Dysregulation of interleukin-8 is involved in the onset and relapse of schizophrenia: An independent validation and meta-analysis

Junwei Yan; Qingrong Xia; Xuejun Sun; Pei Yang; Hua Gao; Zhongde Pan; Jianliang Gao; Loufeng Zhang; Meiti Wang; Keming Wang; Chao Li; Xulai Zhang; Peijun Ju; Cuizhen Zhu

doi:10.1016/j.pnpbp.2024.111018

Dysregulation of interleukin-8 is involved in the onset and relapse of schizophrenia: An independent validation and meta-analysis

Prog Neuropsychopharmacol Biol Psychiatry. 2024 Apr 24:133:111018. doi: 10.1016/j.pnpbp.2024.111018. Online ahead of print.

Authors

Junwei Yan¹, Qingrong Xia¹, Xuejun Sun², Pei Yang², Hua Gao³, Zhongde Pan⁴, Jianliang Gao³, Loufeng Zhang³, Meiti Wang⁵, Keming Wang¹, Chao Li¹, Xulai Zhang⁶, Peijun Ju⁷, Cuizhen Zhu⁸

Affiliations

¹ Brain Neurobiomedical Research Center, Affiliated Psychological Hospital of Anhui Medical University, Hefei, Anhui 230022, China; Science and Education Department, Hefei Fourth People's Hospital, Anhui Mental Health Center, Hefei, Anhui 230022, China; Science and Education Department, Anhui Clinical Center for Mental and Psychological Diseases, Hefei, Anhui 230022, China.
² Lc-Bio Technology Co. Ltd, Hangzhou, Zhe Jiang 31000, China.
³ Psychiatry Department, Hefei Fourth People's Hospital, Hefei, Anhui 230022, China.
⁴ Psychiatry Department, Academy of Forensic Science, Shanghai 200061, China.
⁵ Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai key Laboratory of Psychotic Disorders, Shanghai Institute of Traditional Chinese Medicine for Mental Health, Shanghai 201108, China.
⁶ Geriatric Psychology Department, Anhui Clinical Center for Mental and Psychological Diseases, Hefei, Anhui 230022, China.
⁷ Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai key Laboratory of Psychotic Disorders, Shanghai Institute of Traditional Chinese Medicine for Mental Health, Shanghai 201108, China. Electronic address: jupeijunpp@163.com.
⁸ Brain Neurobiomedical Research Center, Affiliated Psychological Hospital of Anhui Medical University, Hefei, Anhui 230022, China; Science and Education Department, Hefei Fourth People's Hospital, Anhui Mental Health Center, Hefei, Anhui 230022, China; Science and Education Department, Anhui Clinical Center for Mental and Psychological Diseases, Hefei, Anhui 230022, China. Electronic address: zhucuizhen88@126.com.

PMID: 38670447
DOI: 10.1016/j.pnpbp.2024.111018

Abstract

As a major mental health disorder, symptoms of schizophrenia (SCZ) include delusions, reduced motivation, hallucinations, reduced motivation and a variety of cognitive disabilities. Many of these symptoms are now known to be associated with abnormal regulation of the immune system. Low blood levels of cytokines and chemokines have been suggested to be one of the underlying causes of SCZ. However, their biological roles at different stages of SCZ remain unclear. Our objective was to investigate expression patterns of cytokines and chemokines at different stages of onset and relapse in SCZ patients and to conduct an analysis of their relationship to disease progression. We also aimed to identify immune features associated with different disease trajectories in patients with SCZ. Gene set enrichment analysis (GSEA) was used to interrogate the GSE27383 dataset and identify key genes associated with inflammation. These results led us to recruit 36 healthy controls, 40 patients with first-episode psychosis (FEP), and 39 patients with SCZ relapse. Meso Scale Discovery technology was used to independently validate serum levels of 35 cytokines and chemokines. This was followed by a meta-analysis to gain a more comprehensive understanding of the role of interleukin-8 (IL-8/CXCL8) in SCZ. Analysis of the GSE27383 database revealed 3596 genes with distinct expression patterns. A significant portion of these genes were identified as inflammation-related and showed remarkable enrichment in three key pathways: IL-17, cytokine-cytokine receptor, and AGE-RAGE signaling in diabetic complications. We observed co-expression of CXCL8 and IL-16 within these three pathways. In a subsequent analysis of independently validated samples, a notable discrepancy was detected in the inflammatory status between individuals experiencing FEP and those in relapse. In particular, expression of CXCL8 demonstrated superior predictive capability in FEP and relapsed patients. Notably, results of the meta-analysis confirmed that Chinese and European populations were consistent with the overall results (Z = 4.60, P < 0.001; Z = 3.70, P < 0.001). However, in the American subgroup, there was no significant difference in CXCL8 levels between patients with SCZ compared to healthy controls (Z = 1.09, P = 0.277). Our findings suggest that the inflammatory response in patients with SCZ differs across the different stages, with CXCL8 emerging as a potential predictive factor. Collectively, our data suggest that CXCL8 has the potential to serve as a significant immunological signature of SCZ subtypes. Trial registration: The clinical registration number for this trial is ChiCTR2100045240 (Registration Date: 2021/04/09).

Keywords: Chemokines; Cytokines; Inflammatory; Meta-analysis; Schizophrenia.