2. Academic Validation
  3. CHI3L1 signaling impairs hippocampal neurogenesis and cognitive function in autoimmune-mediated neuroinflammation

CHI3L1 signaling impairs hippocampal neurogenesis and cognitive function in autoimmune-mediated neuroinflammation

  • Sci Adv. 2023 Sep 29;9(39):eadg8148. doi: 10.1126/sciadv.adg8148.
Wei Jiang 1,  Fan Zhu 1,  Huiming Xu 1,  Li Xu 1,  Haoyang Li 1,  Xin Yang 2,  Shabbir Khan Afridi 3,  Shuiqing Lai 4,  Xiusheng Qiu 5,  Chunxin Liu 1,  Huilu Li 6,  Youming Long 6,  Yuge Wang 1,  Kevin Connolly 2,  Jack A Elias 2,  Chun Geun Lee 2,  Yaxiong Cui 7,  Yu-Wen Alvin Huang 2 8,  Wei Qiu 1,  Changyong Tang 1
Affiliations

Affiliations

  • 1 Department of Neurology, The Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Guangzhou, Guangdong Province 510630, China.
  • 2 Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, 70 Ship Street, Providence, RI 02903, USA.
  • 3 Faculty of Biological Sciences, School of Biomedical Sciences, University of Leeds, Leeds LS2 9JT, UK.
  • 4 Department of Endocrinology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, 106 Zhongshan Er Road, Guangzhou, Guangdong Province 510080, China.
  • 5 Vaccine Research Institute, The Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Guangzhou, Guangdong Province 510630, China.
  • 6 Department of Neurology, The Second Affiliated Hospital of Guangzhou Medical University, 250 Changgang East Road, Guangzhou, Guangdong Province 510260, China.
  • 7 State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, IDG/McGovern Institute for Brain Research, Beijing Advanced Innovation Center for Structural Biology, School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China.
  • 8 Center for Translational Neuroscience, Carney Institute for Brain Science, Brown University, 70 Ship Street, Providence, RI 02903, USA.
PMID: 37756391 DOI: 10.1126/sciadv.adg8148
Abstract

Chitinase-3-like protein 1 (CHI3L1) is primarily secreted by activated astrocytes in the brain and is known as a reliable biomarker for inflammatory central nervous system (CNS) conditions such as neurodegeneration and autoimmune disorders like neuromyelitis optica (NMO). NMO is an astrocyte disease caused by autoantibodies targeting the astroglial protein Aquaporin 4 (AQP4) and leads to vision loss, motor deficits, and cognitive decline. In this study examining CHI3L1's biological function in neuroinflammation, we found that CHI3L1 expression correlates with cognitive impairment in our NMO patient cohort. Activated astrocytes secrete CHI3L1 in response to AQP4 autoantibodies, and this inhibits the proliferation and neuronal differentiation of neural stem cells. Mouse models showed decreased hippocampal neurogenesis and impaired learning behaviors, which could be rescued by depleting CHI3L1 in astrocytes. The molecular mechanism involves CHI3L1 engaging the CRTH2 receptor and dampening β-catenin signaling for neurogenesis. Blocking this CHI3L1/CRTH2/β-catenin cascade restores neurogenesis and improves cognitive deficits, suggesting the potential for therapeutic development in neuroinflammatory disorders.

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