Activation of Interleukin33-NFκB Axis in granulosa cells during atresia and its role in disposal of Atretic follicles.

It has been previously shown that the cytokine interleukin33 (IL33) is required for two processes, i.e. autophagic digestion of granulosa cells and recruitment of macrophages into atretic follicles, for full disposal of atretic follicles. Now, this study shows that activation of IL33-ST2 (IL33 receptor)-NFκB axis in granulosa in early atretic follicles may regulate those two events. Injection of hCG has been shown to induce a transient peak of IL33 expression with synchronized atresia. In this model, IL33-independent expression of ST2 in granulosa cells was detected in early atretic follicles before macrophage invasion. The activation of NFκB pathway in ovaries was further demonstrated in vivo in Tg mice with luciferase-reporter for NFκB activation; the activation was microscopically localized to granulosa cells in early atretic follicles. Importantly, antibody blockage of IL33 or IL33 KO (Il33-/-) not only inhibited NFκB activity in ovaries, but also altered expression of two key genes, i.e. reduction in proinflammatory IL6 expression, and a surge of potential autophagy-inhibitory mTOR expression in atretic follicles. In contrast, apoptosis and other genes such as IL1β were not affected. In conclusion, in parallel to apoptosis, atresia signals also trigger activation of the IL33-ST2-NFκB pathway in granulosa, which leads to (1) down-regulated expression of mTOR that is a negative regulator of autophagy, and (2) up-regulated expression of proinflammatory IL6.