Authors :
Presenting Author: Md Aktaruzzaman, B. Pharm (Professional) – The University of Tennessee Health Science Center
Eun Bee Cho, PhD – The University of Tennessee Health Science Center
Chenyao Jiang, BS – The University of Tennessee Health Science Center
Md Asaduzzaman Rakib, MS – The University of Tennessee Health Science Center
Chao-Yie Yang, PhD – The University of Tennessee Health Science Center
Ying Yu, PhD – The University of Tennessee Health Science Center
Jianxiong Jiang, PhD – The University of Tennessee Health Science Center
Rationale:
Neuroinflammation is increasingly recognized as an important driving force for epileptogenesis. However, therapeutic approaches targeting specific immune pathways remain limited. Interleukin-33 (IL-33) is a well-characterized immunomodulatory cytokine that acts as an alarmin and plays crucial roles in brain homeostasis. Cellular damage or stress triggers the release of IL-33, which activates innate immune pathways via its receptor, interleukin-1 receptor like-1 (IL-1RL1 or ST2). The distinct expression patterns of IL-33 and ST2 in glial cells position them as promising therapeutic targets in neuroinflammatory disorders. This study aims to elucidate the role of IL-33/ST2 signaling in glial cells and assess the therapeutic efficacy of pharmacological ST2 inhibition in preclinical models of neuroinflammation and status epilepticus (SE).Methods:
We first examined the expression of IL-33 and two ST2 isoforms: transmembrane ST2 (ST2L) and soluble ST2 (sST2), in mouse primary microglia and astrocytes stimulated by LPS. Several novel small-molecule inhibitors selective for ST2 receptor were developed and evaluated for anti-inflammatory effects on activated microglia as well as pharmacokinetic properties in mice. Using a drug-like compound, we investigated the effects of ST2 inhibition in mouse models of LPS-provoked neuroinflammation and pilocarpine-induced SE.Results:
LPS was able to induce IL-33 in microglia but not in astrocytes. In contrast, both ST2 isoforms (ST2L and sST2) were upregulated by LPS stimulation in astrocytes but downregulated in microglia. Among the novel ST2 inhibitors tested, XY-280 showed the most consistent anti-inflammatory activities. With systemic administration in mice, XY-280 had a plasma half-life of 11.9 hours and a brain-to-plasma ratio up to 29.7, supporting its use for CNS conditions. In the LPS-induced neuroinflammation model, treatment with XY-280 resulted in a significant reduction in inflammatory cytokines and chemokines. Similarly, in the pilocarpine SE model, ST2 inhibition substantially diminished neuroinflammation, as indicated by decreased levels of inflammatory mediators and reactive gliosis. Ongoing experiments focus on the effects of XY-280 on neuronal death, blood-brain barrier disruption, unprovoked seizures, and behavioral deficits after SE.
Conclusions:
These findings establish the IL-33/ST2 axis in glial cells as a key contributor to SE-triggered neuroinflammation, which is believed to exacerbate brain damage and promote acquired epileptogenesis. Targeting ST2 receptor by our novel, brain-penetrant inhibitors might represent a new strategy to reduce neuroinflammation and long-term sequelae after precipitating events like SE, thereby providing a potential disease-modifying treatment for epilepsy.
Funding:
NIH/NINDS grants R01NS100947 and R21NS136070.