TLR7 (Toll-Like Receptor 7) Facilitates Heme Scavenging Through the BTK (Bruton Tyrosine Kinase)–CRT (Calreticulin)–LRP1 (Low-Density Lipoprotein Receptor–Related Protein-1)–Hx (Hemopexin) Pathway in Murine Intracerebral Hemorrhage. Issue 12 (December 2018)

• Record Type: Journal Article
• Authors: Wang, Gaiqing; Guo, Zhenni; Tong, Lusha; Xue, Fang; Krafft, Paul R.; Budbazar, Enkhjargal; Zhang, John H.; Tang, Jiping
• Is Part Of: Stroke. Volume 49:Issue 12(2018)
• Publication Date: 2018-12
• Subjects: Bruton tyrosine kinase -- calreticulin -- heme scavenging -- imiquimod -- intracerebral hemorrhage -- toll-like receptor; Cerebrovascular disease -- Periodicals; Cerebral circulation -- Periodicals; 616.81
• DOI: 10.1161/STROKEAHA.118.022155
• Languages: English
• ISSNs: 0039-2499

Abstract

Abstract : Background and Purpose—: Heme and iron are considered to be key factors responsible for secondary insults after intracerebral hemorrhage (ICH). Our previous study showed that LRP1 (low-density lipoprotein receptor–related protein-1)–Hx (hemopexin) facilitates removal of heme. The TLR7 (Toll-like receptor 7)–BTK (Bruton tyrosine kinase)–CRT (calreticulin) pathway regulates the expression of LRP1-Hx. This study is designed to clarify whether TLR7 activation facilitates heme scavenging and to establish the potential role of the BTK-CRT-LRP1-Hx signaling pathway in the pathophysiology of ICH. Methods—: ICH was induced by stereotactic, intrastriatal injection of type VII collagenase. Mice received TLR7 agonist (imiquimod) via intraperitoneal injection after ICH induction. TLR7 inhibitor (ODN2088), BTK inhibitor (LFM-A13), and CRT agonist (thapsigargin) were given in different groups to further evaluate the underlying pathway. Mice were randomly divided into sham, ICH+vehicle (normal saline), ICH+Imiquimod (2.5, 5, and 10 μg/g), ICH+ODN2088, ICH+LFM-A13, ICH+thapsigargin, and ICH+ODN2088+thapsigargin. Imiquimod was administered twice daily starting at 6 hours after ICH; ODN2088 was administered by intracerebroventricular injection at 30 minutes, and LFM-A13 or thapsigargin was administered by intraperitoneal injection at 3 hours after ICH induction. Neurological scores, cognitive abilities, as well as brain edema, blood-brain barrier permeability, hemoglobin level, brain expression of TLR7/BTK/CRT/LRP1/Hx were analyzed. Results—: Low dosage imiquimod significantly attenuated hematoma volume, brain edema, BBB permeability, and neurological deficits after ICH. Imiquimod also increased protein expressions of TLR7, BTK, CRT, LRP1, and Hx; ODN2088 reduced TLR7, BTK, CRT, LRP1, and Hx expressions. Conclusions—: TLR7 plays an important role in heme scavenging after ICH by modulating the BTK-CRT-LRP1-Hx pathway. TLR7 may offer protective effects by promoting heme resolution and reduction of brain edema after ICH. Abstract : Supplemental Digital Content is available in the text.