CCR1 Activation Promotes Neuroinflammation Through CCR1/TPR1/ERK1/2 Signaling Pathway After Intracerebral Hemorrhage in Mice

Jun Yan, Gang Zuo, Prativa Sherchan, Lei Huang, Umut Ocak, Weilin Xu, Zachary D. Travis, Wenna Wang, John H. Zhang, Jiping Tang

Research output: Contribution to journalArticlepeer-review

Abstract

The activation of C-C chemokine receptor type 1 (CCR1) has been shown to be pro-inflammatory in several animal models of neurological diseases. The objective of this study was to investigate the activation of CCR1 on neuroinflammation in a mouse model of intracerebral hemorrhage (ICH) and the mechanism of CCR1/tetratricopeptide repeat 1 (TPR1)/extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway in CCR1-mediated neuroinflammation. Adult male CD1 mice (n = 210) were used in the study. The selective CCR1 antagonist Met-RANTES was administered intranasally at 1 h after autologous blood injection. To elucidate potential mechanism, a specific ERK1/2 activator (ceramide C6) was administered prior to Met-RANTES treatment; CCR1 activator (recombinant CCL5, rCCL5) and TPR1 CRISPR were administered in naïve mouse. Neurobehavioral assessments, brain water content, immunofluorescence staining, and western blot were performed. The endogenous expressions of CCR1, CCL5, TPR1, and p-ERK1/2 were increased in the brain after ICH. CCR1 were expressed on microglia, neurons, and astrocytes. The inhibition of CCR1 with Met-RANTES improved neurologic function, decreased brain edema, and suppressed microglia/macrophage activations and neutrophil infiltration after ICH. Met-RANTES treatment decreased expressions of CCR1, TPR1, p-ERK, TNF-α, and IL-1β, which was reversed by ceramide C6. The brain CCR1 activation by rCCL5 injection in naïve mouse resulted in neurological deficits and increased expressions of CCR1, TPR1, p-ERK, TNF-α, and IL-1β. These detrimental effects of rCCL5 were reversed by TPR1 knockdown using TPR1 CRISPR. Our study demonstrated that CCR1 activation promoted neuroinflammation through CCR1/TPR1/ERK1/2 signaling pathway after ICH in mice. CCR1 inhibition with Met-RANTES attenuated neuroinflammation, thereby reducing brain edema and improving neurobehavioral functions. Targeting CCR1 activation may provide a promising therapeutic approach in the management of ICH patients.

Original languageEnglish
Pages (from-to)1170-1183
Number of pages14
JournalNeurotherapeutics
Volume17
Issue number3
DOIs
StatePublished - Jul 1 2020

ASJC Scopus Subject Areas

  • Pharmacology
  • Clinical Neurology
  • Pharmacology (medical)

Keywords

  • C-C chemokine receptor type 1
  • Intracerebral hemorrhage
  • Met-RANTES
  • brain edema
  • neuroinflammation
  • Inflammation/metabolism
  • Male
  • Heterotrimeric GTP-Binding Proteins/metabolism
  • Brain/drug effects
  • MAP Kinase Signaling System/drug effects
  • Animals
  • Receptors, CCR1/agonists
  • Chemokine CCL5/pharmacology
  • Cerebral Hemorrhage/drug therapy
  • Mice
  • Adaptor Proteins, Vesicular Transport/metabolism

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