Inhibition of Colony Stimulating Factor 1 Receptor Suppresses Neuroinflammation and Neonatal Hypoxic-Ischemic Brain Injury

Bohao Zhang; Yunwei Ran; Siting Wu; Fang Zhang; Huachen Huang; Changlian Zhu; Shusheng Zhang; Xiaoan Zhang

doi:10.3389/fneur.2021.607370

Inhibition of Colony Stimulating Factor 1 Receptor Suppresses Neuroinflammation and Neonatal Hypoxic-Ischemic Brain Injury

Front Neurol. 2021 Feb 18:12:607370. doi: 10.3389/fneur.2021.607370. eCollection 2021.

Authors

Bohao Zhang^{1

2}, Yunwei Ran³, Siting Wu⁴, Fang Zhang⁴, Huachen Huang⁴, Changlian Zhu^{1

5}, Shusheng Zhang², Xiaoan Zhang¹

Affiliations

¹ Henan Key Laboratory of Child Brain Injury, Institute of Neuroscience and Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
² Center of Advanced Analysis & Gene Sequencing, Zhengzhou University, Zhengzhou, China.
³ Medical Research Center, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
⁴ Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China.
⁵ Department of Clinical Neuroscience, Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.

Abstract

Hypoxic-ischemic (HI) brain injury is a major cause of neonatal death or lifetime disability without widely accepted effective pharmacological treatments. It has been shown that the survival of microglia requires colony-stimulating factor 1 receptor (CSF1R) signaling and microglia participate in neonatal HI brain injury. We therefore hypothesize that microglia depletion during a HI insult period could reduce immature brain injury. In this study, CD1 mouse pups were treated with a CSF1R inhibitor (PLX3397, 25 mg/kg/daily) or a vehicle from postnatal day 4 to day 11 (P4-11), and over 90% of total brain microglia were deleted at P9. Unilateral hemisphere HI injury was induced at P9 by permanently ligating the left common carotid arteries and exposing the pups to 10% oxygen for 30 min to produce moderate left hemisphere injury. We found that the PLX3397 treatment reduced HI brain injury by 46.4%, as evaluated by the percentage of brain infarction at 48 h after HI. Furthermore, CSF1R inhibition suppressed the infiltration of neutrophils (69.7% reduction, p = 0.038), macrophages (77.4% reduction, p = 0.009), and T cells (72.9% reduction, p = 0.008) to the brain, the production of cytokines and chemokines (such as CCL12, CCL6, CCL21, CCL22, CCL19, IL7, CD14, and WISP-1), and reduced neuronal apoptosis as indicated by active caspase-3 labeled cells at 48 h after HI (615.20 ± 156.84/mm² vs. 1,205.00 ± 99.15/mm², p = 0.013). Our results suggest that CSF1R inhibition suppresses neuroinflammation and neonatal brain injury after acute cerebral hypoxia-ischemia in neonatal mice.

Keywords: PLX3397; colony stimulating factor 1 receptor; microglia; neonatal hypoxic-ischemic brain injury; neuroinflammation.