2. Academic Validation
  3. Targeting CIRP and IL-6R-mediated microglial inflammation to improve outcomes in intracerebral hemorrhage

Targeting CIRP and IL-6R-mediated microglial inflammation to improve outcomes in intracerebral hemorrhage

  • J Adv Res. 2025 Sep 9:S2090-1232(25)00695-2. doi: 10.1016/j.jare.2025.09.012.
Lisha Ye 1,  Xiaoyan Tang 2,  Fangming Liu 2,  Tianjiao Wei 2,  Ting Xu 2,  Zhenglin Jiang 2,  Lihua Xu 2,  Chao Xiang 3,  Xiaoyu Yuan 4,  Lihua Shen 5,  Jianjun Gu 6,  Qianqian Luo 7,  Guohua Wang 8
Affiliations

Affiliations

  • 1 Department of Neurophysiology and Neuropharmacology, Institute of Special Environmental Medicine and Co-innovation Center of Neuroregeneration, Nantong University, 9 Seyuan Road, Nantong, Jiangsu 226019, China; Beijing Institute of Brain Disorders, No. 10 Xitoutiao, Beijing 100069, China.
  • 2 Department of Neurophysiology and Neuropharmacology, Institute of Special Environmental Medicine and Co-innovation Center of Neuroregeneration, Nantong University, 9 Seyuan Road, Nantong, Jiangsu 226019, China.
  • 3 Department of Neurosurgery, Zhengzhou University People's Hospital (Henan Provincial People's Hospital), 7 Weiwu Road, Zhengzhou, Henan 450000, China.
  • 4 Department of Emergency, Affiliated Hospital of Nantong University, Nantong 226001, China.
  • 5 Department of Neurology, Affiliated Hospital of Nantong University, Nantong 226001, China.
  • 6 Department of Neurosurgery, Zhengzhou University People's Hospital (Henan Provincial People's Hospital), 7 Weiwu Road, Zhengzhou, Henan 450000, China. Electronic address: gujianjundt@163.com.
  • 7 Department of Neurophysiology and Neuropharmacology, Institute of Special Environmental Medicine and Co-innovation Center of Neuroregeneration, Nantong University, 9 Seyuan Road, Nantong, Jiangsu 226019, China. Electronic address: qianqianluo@ntu.edu.cn.
  • 8 Beijing Institute of Brain Disorders, No. 10 Xitoutiao, Beijing 100069, China; Department of Neurology, Xuanwu Hospital, Capital Medical University, 45 Changchun Street, Beijing 100053, China. Electronic address: wangguohua@xwhosp.org.
PMID: 40934970 DOI: 10.1016/j.jare.2025.09.012
Abstract

Introduction: Cold-inducible RNA-binding protein (CIRP) is an emerging inflammatory mediator implicated in neuronal injury following intracerebral hemorrhage (ICH). However, the underlying mechanisms by which CIRP contributes to neuroinflammation remain unclear.

Objectives: To investigate the role of neuron-derived CIRP in activating microglial inflammation via IL-6 receptor (IL-6R) signaling after ICH and to evaluate the therapeutic potential of targeting CIRP and IL-6R using a designed peptide inhibitor.

Methods: Single-cell RNA Sequencing was performed to identify key genes and pathways involved in microglial responses post-ICH. A peptide inhibitor, Tat-CIRP-CMA (TCC), was designed to target CIRP and IL-6R and tested in both in vitro (oxygen-glucose deprivation model) and in vivo (rat ICH model) systems. The effects of TCC on neuronal CIRP release, microglial activation, inflammation, and phagocytic function were assessed. A microglia-specific IL-6Rα knockout mouse model was used to further validate the functional relevance of the IL-6R/ signal transducer and activator of transcription 3 (STAT3) pathway. Clinical analysis of human ICH patients evaluated the correlation between peripheral CIRP expression and infarct volume.

Results: Neuron-derived CIRP activates microglia through IL-6R and downstream STAT3 signaling, driving pro-inflammatory responses in ICH. TCC treatment significantly reduced neuronal CIRP release, suppressed microglial activation, and decreased inflammatory cytokine levels. TCC inhibited the IL-6R /STAT3 pathway and enhanced microglial phagocytosis of red blood cells. Microglia-specific IL-6Rα deletion mirrored the anti-inflammatory and neuroprotective effects observed with TCC, reducing hematoma volume and improving sensory and behavioral outcomes. In human ICH patients, elevated peripheral CIRP expression positively correlated with infarct volume, supporting its value as a biomarker for ICH severity and prognosis.

Conclusion: CIRP plays a pivotal role in post-ICH neuroinflammation by acting on IL-6R in microglia. The TCC peptide inhibitor effectively reduces CIRP-IL-6R mediated inflammation and supports neuroprotection. CIRP represents a promising therapeutic target and biomarker for ICH.

Keywords

Cold-inducible RNA-binding proteins; Intracerebral hemorrhage; Microglial polarization; Neuroinflammation; Tat peptides.

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