Interleukin-9 Regulates NF-kB-Mediated Activation of Astrocytes in Multiple Sclerosis Brain

Interleukin-9 (IL-9) is an immune molecule with multiple roles in a variety of cell types. IL-9-induced cell responses are mediated by the IL-9 receptor (IL-9R). Recent evidence demonstrates that expression of IL-9R in post mortem brain tissues of patients with multiple sclerosis (MS) is associated with a protective, anti-inflammatory role of IL-9 in MS. In this study, we investigated the expression of IL-9R in cells resident in the CNS of patients with MS. We found that astrocytes express IL-9R, indicating their expected responsiveness to IL-9. Astrocytes play a critical role in MS, where the inflammatory environment turns them into reactive cells, which actively contribute to the disease. The transcription factor nuclear factor-kB (NF-kB) regulates the response of reactive astrocytes and their potential pathogenic activities during CNS inflammation.

To address the role of IL-9 in proinflammatory astrocytes, we used 3 different human in vitro models: (1) human astrocytoma cell line (U-373 MG), (2) primary normal human astrocytes, and (3) induced pluripotent stem cell-derived astrocytes. We used interleukin-1β for their conversion into proinflammatory astrocytes.

We found that IL-9 contributes to the switch of astrocytes from an inflammatory to an anti-inflammatory profile by downregulating NF-kB activation. Moreover, we demonstrated that IL-9 inhibits granulocyte-macrophage colony-stimulating factor (GM-CSF) expression driven by NF-kB.

Because GM-CSF production by astrocytes is linked to microglial activation and CNS inflammation, these results indicate that IL-9 regulates the astrocyte-microglia axis and has potential therapeutic anti-inflammatory implications in MS.