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Cerebrospinal Fluid from Patients After Craniotomy with the Appearance of Interleukin-6 Storm Can Activate Microglia to Damage the Hypothalamic Neurons in Mice

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Abstract

We monitored CSF (cerebrospinal fluid) for Th1/Th2 inflammatory cytokines in a patient with unexplained postoperative disturbance of consciousness after craniotomy and found that the level of IL-6 (interleukin-6) concentrations was extremely high, meeting the traditional criteria for an inflammatory cytokine storm. Subsequently, the cerebrospinal fluid specimens of several patients were tested, and it was found that IL-6 levels were increased in different degrees after craniotomy. Previous studies have focused more on mild and long-term IL-6 elevation, but less on the effects of this short-term IL-6 inflammatory cytokine storm. Cerebrospinal fluid rich in IL-6 may play a significant role in patients after craniotomy. The objective is to explore the degree of IL-6 elevation and the incidence of IL-6 inflammatory cytokine storm in patients after craniotomy, as well as the effect of IL-6 elevation on the brain. In this study, the levels and clinical manifestations of inflammatory factors in cerebrospinal fluid after craniotomy were statistically classified, and the underlying mechanisms were discussed preliminarily. CSF specimens of patients after craniotomy were collected, IL-6 level was measured at 1, 5, and 10 days after operation, and cognitive function was analyzed at 1, 10, and 180 days after surgery. Craniotomy mouse model, cerebrospinal fluid of patients with the appearance of IL-6 storm after craniotomy, and IL-6 at the same concentration stimulation model were established. Behavioral tests, fluorescence in situ hybridization (FISH), pathological means, western blot, and ELISA (enzyme-linked immune-sorbent assay) were performed for verification. CSF from patients after craniotomy caused disturbance of consciousness in mice, affected neuronal damage in the hypothalamus, activation of microglia in the hypothalamus, and decreased expression of barrier proteins in the hypothalamus and brain. The large amount of interleukin-6 in CSF after craniotomy was found to be mainly derived from astrocytes. The IL-6 level in CSF after craniotomy correlated inversely with patients’ performance in MoCA test. High levels of IL-6 in the cerebrospinal fluid derived from astrocytes after craniotomy may lead to disruption of the brain-cerebrospinal fluid barrier, most notably around the hypothalamus, which might result in inflammatory activation of microglia to damage the hypothalamic neurons and impaired cognitive function/more gradual cognitive repairment in patients after craniotomy with the appearance of IL-6 storm.

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Acknowledgements

Deepest gratitude goes first and foremost to those who provided their constant encouragement and guidance. Without their consistent and illuminating instruction, this thesis could not have reached its present form. Besides, heartfelt gratitude is given to those who led me into the world of translation. I am also greatly indebted to all the professors and teachers who have instructed and helped me a lot in the period of the research. I am indebted to the participants of this study who generously volunteered their time and effort. Without their participation, this research would not have been possible. Last but not least, I would like to express my deepest gratitude to my family and friends for their unwavering support, understanding, and encouragement throughout this journey. Their love, patience, and belief in me have been the driving force behind my perseverance. In conclusion, I extend my appreciation to all individuals who have played a part, big or small, in the completion of this research. Their contributions have been indispensable and greatly appreciated.

Funding

Province natural science fund of Guangdong (2021A1515111147), Medical Scientific Research Foundation of Guangdong Province of China (B2018245), Clinical Research Program of Nanfang Hospital, Southern Medical University (2018CR029), Clinical Research Startup Program of Southern Medical University by High-level University Construction Funding of Guangdong Provincial Department of Education (LC2016PY012, LC2019ZD004), and President Foundation of Nanfang Hospital, Southern Medical University (2018C017).

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Authors and Affiliations

  1. Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou City, Guangdong Province, China

    Haorun Huang, **xian Liao, An Zhang, Binghui Qiu, Fen Mei, Fan Liu, Songtao Qi & Yun Bao

  2. The First Clinical College, Southern Medical University, Guangzhou City, Guangdong Province, China

    Kai Zeng, Chunen Yang, Haidie Ma & Wenjie Ding

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  1. Haorun Huang
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Contributions

Y. B., S. Q., F. M., and B. Q. contributed to the conception of the study; H. H., A. Z., K. Z., C. Y., and X. L. performed the experiment; H. H., F. M., F. L., H. M., and W. D. contributed significantly to the analysis and manuscript preparation; H. H. and Y. B. performed the data analyses and wrote the manuscript; Y. B. and B. Q. helped perform the analysis with constructive discussions.

Corresponding authors

Correspondence to Songtao Qi or Yun Bao.

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Ethics Approval

The study was approved by the medical ethics committee of Nanfang Hospital, Southern Medical University (no. NFEC-2023–414). And the animal study was approved by the Committee on the Ethics of Animal Experiments of Nanfang Hospital, Southern Medical University (no. NFYY-2021–0826). The medical ethics committee approved a waiver of consent for collection of these data as part of routine clinical care and quality control.

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All the patients were consent to participate in the research.

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Haorun Huang, **xian Liao, An Zhang, and Binghui Qiu are co-first authors of this article.

Supplementary Information

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12035_2023_3693_MOESM1_ESM.tif

Supplementary Fig. 1. Co-staining fluorescence pattern of IL-6 mRNA probe and GFAP antibody in the craniotomy area (Red fluorescence was IL-6 mRNA probe. Green fluorescence was GFAP antibody expression. The blue-purple fluorescence was DAPI. MERGE is the mixed image) (TIF 1344 KB)

12035_2023_3693_MOESM2_ESM.tif

Supplementary Fig. 2. Co-staining fluorescence pattern of IL-6 mRNA probe and GFAP antibody in the craniotomy area (magnification 10 times and 20 times. Red fluorescence was IL-6 mRNA probe. Green fluorescence was GFAP antibody expression. The blue-purple fluorescence was DAPI. MERGE is the mixed image) (TIF 1028 KB)

Supplementary Fig. 3. H&E staining of the modeling area of the craniotomy model mouse (TIF 2165 KB)

Supplementary Fig. 4. Nissl staining of the modeling area of the craniotomy model mouse (TIF 2581 KB)

12035_2023_3693_MOESM5_ESM.tif

Supplementary Fig. 5. Co-staining fluorescence pattern of IL-6 mRNA probe and GFAP antibody in the craniotomy area after using IL-6 Receptor Antagonist (Tocilizumab) (TIF 869 KB)

12035_2023_3693_MOESM6_ESM.tif

Supplementary Fig. 6. Multivariate correlation analysis on the clinical data of the patients. The results showed that the patient's cerebrospinal fluid IL-6 value was an independent influencing factor for MoCA (p=0.038) (TIF 169 KB)

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Huang, H., Liao, X., Zhang, A. et al. Cerebrospinal Fluid from Patients After Craniotomy with the Appearance of Interleukin-6 Storm Can Activate Microglia to Damage the Hypothalamic Neurons in Mice. Mol Neurobiol 61, 2707–2718 (2024). https://doi.org/10.1007/s12035-023-03693-1

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