Interleukin-17 Promotes the Infiltration of CD8+ T Cells into the Brain in a Mouse Model for Alzheimer’s Disease

ABSTRACT

Background

Interleukin-17 (IL-17) family cytokines play critical roles in inflammation and pathogen resistance. Inflammation in the central nervous system, denoted as neuroinflammation, promotes the onset and progression of Alzheimer’s disease (AD). Previous studies showed that IL-17A neutralizing antibody treatment alleviated Amyloid β (Aβ) burden in rodent models of AD, while overexpression of IL-17A in mouse lateral ventricles rescued part of the AD pathology. However, the involvement of IL-17 in AD and its mechanism of action remain largely unknown.

Methods

To investigate the role of IL-17 in AD, we crossed mice lacking the common receptor of IL-17 signaling (IL-17RA knockout mice) to the APP/PS1 mouse model of AD. We then analyzed the composition of immune cells and cytokines/chemokines during different phases of AD pathology, and interrogated the underlying mechanism by which IL-17 may regulate immune cell infiltration into AD brains.

Results

Ablation of IL-17RA in APP/PS1 mice decreased infiltration of CD8+ T cells and myeloid cells to mouse brain. IL-17 was able to promote the production of myeloid- and T cell-attracting chemokines CXCL1 and CXCL9/10 in primary glial cells. We also observed that IL-17 is upregulated in the late stage of AD development, and ectopic expression of IL-17 via adenoviral infection to the cortex trended towards worsened cognition in APP/PS1 mice, suggesting a pathogenic role of excessive IL-17 in AD.

Conclusion

Our data show that IL-17 signaling promotes neuroinflammation in AD by accelerating the infiltration of CD8+ T lymphocytes and Gr1+ CD11b+ myeloid cells.

KEYWORDS:

• Alzheimer’s disease
• CD8⁺ T cells
• IL-17
• myeloid cells
• neuroinflammation

Acknowledgements

We also thank Dr. Riqiang Yan, Dr. Xiangyou Hu, and Dr. Xin-Ming Ma at the Department of Neuroscience at UConn Health for their advice and assistance. We thank Dr. Evan Jellison and the UConn Health Flow Cytometry Core for technical assistance, and Drs. Christopher Bonin and Geneva Hargis for scientific editing.

Disclosure statement

No potential conflict of interest was reported by the authors.

Author contributions

X.Y., J.W., and K.W. conceived the project., X.Y., J.C., J.P., Z.Z., J.Z., C.Z., Q.W., Y.W., M.L., and K.W. performed the experiments and analyzed the data. J.W. and A.V. provided conceptual advice. X.Y. and K.W. wrote the manuscript, with all authors contributing to the writing, editing, and providing key advice.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/08820139.2022.2136525.

Additional information

Funding

This work was conducted at UConn Health and the Shenzhen PKU-HKUST Medical Center. The work was supported by the institutional startup funds to K.W.; X.Y. was supported by the China Scholarship Council, National Natural Scientific Foundation of China [Grants 81802860] and China Postdoctoral science Foundation Grant [Grant 2018M633094]; Y.W. was supported by National Natural Scientific Foundation of China [Grants 81801356] and Science foundation of Health and Family Planning commission of Shenzhen Municipality [Grant SZBC2018017]; J.Z. was supported by Guangxi Natural Science Foundation [2020GXNSFDA238009] and Guangxi Science and Technology Program [AD19110006]. J.W. was supported by National Key R&D Program [2016YFA0501903], Natural Scientific Foundation of Guangdong Province [Grant 2016A030312016] and Shenzhen Basic Research [Grants JCYJ20170815153617033, and JCYJ20170306161450254].