CCR5 Activation Promotes NLRP1-Dependent Neuronal Pyroptosis via CCR5/PKA/CREB Pathway After Intracerebral Hemorrhage

Authors

Jun Yan, Department of Neurosurgery, Guangxi Medical University Cancer Hospital, Nanning, China (J.Y.).
Weilin Xu, Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China (W.X.).
Cameron Lenahan, Department of Biomedical Sciences, Burrell College of Osteopathic Medicine, Las Cruces, NM (C.L.).
Lei Huang, Department of Neurosurgery (L.H., J.H.Z.), Loma Linda University, CA.Follow
Jing Wen, Department of Rheumatism, First Affiliated Hospital of Guangxi Medical University, Nanning, China (J.W.).
Gaigai Li, Department of Neurology, Tongji Hospital, Tongji Medical college, Huazhong University of Science and Technology, Wuhan, China (G.L.).
Xin Hu, Department of Neurosurgery, West China Hospital of Sichuan University, Chengdu, China (X.H.).
Wen Zheng, Department of Neurology, The Third Xiangya Hospital of Central South University, Changsha, China (W.Z.).
John H. Zhang, Department of Neurosurgery (L.H., J.H.Z.), Loma Linda University, CA.Follow
Jiping Tang, Department of Physiology and Pharmacology (L.H., J.H.Z., J.T.), Loma Linda University, CA.Follow

Document Type

Article

Publication Date

12-1-2021

Publication Title

Stroke

E-ISSN

1524-4628

Abstract

BACKGROUND AND PURPOSE: Neuronal pyroptosis is a type of regulated cell death triggered by proinflammatory signals. CCR5 (C-C chemokine receptor 5)-mediated inflammation is involved in the pathology of various neurological diseases. This study investigated the impact of CCR5 activation on neuronal pyroptosis and the underlying mechanism involving cAMP-dependent PKA (protein kinase A)/CREB (cAMP response element binding)/NLRP1 (nucleotide-binding domain leucine-rich repeat pyrin domain containing 1) pathway after experimental intracerebral hemorrhage (ICH). METHODS: A total of 194 adult male CD1 mice were used. ICH was induced by autologous whole blood injection. Maraviroc (MVC)-a selective antagonist of CCR5-was administered intranasally 1 hour after ICH. To elucidate the underlying mechanism, a specific CREB inhibitor, 666-15, was administered intracerebroventricularly before MVC administration in ICH mice. In a set of naive mice, rCCL5 (recombinant chemokine ligand 5) and selective PKA activator, 8-Bromo-cAMP, were administered intracerebroventricularly. Short- and long-term neurobehavioral assessments, Western blot, Fluoro-Jade C, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), and immunofluorescence staining were performed. RESULTS: The brain expression of CCL5 (chemokine ligand 5), CCR5, PKA-Cα (protein kinase A-Cα), p-CREB (phospho-cAMP response element binding), and NLRP1 was increased, peaking at 24 hours after ICH. CCR5 was expressed on neurons, microglia, and astrocytes. MVC improved the short- and long-term neurobehavioral deficits and decreased neuronal pyroptosis in ipsilateral brain tissues at 24 hours after ICH, which were accompanied by increased PKA-Cα and p-CREB expression, and decreased expression of NLRP1, ASC (apoptosis-associated speck-like protein containing a CARD), C-caspase-1, GSDMD (gasdermin D), and IL (interleukin)-1β/IL-18. Such effects of MVC were abolished by 666-15. At 24 hours after injection in naive mice, rCCL5 induced neurological deficits, decreased PKA-Cα and p-CREB expression in the brain, and upregulated NLRP1, ASC, C-caspase-1, N-GSDMD, and IL-1β/IL-18 expression. Those effects of rCCL5 were reversed by 8-Bromo-cAMP. CONCLUSIONS: CCR5 activation promoted neuronal pyroptosis and neurological deficits after ICH in mice, partially through the CCR5/PKA/CREB/NLRP1 signaling pathway. CCR5 inhibition with MVC may provide a promising therapeutic approach in managing patients with ICH.

Volume

52

Issue

12

First Page

4021

Last Page

4032

DOI

10.1161/STROKEAHA.120.033285

PubMed ID

34719258

Recommended Citation

Yan, Jun; Xu, Weilin; Lenahan, Cameron; Huang, Lei; Wen, Jing; Li, Gaigai; Hu, Xin; Zheng, Wen; Zhang, John H.; and Tang, Jiping, "CCR5 Activation Promotes NLRP1-Dependent Neuronal Pyroptosis via CCR5/PKA/CREB Pathway After Intracerebral Hemorrhage" (2021). Loma Linda University Faculty Publications. 293.
https://scholarsrepository.llu.edu/fac_pubs/293