Mol Neurobiol. 2025 Dec 3;63(1):240. doi: 10.1007/s12035-025-05482-4.
ABSTRACT
Pachymic Acid (PA), identified for its potential therapeutic efficacy in cerebral ischemic injury, has raised questions regarding its underlying molecular mechanisms. This investigation delineates the role of PA in modulating the migration of intestinal type 2 innate lymphoid cells (ILC2s) and its consequent impact on ameliorating brain ischemic injury. The Middle Cerebral Artery Occlusion/Reperfusion (MCAO/R) mouse model was established using C57BL/6 mice and treated with PA pre- and post-injury. Transcriptome sequencing was performed to assess potential genes regulated by PA. ILC2s were isolated for in vivo transfer experiments. Mice were euthanized at 6, 12, and 24 h after MCAO/R surgery to assess the relationship between ILC2s aggregation and the duration of MCAO/R injury. Pathological damage to brain and intestine tissue was assessed using histopathological, biochemical analysis and immunochemical techniques. PA significantly alleviated inflammation and neuronal apoptosis in the brain tissue after MCAO/R in mice. Notably, PA restored intestinal barrier function, reinforcing intestinal tight junctions and diminishing systemic lipopolysaccharide (LPS) levels. Upon Interleukin-33 (IL-33) activation, a surge in ILC2s was observed at 6 h post-MCAO/R, markedly reducing inflammation and apoptosis in the brain tissue. Intriguingly, ILC2s migrated from the intestine to the brain post-MCAO/R injury. Pre-treatment with PA expedited this migration, leading to an increased accumulation of ILC2s in the brain tissue. Transcriptomic analysis revealed that PA reversed 24% of the aberrantly expressed genes induced by MCAO/R. Moreover, overexpression of Dynein Axonemal Heavy Chain 9 (DNAH9) significantly attenuated both intestinal and cerebral damage in the MCAO/R model, whereas the protective effects of PA were reversed by DNAH9 knockdown. Collectively, these data underscore the pivotal role of ILC2s migration in brain injury repair, with PA mediating this migration through DNAH9 expression modulation. These findings provide robust support for the development of ischemic stroke therapeutics and the exploration of new treatment targets.
PMID:41335398 | DOI:10.1007/s12035-025-05482-4
