Altered monocyte subpopulations and their association with autism spectrum disorder risk in children

Wenhua Li; Lingling Zhang; Yiran Xu; Hongwei Li; Bingbing Li; Shuang Sun; Xiaoli Zhang; Guiqin Duan; Yiwen Chen; Jie Zhang; Yangyang Cao; Xiaoping Li; Qianqian Liu; Yanan Wu; Shan Zhang; Jianmei W Leavenworth; Xiaoyang Wang; Changlian Zhu

doi:10.1016/j.bbi.2025.02.028

Altered monocyte subpopulations and their association with autism spectrum disorder risk in children

Brain Behav Immun. 2025 May:126:315-326. doi: 10.1016/j.bbi.2025.02.028. Epub 2025 Feb 25.

Authors

Wenhua Li¹, Lingling Zhang², Yiran Xu², Hongwei Li³, Bingbing Li², Shuang Sun⁴, Xiaoli Zhang², Guiqin Duan⁴, Yiwen Chen², Jie Zhang², Yangyang Cao², Xiaoping Li², Qianqian Liu², Yanan Wu², Shan Zhang¹, Jianmei W Leavenworth⁵, Xiaoyang Wang⁶, Changlian Zhu⁷

Affiliations

¹ Henan Key Laboratory of Child Brain Injury and Henan Pediatric Clinical Research Center, Institute of Neuroscience and the Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China; Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg 40530, Sweden.
² Henan Key Laboratory of Child Brain Injury and Henan Pediatric Clinical Research Center, Institute of Neuroscience and the Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
³ Henan Key Laboratory of Child Brain Injury and Henan Pediatric Clinical Research Center, Institute of Neuroscience and the Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China; Department of Laboratory Medicine, Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
⁴ Center for Child Behavioral Development, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
⁵ Department of Neurosurgery and Department of Microbiology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham AL 35233, USA.
⁶ Henan Key Laboratory of Child Brain Injury and Henan Pediatric Clinical Research Center, Institute of Neuroscience and the Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China; Centre of Perinatal Medicine and Health, Institute of Clinical Science, University of Gothenburg 40530 Gothenburg, Sweden.
⁷ Henan Key Laboratory of Child Brain Injury and Henan Pediatric Clinical Research Center, Institute of Neuroscience and the Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China; Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg 40530, Sweden; Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden. Electronic address: changlian.zhu@neuro.gu.se.

PMID: 40010548
DOI: 10.1016/j.bbi.2025.02.028

Abstract

Objective: Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficits in social communication, restricted interests, and repetitive behaviors. Emerging evidence suggests a link between immune dysregulation and ASD. This study investigates alterations in monocyte subpopulations and cytokine production in children with ASD and their potential associations with ASD risk and severity.

Methods: Initially, the immune status of peripheral blood mononuclear cells was assessed in cohort-I of 96 typically developing (TD) children and 92 children diagnosed with ASD using flow cytometry. Subsequently, the secretion of cytokines IL-6 and IL-10 by monocytes was evaluated following stimulation with a leukocyte activation mixture and intracellular protein staining technique in cohort-II.

Results: Children with ASD exhibited significantly higher levels of total monocytes, classical monocytes (CD14^hi/CD16^-), and non-classical monocytes (CD14^low/CD16⁺) compared to TD children (p < 0.001). Elevated levels of classical monocytes (β: 0.395; 95 %CI: 0.260-0.530; p < 0.001) and non-classical monocytes (β: 0.629; 95 %CI: 0.516-0.742; p < 0.001) were significantly associated with ASD after adjusting for age, sex and body mass index. Furthermore, increased production of IL-6 by monocytes was observed in children with ASD (p = 0.001). Logistic regression analysis revealed that classical monocytes (OR: 1.104; 95 %CI: 1.062-1.147; p < 0.001), non-classical monocytes (OR: 2.913; 95 %CI: 2.130-3.986; p < 0.001) and IL-6 production by monocytes (OR: 1.306; 95 %CI: 1.096-1.557; p = 0.003) are risk factors for ASD. Spearman correlation analysis revealed a negative correlation between classical monocyte levels and adaptive behavior developmental quotient (DQ) (r = - 0.377; p = 0.001), fine motor DQ (r = - 0.329; p = 0.003) and personal-social DQ (r = - 0.247; p = 0.029) in children with ASD.

Conclusion: Elevated classical and non-classical monocytes are potential risk factors for ASD and may influence neurodevelopmental outcomes. Further research is needed to elucidate the precise mechanisms and therapeutic implications.

Keywords: Adaptive behavior; Autism spectrum disorder; Cytokine; Flow cytometry; Monocyte.

MeSH terms

Autism Spectrum Disorder* / immunology
Autism Spectrum Disorder* / metabolism
Child
Child, Preschool
Cohort Studies
Cytokines / metabolism
Female
Humans
Interleukin-10 / metabolism
Interleukin-6 / metabolism
Leukocytes, Mononuclear / immunology
Leukocytes, Mononuclear / metabolism
Male
Monocytes* / immunology
Monocytes* / metabolism
Risk Factors

Substances

Interleukin-6
Interleukin-10
Cytokines