Recovery from ischemic stroke depends upon a Treg lymphokine-induced meningeal lymphatic growth and drainage
Y Bai, Y L Lei, J W Wang, L G Gong, Q L Lu, C C R RuanAbstract
Background
Hypertension worsens outcomes and increases mortality in stroke patients. Meningeal lymphatics have been reported to play a critical protective role against ischemic stroke, but how hypertension impacts this process remains unknown.
Methods
Meningeal lymphatic vessels (MLVs) were detected via whole-mount staining. Meningeal lymphatic drainage was assessed by tracing cerebrospinal fluid (CSF)-to-cervical lymph node (CLN) transport of injected agents using magnetic resonance imaging (MRI), in vivo optical imaging, and immunostaining.
Results
Using a hypertension-ischemic stroke model (Angiotensin II (Ang II)-infused mice with middle cerebral artery occlusion (MCAO)), we observed Ang II-induced hypertension impaired MLV function and induced regulatory T cell (Treg) senescence in MCAO mice. Furthermore, we find that Treg cells secrete the small purine metabolite guanosine (GUO), that improves stroke outcomes via promoting meningeal lymphatic growth and drainage after MCAO. By contrast, senescent Treg cells highly express P53, which then directly binds to the rate-limiting enzyme guanosine monophosphate synthase (GMPS) involved in GUO synthesis, thereby inhibiting GMPS enzyme activity and leading to reduced GUO production. Mechanistically, we discovered that GUO binds to Kruppel like factor 4 (KLF4), altering its phosphorylation pattern and promoting its nuclear translocation. KLF4 directly enhances the transcription of prospero-related homeobox 1 (Prox1), promoting meningeal lymphatic growth and drainage and improving stroke outcomes. Administration of GUO improves MLVs function and stroke outcome in GMPS knockout (KO) mice. These protective effects of GUO are not observed in KLF4 KO mice. Of potential clinical relevance, we show that the GUO level and the density of MLVs are positively correlated with the prognosis in ischemic stroke patients.
Conclusions
Treg cell-derived GUO promotes meningeal lymphatic growth and drainage after ischemic stroke. Administration of GUO may be a potential therapeutic strategy for improving outcomes in hypertension-related stroke.