IL-17 induces MIP-1α expression in primary mouse astrocytes via TRPC channel
Yuan Zhang1, Rongrong Huang1, Yanhong Zhang1
1Department of Pharmacology, School of Medicine, Southeast University, Nanjing, 210009, Jiangsu, China.
Abstract:
Our previous study demonstrated IL-17-mediated induction of MIP-1α through its binding to the cognate IL-17RA and MIP-1α was involved in astrocyte activation. Transient receptor potential canonical (TRPC) channel was involved in astrocyte activation, however, whether TRPC channel regulates MIP-1α expression in the context of multiple sclerosis (MS) remains largely unknown. In this study we identify the essential role of TRPC channel in IL-17-mediated MIP-1α expression and astrocyte activation. Moreover, treatment of astrocytes with IL-17 activated MAPKs and PI3K/Akt signaling pathways with downstream NF-κB pathways. Interestingly, the TRPC blocker-SKF96365 (10 μM) and Norgestimate (10 μM) significantly inhibited the increased expression of MIP-1α via suppression of IL-17-mediated ERK, p38 and JNK MAPKs and PI3K/Akt pathway activation, thereby underscoring the role of TRPC channel in this process. Together these data underpin the role of TRPC channel as a novel target that regulates MIP-1α expression and cell activation-mediated by IL-17 with implications for therapeutic intervention for reversal of neuroinflammation inflicted by IL-17. Understanding the regulation of MIP-1α expression may provide insights into the development of potential therapeutic targets for neuroinflammation associated with MS.
Insights
Transient receptor potential canonical (TRPC) channels are essential for Interleukin-17 (IL-17)-induced Macrophage Inflammatory Protein-1 alpha (MIP-1α) expression and astrocyte activation, offering a potential therapeutic target for multiple sclerosis (MS) neuroinflammation.
Area of Science:
- Neuroimmunology
- Cellular Signaling
- Ion Channel Physiology
Background:
- Interleukin-17 (IL-17) induces Macrophage Inflammatory Protein-1 alpha (MIP-1α), contributing to astrocyte activation.
- Transient receptor potential canonical (TRPC) channels are implicated in astrocyte activation, but their role in IL-17-mediated MIP-1α expression in multiple sclerosis (MS) is unclear.
Purpose of the Study:
- To investigate the role of TRPC channels in IL-17-mediated MIP-1α expression and astrocyte activation in the context of MS.
- To elucidate the signaling pathways involved in this process.
Main Methods:
- Treatment of astrocytes with IL-17 and TRPC channel blockers (SKF96365, Norgestimate).
- Analysis of MIP-1α expression.
- Assessment of MAPK and PI3K/Akt signaling pathway activation, including downstream NF-κB.
Main Results:
- TRPC channels are essential for IL-17-mediated MIP-1α expression and astrocyte activation.
- IL-17 activates MAPKs (ERK, p38, JNK) and PI3K/Akt pathways, leading to NF-κB activation.
- TRPC blockers significantly inhibited MIP-1α expression by suppressing IL-17-induced MAPK and PI3K/Akt pathway activation.
Conclusions:
- TRPC channels represent a novel therapeutic target for regulating IL-17-mediated MIP-1α expression and astrocyte activation.
- Targeting TRPC channels may offer a strategy for reversing neuroinflammation in MS.
- Understanding MIP-1α regulation provides insights for developing therapies for MS-associated neuroinflammation.
