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Systems biological assessment of altered cytokine responses to bacteria and fungi reveals impaired immune functionality in schizophrenia

Molecular Psychiatry volume 27, pages 1205–1216 (2022)Cite this article

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Abstract

Evidence suggests that complex interactions between the immune system and brain have important etiological and therapeutic implications in schizophrenia. However, the detailed cellular and molecular basis of immune dysfunction in schizophrenia remains poorly characterized. To better understand the immune changes and molecular pathways, we systemically compared the cytokine responses of peripheral blood mononuclear cells (PBMCs) derived from patients with schizophrenia and controls against bacterial, fungal, and purified microbial ligands, and identified aberrant cytokine response patterns to various pathogens, as well as reduced cytokine production after stimulation with muramyl dipeptide (MDP) in schizophrenia. Subsequently, we performed single-cell RNA sequencing on unstimulated and stimulated PBMCs from patients and controls and revealed widespread suppression of antiviral and inflammatory programs as well as impaired chemokine/cytokine–receptor interaction networks in various immune cell subpopulations of schizophrenic patients after MDP stimulation. Moreover, serum MDP levels were elevated in these patients and correlated with the course of the disease, suggesting increased bacterial translocation along with disease progression. In vitro assays revealed that MDP pretreatment altered the functional response of normal PBMCs to its re-stimulation, which partially recapitulated the impaired immune function in schizophrenia. In conclusion, we delineated the molecular and cellular landscape of impaired immune function in schizophrenia, and proposed a mutual interplay between innate immune impairment, reduced pathogen clearance, increased MDP translocation along schizophrenia development, and blunted innate immune response. These findings provide new insights into the pathogenic mechanisms that drive systemic immune activation, neuroinflammation, and brain abnormalities in schizophrenia.

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Fig. 1: Aberrant cytokine response patterns upon stimulation with various pathogens and microbial ligands in patients with schizophrenia.
Fig. 2: Unsupervised hierarchical clustering of the cytokine responses in the PBMCs obtained from the healthy controls (right, n = 17) and patients with schizophrenia (left, n = 20) induced by various pathogens and microbial ligands.
Fig. 3: Single-cell transcriptional profiling of naive and MDP-stimulated PBMCs.
Fig. 4: Consistent suppression of the MDP-stimulated antiviral and inflammatory gene programs in patients with schizophrenia.
Fig. 5: Elevated levels of MDP in schizophrenia.

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Data availability

The raw scRNA-seq data reported in this paper have been deposited (PRJCA006766) in the Genome Sequence Archive (GSA) database under accession identification HRA001425 that are publicly accessible at https://ngdc.cncb.ac.cn/gsa.

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Acknowledgements

This work was funded by the National Natural Science Foundation of China (No. 81771471), Natural Science Basic Research Project of Natural Science Fund of Shaanxi Province (2016JQ8026), Outstanding Youth Science Foundation project of National Natural Science Foundation of China (82022023), Clinical Research Award of the First Affiliated Hospital of Xi’an Jiaotong University (No. XJTU1AF-CRF-2016-005), and Key Research and Development Program of Shaanxi (No. 2020ZDLSF02-10).

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  1. These authors contributed equally: Yuan Gao, Yajuan Fan.

Authors and Affiliations

  1. Department of Psychiatry, The First Affiliated Hospital of Xi’an Jiaotong University, 277 Yanta West Road, Xi’an, 710061, China

    Yuan Gao, Yajuan Fan, Zai Yang, Qingyan Ma, Binbin Zhao, Xiaoyan He, Fengjie Gao, Li Qian, Wei Wang, Ce Chen, Yunchun Chen, Chengge Gao, Xiancang Ma & Feng Zhu

  2. Center for Brain Science, The First Affiliated Hospital of Xi’an Jiaotong University, 277 Yanta West Road, Xi’an, 710061, China

    Yuan Gao, Yajuan Fan, Zai Yang, Qingyan Ma, Binbin Zhao, Xiaoyan He, Fengjie Gao, Li Qian, Wei Wang, Ce Chen, Yunchun Chen, Chengge Gao, Xiancang Ma & Feng Zhu

  3. Clinical Research Center for Psychiatric Medicine of Shaanxi Province, The First Affiliated Hospital of Xi’an Jiaotong University, 277 Yanta West Road, Xi’an, 710061, China

    Yuan Gao, Yajuan Fan, Zai Yang, Qingyan Ma, Binbin Zhao, Xiaoyan He, Fengjie Gao, Li Qian, Wei Wang, Ce Chen, Yunchun Chen, Chengge Gao, Xiancang Ma & Feng Zhu

  4. Center for Translational Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, 277 Yanta West Road, Xi’an, 710061, China

    Feng Zhu

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Contributions

XM, FZ, and WW designed the project. ZY, QM, BZ, XH, FG, and LQ recruited volunteers and collected samples for the study. YG and ZY performed research. YG and YF performed the data analyses. YG and FZ interpreted the results and wrote the paper. All authors contributed to revision of the paper.

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Correspondence to Xiancang Ma or Feng Zhu.

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Gao, Y., Fan, Y., Yang, Z. et al. Systems biological assessment of altered cytokine responses to bacteria and fungi reveals impaired immune functionality in schizophrenia. Mol Psychiatry 27, 1205–1216 (2022). https://doi.org/10.1038/s41380-021-01362-0

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