to ameliorate EAE.