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

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 signalregulated 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. Key Words Intracerebral hemorrhage . C-C chemokine receptor type 1 . Met-RANTES . brain edema . neuroinflammation Jun Yan and Gang Zuo contributed equally to this work.

Albumin Reduces Oxidative Stress and Neuronal Apoptosis via the ERK/Nrf2/HO‐1 Pathway after Intracerebral Hemorrhage in Rats

“…The rotarod and foot-fault tests were performed at days 7, 14, and 21 post-ICH, and the water maze tests were performed at days 22-27 after ICH as previously described [ 34 ]. For the water maze testing, the swim distance and escape latency were recorded from testing days 1 to 5 by a video tracking system.…”

Effects of homocysteine-induced endoplasmic reticulum protein on endoplasmic reticulum stress, autophagy, and neuronal apoptosis following intracerebral hemorrhage

“…The mice were injected with sodium pentobarbital (50 mg/kg) intraperitoneally, and a skull hole (1 mm in diameter) was drilled certain 3.5 mm outside the middle near the right coronal suture in a stereotaxic frame. Autologous whole blood (15 μl) was collected from the tail tip into a sterile syringe ( Shi et al, 2020 ; Yan et al, 2020 ). The sterile syringe was tactically inserted into the right basal ganglia (coordinates: 0.2 mm anterior, 3.5 mm ventral, and 2.5 mm lateral to the bregma) ( Ng et al, 2020 ).…”

“…After incubating for 4 h at 37 °C with 5% carbon dioxide, the medium was replaced with NEUROBASALTM medium supplemented with 2% B27. The neurons were used for experiments after 7‐d culture ( Croci et al, 2020 ; Yan et al, 2020 ).…”

Metal ion-responsive nanocarrier derived from phosphonated calix[4]arenes for delivering dauricine specifically to sites of brain injury in a mouse model of intracerebral hemorrhage

“…Mice (5-week-old male; Orient Bio, Hunan, China) were anesthetized with continuous isoflurane (4% induction, 1.5-2% maintenance) and immobilized on a stereotactic frame (Stoelting, Wood Dale, IL, USA). After making a small midline sagittal incision in the skin overlying the skull, a craniotomy was performed 0.5 mm anterior and 2.4 mm right relative to the bregma [20,21] (Additional file 1: Figure S2). Autologous blood was collected onto a sterile surface by needle prick of the tail artery after first cleaning the area with 70% ethanol and gently warming the tail for 2 min with a heat lamp.…”